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1.
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2.
  • Abreu-Vieira, G, et al. (author)
  • Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis
  • 2015
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 308:9, s. E822-E829
  • Journal article (peer-reviewed)abstract
    • Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen and for the distribution of the generated heat to the rest of the body. Therefore, it is fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here, we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel noninvasive method to detect BAT perfusion, we demonstrate that adrenergically stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and therefore, it is not a reliable parameter for the estimation of BAT activation and heat generation.
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3.
  • Abreu-Vieira, Gustavo, 1987-, et al. (author)
  • Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis : Regulation of brown adipose tissue blood flow
  • 2015
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:9, s. E822-E829
  • Journal article (peer-reviewed)abstract
    • Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.
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4.
  • Ahrén, Bo, et al. (author)
  • Insufficient islet compensation to insulin resistance vs. reduced glucose effectiveness in glucose-intolerant mice
  • 2002
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 283:4, s. 738-744
  • Journal article (peer-reviewed)abstract
    • This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at 1 wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness (S-G) and disposition index (DI), i.e., insulin sensitivity (SI) times early or total insulin secretion. Glucose disappearance (KG) and SI were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced SI, as judged by normal DI50 min. In contrast, early (10 min) insulin secretion was not sufficiently increased; DI10 min was reduced after 1, 3, and 10 mo. SG was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding.
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5.
  • Akerud, Helena, et al. (author)
  • Lactate distribution in culture medium of human myometrial biopsies incubated under different conditions
  • 2009
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 297:6, s. E1414-E1419
  • Journal article (peer-reviewed)abstract
    • It is generally believed that a relationship exists between muscle fatigue and intracellular accumulation of lactate. This reasoning is relevant to obstetrical issues. Myocytes in uterus work together during labor, and the contractions need to be strong and synchronized for a child to be delivered. At labor dystocia, the progress of labor becomes slow or arrested after a normal beginning. It has been described that, during labor dystocia, when the force of the contractions is low, the uterus is under hypoxia, and anaerobic conditions with high levels of lactate in amniotic fluid dominate. The purpose of this study was to examine whether myometrial cells are involved in the production of lactate in amniotic fluid and whether there are differences in production and distribution of lactate in cells incubated under aerobic and anaerobic conditions. We also wanted to elucidate the involvement of specific membrane-bound lactate carriers. Women undergoing elective caesarean section were included. Myometrial biopsies from uteri were collected and subjected to either immunohistochemistry to identify lactate carriers or in vitro experiments to analyze production of lactate. The presence of lactate carriers named monocarboxylate transporters 1 and 4 was verified. Myometrial cells produced lactate extracellularly, and the lactate carriers operated differently under anaerobic and aerobic conditions; while being mainly unidirectional under anaerobic conditions, they became bidirectional under aerobic conditions. Human myometrial cells produced and delivered lactate to the extracellular medium under both anaerobic and aerobic conditions. The delivery was mediated by lactate carriers.
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6.
  • Al-Khalili, L, et al. (author)
  • Prior serum- and AICAR-induced AMPK activation in primary human myocytes does not lead to subsequent increase in insulin-stimulated glucose uptake
  • 2004
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:3, s. E553-E557
  • Journal article (peer-reviewed)abstract
    • Exposing isolated rat skeletal muscle to 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside [AICAR, a pharmacological activator of AMP-activated protein kinase (AMPK)] plus serum leads to a subsequent increase in insulin-stimulated glucose transport (Fisher JS, Gao J, Han DH, Holloszy JO, and Nolte LA. Am J Physiol Endocrinol Metab 282: E18–E23, 2002). Our goal was to determine whether preincubation of primary human skeletal muscle cells with human serum and AICAR (Serum+AICAR) would also induce a subsequent elevation in insulin-stimulated glucose uptake. Cells were preincubated for 1 h under 4 conditions: 1) without AICAR or serum (Control), 2) with serum, 3) with AICAR, or 4) with Serum+AICAR. Some cells were then collected for immunoblot analysis to assess phosphorylation of AMPK (pAMPK) and its substrate acetyl-CoA carboxylase (ACC). Other cells were incubated for an additional 4 h without AICAR or serum and then used to measure basal or insulin-stimulated 2-deoxyglucose (2-DG) uptake. Level of pAMPK was increased ( P < 0.01) for myotubes exposed to Serum+AICAR vs. all other groups. Phosphorylated ACC (pACC) levels were higher for both Serum+AICAR ( P < 0.05) and AICAR ( P < 0.05) vs. Control and Serum groups. Basal ( P < 0.05) and 1.2 nM insulin-stimulated ( P < 0.005) 2-DG uptake was higher for Serum vs. all other preincubation conditions at equal insulin concentration. Regardless of insulin concentration (0, 1.2, or 18 nM), 2-DG was unaltered in cells preincubated with Serum+AICAR vs. Control cells. In contrast to results with isolated rat skeletal muscle, increasing the pAMPK and pACC in human myocytes via preincubation with Serum+AICAR was insufficient to lead to a subsequent enhancement in insulin-stimulated glucose uptake.
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7.
  • Améen, Caroline, 1975, et al. (author)
  • Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver.
  • 2004
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:6
  • Journal article (peer-reviewed)abstract
    • We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.
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8.
  • Andersson, Agneta, et al. (author)
  • Effects of physical exercise on phospholipid fatty acid composition in skeletal muscle
  • 1998
  • In: American Journal of Physiology. Endocrinology and Metabolism. - 0193-1849 .- 1522-1555. ; 274:37, s. E432-E438
  • Journal article (peer-reviewed)abstract
    • The effects of low-intensity exercise on the fatty acid composition in skeletal muscle and in serum were studied in 19 sedentary, middle-aged Swedish men. During a 10-wk period, all subjects were given a standardized diet with an identical fat composition. After 4 wk on this diet, they were randomly allocated to a daily exercise program (55% peak oxygen uptake) or to continue to live a sedentary life for the remaining 6 wk. Aerobic capacity (submaximal bicycle test) and peripheral insulin sensitivity (hyperinsulinemic euglycemic clamp) improved with training, whereas the body weight as well as the body composition (underwater weighing and bioimpedance) were unchanged. The proportions of palmitic acid (16:0) and linoleic acid [18:2(n-6)] and the sum of n-6 fatty acids [18:2(n-6), 20:3(n-6), 20:4(n-6)] were decreased in skeletal muscle phospholipids, whereas the proportion of oleic acid [18:1(n-9)] was increased, by training. The fatty acid profile in skeletal muscle triglycerides remained unchanged. We conclude that regular low-intensity exercise influences the fatty acid composition of the phospholipids in skeletal muscle, which hypothetically may contribute to changes of the skeletal muscle membrane fluidity and influence the peripheral insulin sensitivity.
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9.
  • Andersson, Agneta, et al. (author)
  • Fatty acid profile of skeletal muscle phospholipids in trained and untrained young men
  • 2000
  • In: American Journal of Physiology. Endocrinology and Metabolism. - 0193-1849 .- 1522-1555. ; 279:4, s. E744-E751
  • Journal article (peer-reviewed)abstract
    • Endurance trained (n = 14) and untrained young men (n = 15) were compared regarding the fatty acid profile of the vastus lateralis muscle after 8 wk on diets with a similar fatty acid composition. The skeletal muscle phospholipids in the trained group contained lower proportions of palmitic acid (16:0) (-12.4%, P < 0.001) and di-homo-gamma-linolenic acid [20:3(n-6)] (-15.3%, P = 0.018), a lower n-6-to-n-3 ratio (-42.0%, P = 0.015), higher proportions of stearic acid (18:0) (+9.8%, P = 0.004) and sum of n-3 polyunsaturated fatty acids (+33.8%, P = 0.009), and a higher ratio between 20:4(n-6) to 20:3(n-6) (+18.4%, P = 0.006) compared with those in the untrained group. The group differences in 16:0, 20:3(n-6), 18:0/16:0, and 20:4(n-6)/20:3(n-6) were independent of fiber-type distribution. The trained group also showed a lower proportion of 16:0 (-7.9%, P < 0.001) in skeletal muscle triglycerides irrespective of fiber type. In conclusion, the fatty acid profile of the skeletal muscle differed between trained and untrained individuals, although the dietary fatty acid composition was similar. This difference was not explained by different fiber-type distribution alone but appears to be a direct consequence of changes in fatty acid metabolism due to the higher level of physical activity.
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10.
  • Annerén, Cecilia, et al. (author)
  • Glucose intolerance and reduced islet blood flow in transgenic mice expressing the FRK tyrosine kinase under the control of the rat insulin promoter
  • 2007
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 292:4, s. E1183-E1190
  • Journal article (peer-reviewed)abstract
    • The FRK tyrosine kinase has previously been shown to transduce β-cell cytotoxic signals in response to cytokines and streptozotocin and to promote β-cell proliferation and an increased β-cell mass. We therefore aimed to further evaluate the effects of overexpression of FRK tyrosine kinase in β-cells. A transgenic mouse expressing kinase-active FRK under control of the insulin promoter (RIP-FRK) was studied with regard to islet endocrine function and vascular morphology. Mild glucose intolerance develops in RIP-FRK male mice of at least 4 mo of age. This effect is accompanied by reduced glucose-stimulated insulin secretion in vivo and reduced second-phase insulin secretion in response to glucose and arginine upon pancreas perfusion. Islets isolated from the FRK transgenic mice display a glucose-induced insulin secretory response in vitro similar to that of control islets. However, islet blood flow per islet volume is decreased in the FRK transgenic mice. These mice also exhibit a reduced islet capillary lumen diameter as shown by electron microscopy. Total body weight and pancreas weight are not significantly affected, but the β-cell mass is increased. The data suggest that long-term expression of active FRK in β-cells causes an in vivo insulin-secretory defect, which may be the consequence of islet vascular abnormalities that yield a decreased islet blood flow.
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11.
  • Apró, William, et al. (author)
  • Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.
  • 2013
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 305:1, s. E22-32
  • Journal article (peer-reviewed)abstract
    • The current dogma is that the muscle adaptation to resistance exercise is blunted when combined with endurance exercise. The suggested mechanism (based on rodent experiments) is that activation of adenosine monophosphate-activated protein kinase (AMPK) during endurance exercise impairs muscle growth through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). The purpose of this study was to investigate potential interference of endurance training on the signaling pathway of resistance training [mTORC1 phosphorylation of ribosomal protein S6 kinase 1 (S6K1)] in human muscle. Ten healthy and moderately trained male subjects performed on two separate occasions either acute high-intensity and high-volume resistance exercise (leg press, R) or R followed by 30 min of cycling (RE). Muscle biopsies were collected before and 1 and 3 h post resistance exercise. Phosphorylation of mTOR (Ser(2448)) increased 2-fold (P < 0.05) and that of S6K1 (Thr(389)) 14-fold (P < 0.05), with no difference between R and RE. Phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr(56)) was reduced ∼70% during recovery in both trials (P < 0.05). An interesting finding was that phosphorylation of AMPK (Thr(172)) and acetyl-CoA carboxylase (ACC, Ser(79)) decreased ∼30% and ∼50%, respectively, 3 h postexercise (P < 0.05). Proliferator-activated receptor-γ coactivator-1 (PGC-1α) mRNA increased more after RE (6.5-fold) than after R (4-fold) (RE vs. R: P < 0.01) and was the only gene expressed differently between trials. These data show that the signaling of muscle growth through the mTORC1-S6K1 axis after heavy resistance exercise is not inhibited by subsequent endurance exercise. It is also suggested that prior activation of mTORC1 signaling may repress subsequent phosphorylation of AMPK.
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12.
  • Apró, William, et al. (author)
  • Resistance exercise induced S6K1 kinase activity is not inhibited in human skeletal muscle despite prior activation of AMPK by high intensity interval cycling.
  • 2015
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:6, s. E470-E481
  • Journal article (peer-reviewed)abstract
    • Combining endurance and strength training in the same session has been reported to reduce the anabolic response to the latter form of exercise. The underlying mechanism, based primarily on results from rodent muscle, is proposed to involve AMPK-dependent inhibition of mTORC1 signaling. This hypothesis was tested in eight trained male subjects who in a randomized order performed either resistance exercise only (R) or interval cycling followed by resistance exercise (ER). Biopsies taken from the vastus lateralis before and after endurance exercise and repeatedly after resistance exercise were assessed for glycogen content, kinase activity, protein phosphorylation and gene expression. Mixed muscle fractional synthetic rate was measured at rest and during 3h of recovery using the stable isotope technique. In ER, AMPK activity was elevated immediately after both endurance and resistance exercise (~90%, P<0.05) but was unchanged in R. Thr389 phosphorylation of S6K1 was increased several-fold immediately after exercise (P<0.05) in both trials and increased further throughout recovery. After 90 and 180 min recovery, S6K1 activity was elevated (~55% and ~110%, respectively, P<0.05) and eEF2 phosphorylation was reduced (~55%, P<0.05) with no difference between trials. In contrast, markers for protein catabolism were differently influenced by the two modes of exercise; ER induced a significant increase in gene and protein expression of MuRF1 (P<0.05), which was not observed following R exercise only. In conclusion, cycling-induced elevation in AMPK activity does not inhibit mTORC1 signaling after subsequent resistance exercise, but may instead interfere with the hypertrophic response by influencing key components in protein breakdown.
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13.
  • Archer, A, et al. (author)
  • Skeletal muscle as a target of LXR agonist after long-term treatment: focus on lipid homeostasis
  • 2014
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 306:5, s. E494-E502
  • Journal article (peer-reviewed)abstract
    • The liver X receptors (LXR)α and LXRβ are transcription factors belonging to the nuclear receptor family, which play a central role in metabolic homeostasis, being master regulators of key target genes in the glucose and lipid pathways. Wild-type (WT), LXRα−/−, and LXRβ−/−mice were fed a chow diet with (treated) or without (control) the synthetic dual LXR agonist GW3965 for 5 wk. GW3965 raised intrahepatic triglyceride (TG) level but, surprisingly, reduced serum TG level through the activation of serum lipase activity. The serum TG reduction was associated with a repression of both catecholamine-stimulated lipolysis and relative glucose incorporation into lipid in isolated adipocytes through activation of LXRβ. We also demonstrated that LXRα is required for basal (nonstimulated) adipocyte metabolism, whereas LXRβ acts as a repressor of lipolysis. On the contrary, in skeletal muscle (SM), the lipogenic and cholesterol transporter LXR target genes were markedly induced in WT and LXRα−/−mice and to a lesser extent in LXRβ−/−mice following treatment with GW3965. Moreover, TG content was reduced in SM of LXRβ−/−mice, associated with increased expression of the main TG-lipase genes Hsl and Atgl. Energy expenditure was increased, and a switch from glucose to lipid oxidation was observed. In conclusion, we provide evidence that LXR might be an essential regulator of the lipid balance between tissues to ensure appropriate control of the flux of fuel. Importantly, we show that, after chronic treatment with GW3965, SM becomes the target tissue for LXR activation, as opposed to liver, in acute treatment.
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14.
  • Arora, Tulika, et al. (author)
  • Microbial fermentation of flaxseed fibers modulates the transcriptome of GPR41-expressing enteroendocrine cells and protects mice against diet-induced obesity
  • 2019
  • In: American Journal of Physiology - Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 316:3
  • Journal article (peer-reviewed)abstract
    • Dietary fibers, an integral part of the human diet, require the enzymatic activity of the gut microbiota for complete metabolism into short-chain fatty acids (SCFAs). SCFAs are important modulators of host metabolism and physiology and act in part as signaling molecules by activating G protein-coupled receptors (GPCRs), such as GPR41. Flaxseed fibers improve metabolism in rodents and mice, but their fermentation profiles, effects on enteroendocrine cells, and associated metabolic benefits are unknown. We fed GPR41-red fluorescent protein mice, an enteroendocrine reporter mouse strain, chow, high-fat diet (HFD), or HFD supplemented either with 10% nonfermentable fiber cellulose or fermentable flaxseed fibers for 12 wk to assess changes in cecal gut microbiota, enteroendocrine cell transcriptome in the ileum and colon, and physiological parameters. We observed that flaxseed fibers restructured the gut microbiota and promoted proliferation of the genera Bifidobacterium and Akkermansia compared with HFD. The shifts in cecal bacterial composition restored levels of the SCFAs butyrate similar to the chow diet, resulting in colonic but not ileal enteroendocrine cell transcriptional changes in genes related to cell cycle, mRNA, and protein transport compared with HFD. Consistent with the effects on enteroendocrine functions, flaxseed fibers also protected mice from diet-induced obesity, potentially by preventing a reduction in energy expenditure induced by an HFD. Our study shows that flaxseed fibers alter cecal microbial ecology, are fermented to SCFAs in the cecum, and modulate enteroendocrine cell transcriptome in the colon, which may contribute to their metabolically favorable phenotype. © 2019 the American Physiological Society.
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15.
  • Arsenijevic, D, et al. (author)
  • Enterostatin decreases postprandial pancreatic UCP2 mRNA levels and increases plasma insulin and amylin
  • 2005
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 289:1, s. 40-45
  • Journal article (peer-reviewed)abstract
    • This study investigated the chronic effect of enterostatin on body weight and some of the associated changes in postprandial metabolism. Rats were adapted to 6 h of food access/day and a choice of low-fat and high-fat (HF) food and then given enterostatin or vehicle by an intraperitoneally implanted minipump delivering 160 nmol enterostatin/h continuously over a 5-day infusion period. Enterostatin resulted in a slight but significant reduction of HF intake and body weight. After the last 6-h food access period, enterostatin-treated animals had lower plasma triglyceride and free fatty acid but higher plasma glucose and lactate levels than control animals. Enterostatin infusion resulted in increased uncoupling protein-2 (UCP2) expression in various tissues, including epididymal fat and liver. UCP2 was reduced in the pancreas of enterostatin-treated animals, and this was associated with increased plasma levels of insulin and amylin. Whether these two hormones are involved in the observed decreased food intake due to enterostatin remains to be determined. As lipid metabolism appeared to be altered by enterostatin, we measured peroxisome proliferator-activated receptor (PPAR) expression in tissues and observed that PPAR alpha, -beta, -gamma 1, and -gamma 2 expression were modified by enterostatin in epididymal fat, pancreas, and liver. This further links altered lipid metabolism with body weight loss. Our data suggest that alterations in UCP2 and PPAR gamma 2 play a role in the control of insulin and amylin release from the pancreas. This implies that enterostatin changes lipid and carbohydrate metabolic pathways in addition to its effects on food intake and energy expenditure.
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16.
  • Axling, Ulrika, et al. (author)
  • Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program
  • 2011
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 300:1, s. 111-121
  • Journal article (peer-reviewed)abstract
    • Andersson U, Henriksson E, Strom K, Alenfall J, Goransson O, Holm C. Rose hip exerts antidiabetic effects via a mechanism involving downregulation of the hepatic lipogenic program. Am J Physiol Endocrinol Metab 300: E111-E121, 2011. First published October 19, 2010; doi:10.1152/ajpendo.00268.2010.-The aim of this study was to investigate the metabolic effects of a dietary supplement of powdered rose hip to C57BL/6J mice fed a high-fat diet (HFD). Two different study protocols were used; rose hip was fed together with HFD to lean mice for 20 wk (prevention study) and to obese mice for 10 wk (intervention study). Parameters related to obesity and glucose tolerance were monitored, and livers were examined for lipids and expression of genes and proteins related to lipid metabolism and gluconeogenesis. A supplement of rose hip was capable of both preventing and reversing the increase in body weight and body fat mass imposed by a HFD in the C57BL/6J mouse. Oral and intravenous glucose tolerance tests together with lower basal levels of insulin and glucose showed improved glucose tolerance in mice fed a supplement of rose hip compared with control mice. Hepatic lipid accumulation was reduced in mice fed rose hip compared with control, and the expression of lipogenic proteins was downregulated, whereas AMP-activated protein kinase and other proteins involved in fatty acid oxidation were unaltered. Rose hip intake lowered total plasma cholesterol as well as the low-density lipoprotein-to-high-density lipoprotein ratio via a mechanism not involving altered gene expression of sterol regulatory element-binding protein 2 or 3-hydroxymethylglutaryl-CoA reductase. Taken together, these data show that a dietary supplement of rose hip prevents the development of a diabetic state in the C57BL/6J mouse and that downregulation of the hepatic lipogenic program appears to be at least one mechanism underlying the antidiabetic effect of rose hip.
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17.
  • Barker, CJ, et al. (author)
  • Phosphorylated inositol compounds in beta -cell stimulus-response coupling
  • 2002
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 283:6, s. E1113-E1122
  • Journal article (peer-reviewed)abstract
    • Pancreatic β-cell function is essential for the regulation of glucose homeostasis in humans, and its impairment leads to the development of type 2 diabetes. Inputs from glucose and cell surface receptors act together to initiate the β-cell stimulus-response coupling that ultimately leads to the release of insulin. Phosphorylated inositol compounds have recently emerged as key players at all levels of the stimulus-secretion coupling process. In this current review, we seek to highlight recent advances in β-cell phosphoinositide research by dividing our examination into two sections. The first involves the events that lead to insulin secretion. This includes both new roles for inositol polyphosphates, particularly inositol hexakisphosphate, and both conventional and 3-phosphorylated inositol lipids. In the second section, we deal with the more novel concept of the autocrine role of insulin. Here, released insulin initiates signal transduction cascades, principally through the activity of phosphatidylinositol 3-kinase. This new round of signal transduction has been established to activate key β-cell genes, particularly the insulin gene itself. More controversially, this insulin feedback has also been suggested to either terminate or enhance insulin secretion events.
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18.
  • Barros, RPA, et al. (author)
  • Participation of ERalpha and ERbeta in glucose homeostasis in skeletal muscle and white adipose tissue
  • 2009
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 297:1, s. E124-E133
  • Journal article (peer-reviewed)abstract
    • Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)β agonists. In the present study, to investigate the relative contributions of ERα and ERβ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ER−/− mice. ERβ−/− mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ERα−/− mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ERα−/− mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ERβ antagonist in SM but had no effect on WAT. In ERβ−/− mice, Tam did not affect GLUT4 in SM but acted as an ERα antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ERα and ERβ, ERβ-mediated repression of GLUT4 predominates in SM but ERα-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ERα predominates in WAT and ERβ in SM.
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19.
  • Benziane, B, et al. (author)
  • Divergent cell signaling after short-term intensified endurance training in human skeletal muscle
  • 2008
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:6, s. E1427-E1438
  • Journal article (peer-reviewed)abstract
    • Endurance training represents one extreme in the continuum of skeletal muscle plasticity. The molecular signals elicited in response to acute and chronic exercise and the integration of multiple intracellular pathways are incompletely understood. We determined the effect of 10 days of intensified cycle training on signal transduction in nine inactive males in response to a 1-h acute bout of cycling at the same absolute workload (164 ± 9 W). Muscle biopsies were taken at rest and immediately and 3 h after the acute exercise. The metabolic signaling pathways, including AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), demonstrated divergent regulation by exercise after training. AMPK phosphorylation increased in response to exercise (∼16-fold; P < 0.05), which was abrogated posttraining ( P < 0.01). In contrast, mTOR phosphorylation increased in response to exercise (∼2-fold; P < 0.01), which was augmented posttraining ( P < 0.01) in the presence of increased mTOR expression ( P < 0.05). Exercise elicited divergent effects on mitogen-activated protein kinase (MAPK) pathways after training, with exercise-induced extracellular signal-regulated kinase (ERK) 1/2 phosphorylation being abolished ( P < 0.01) and p38 MAPK maintained. Finally, calmodulin kinase II (CaMKII) exercise-induced phosphorylation and activity were maintained ( P < 0.01), despite increased expression (∼2-fold; P < 0.05). In conclusion, 10 days of intensified endurance training attenuated AMPK, ERK1/2, and mTOR, but not CaMKII and p38 MAPK signaling, highlighting molecular pathways important for rapid functional adaptations and maintenance in response to intensified endurance exercise and training.
  •  
20.
  • Benziane, B, et al. (author)
  • Effect of exercise and training on phospholemman phosphorylation in human skeletal muscle
  • 2011
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 301:3, s. E456-E466
  • Journal article (peer-reviewed)abstract
    • Phospholemman (PLM, FXYD1) is a partner protein and regulator of the Na+-K+-ATPase (Na+-K+pump). We explored the impact of acute and short-term training exercise on PLM physiology in human skeletal muscle. A group of moderately trained males ( n = 8) performed a 1-h acute bout of exercise by utilizing a one-legged cycling protocol. Muscle biopsies were taken from vastus lateralis at 0 and 63 min (non-exercised leg) and 30 and 60 min (exercised leg). In a group of sedentary males ( n = 9), we determined the effect of a 10-day intense aerobic cycle training on Na+-K+-ATPase subunit expression, PLM phosphorylation, and total PLM expression as well as PLM phosphorylation in response to acute exercise (1 h at ∼72% V̇o2peak). Biopsies were taken at rest, immediately following, and 3 h after an acute exercise bout before and at the conclusion of the 10-day training study. PLM phosphorylation was increased both at Ser63and Ser68immediately after acute exercise (75%, P < 0.05, and 30%, P < 0.05, respectively). Short-term training had no adaptive effect on PLM phosphorylation at Ser63and Ser68, nor was the total amount of PLM altered posttraining. The protein expressions of α1-, α2-,and β1-subunits of Na+-K+-ATPase were increased after training (113%, P < 0.05, 49%, P < 0.05, and 27%, P < 0.05, respectively). Whereas an acute bout of exercise increased the phosphorylation of PKCα/βII on Thr638/641pre- and posttraining, phosphorylation of PKCζ/λ on Thr403/410was increased in response to acute exercise only after the 10-day training. In conclusion, we show that only acute exercise, and not short-term training, increases phosphorylation of PLM on Ser63and Ser68, and data from one-legged cycling indicate that this effect of exercise on PLM phosphorylation is not due to systemic factors. Our results provide evidence that phosphorylation of PLM may play a role in the acute regulation of the Na+-K+-ATPase response to exercise.
  •  
21.
  • Benziane, B, et al. (author)
  • Frontiers: skeletal muscle sodium pump regulation: a translocation paradigm
  • 2008
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:3, s. E553-E558
  • Journal article (peer-reviewed)abstract
    • The skeletal muscle sodium pump plays a major role in the removal of K+ions from the circulation postprandial, or after a physical activity bout, thereby preventing the development of hyperkalemia and fatigue. Insulin and muscle contractions stimulate Na+-K+-ATPase activity in skeletal muscle, at least partially via translocation of sodium pump units to the plasma membrane from intracellular stores. The molecular mechanism of this phenomenon is poorly understood. Due to the contradictory reports in the literature, the very existence of the translocation of Na+-K+-ATPase to the skeletal muscle cell surface is questionable. This review summarizes more than 30 years work on the skeletal muscle sodium pump translocation paradigm. Furthermore, the methodological caveats of major approaches to study the sodium pump translocation in skeletal muscle are discussed. An understanding of the molecular regulation of Na+-K+-ATPase in skeletal muscle will have important clinical implications for the understanding of the development of complications associated with the metabolic syndrome, such as cardiovascular diseases or increased muscle fatigue in diabetic patients.
  •  
22.
  • Berggreen, Christine, et al. (author)
  • Protein kinase B activity is required for the effects of insulin on lipid metabolism in adipocytes.
  • 2009
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 296, s. 635-646
  • Journal article (peer-reviewed)abstract
    • Protein kinase B is known to mediate a number of biological responses to insulin and growth factors, its role in glucose uptake being one of the most extensively studied. In this paper, we have employed a recently described allosteric inhibitor of PKB, Akti, to clarify the role of PKB in lipid metabolism in adipocytes - a subject that has received less attention. Pretreatment of primary rat and 3T3L1 adipocytes with Akti resulted in dose-dependent inhibition of PKB phosphorylation and activation in response to insulin, without affecting upstream insulin signaling (IR, IRS) or the insulin-induced PI3-K dependent activation of the ERK/RSK pathway. PKB activity was required for the insulin-induced activation of PDE3B and for the anti-lipolytic action of insulin. Moreover, inhibition of PKB activity resulted in a reduction in de novo lipid synthesis and in the ability of insulin to stimulate this process. The regulation of the rate-limiting lipogenic enzyme ACC by insulin through dephosphorylation of S79, which is a target for AMPK, was dependent on the presence of active PKB. Lastly, AMPK was shown to be phosphorylated by PKB on S485 in response to insulin and this was associated with a reduction in AMPK activity. In summary, we propose that PKB is required for the positive effects of insulin on lipid storage, and that regulation of PDE3B and AMPK by PKB is important for these effects. Key words: Akt, PDE3B, ACC, AMPK, lipogenesis.
  •  
23.
  • Bishop, David J, et al. (author)
  • Sodium bicarbonate ingestion prior to training improves mitochondrial adaptations in rats.
  • 2010
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 299:2, s. E225-33
  • Journal article (peer-reviewed)abstract
    • We tested the hypothesis that reducing hydrogen ion accumulation during training would result in greater improvements in muscle oxidative capacity and time to exhaustion (TTE). Male Wistar rats were randomly assigned to one of three groups (CON, PLA, and BIC). CON served as a sedentary control, whereas PLA ingested water and BIC ingested sodium bicarbonate 30 min prior to every training session. Training consisted of seven to twelve 2-min intervals performed five times/wk for 5 wk. Following training, TTE was significantly greater in BIC (81.2 +/- 24.7 min) compared with PLA (53.5 +/- 30.4 min), and TTE for both groups was greater than CON (6.5 +/- 2.5 min). Fiber respiration was determined in the soleus (SOL) and extensor digitorum longus (EDL), with either pyruvate (Pyr) or palmitoyl carnitine (PC) as substrates. Compared with CON (14.3 +/- 2.6 nmol O(2).min(-1).mg dry wt(-1)), there was a significantly greater SOL-Pyr state 3 respiration in both PLA (19.6 +/- 3.0 nmol O(2).min(-1).mg dry wt(-1)) and BIC (24.4 +/- 2.8 nmol O(2).min(-1).mg dry wt(-1)), with a significantly greater value in BIC. However, state 3 respiration was significantly lower in the EDL from both trained groups compared with CON. These differences remained significant in the SOL, but not the EDL, when respiration was corrected for citrate synthase activity (an indicator of mitochondrial mass). These novel findings suggest that reducing muscle hydrogen ion accumulation during running training is associated with greater improvements in both mitochondrial mass and mitochondrial respiration in the soleus.
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24.
  • Bjursell, Mikael, 1977, et al. (author)
  • Acutely reduced locomotor activity is a major contributor to Western diet-induced obesity in mice
  • 2008
  • In: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 294:2
  • Journal article (peer-reviewed)abstract
    • The aim of the present study was to investigate the short- and long-term effects of a high-fat Western diet (WD) on intake, storage, expenditure, and fecal loss of energy as well as effects on locomotor activity and thermogenesis. WD for only 24 h resulted in a marked physiological shift in energy homeostasis, including increased body weight gain, body fat, and energy expenditure (EE) but an acutely lowered locomotor activity. The acute reduction in locomotor activity was observed after only 3–5 h on WD. The energy intake and energy absorption were increased during the first 24 h, lower after 72 h, and normalized between 7 and 14 days on WD compared with mice given chow diet. Core body temperature and EE was increased between 48 and 72 h but normalized after 21 days on WD. These changes paralleled plasma T3 levels and uncoupling protein-1 expression in brown adipose tissue. After 21 days of WD, energy intake and absorption, EE, and body temperature were normalized. In contrast, the locomotor activity was reduced and body weight gain was increased over the entire 21-day study period on WD. Calculations based on the correlation between locomotor activity and EE in 2-h intervals at days 21–23 indicated that a large portion of the higher body weight gain in the WD group could be attributed to the reduced locomotor activity. In summary, an acute and persisting decrease in locomotor activity is most important for the effect of WD on body weight gain and obesity in mice.
  •  
25.
  • Blackwood, Sarah J, et al. (author)
  • Elevated heart rate and decreased muscle endothelial nitric oxide synthase in early development of insulin resistance.
  • 2024
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 327:2, s. E172-E182
  • Journal article (peer-reviewed)abstract
    • Insulin resistance (IR) is a risk factor for the development of several major metabolic diseases. Muscle fiber composition is established early in life and is associated with insulin sensitivity. Hence, muscle fiber composition was used to identify early defects in the development of IR in healthy young individuals in the absence of clinical manifestations. Biopsies were obtained from the thigh muscle, followed by an intravenous glucose tolerance test. Indices of insulin action were calculated and cardiovascular measurements, analyses of blood and muscle were performed. Whole-body insulin sensitivity (SIgalvin) was positively related to expression of type I muscle fibers (r=0.49; P<0.001) and negatively related to resting heart rate (HR, r=-0.39; P<0.001), which was also negatively related to expression of type I muscle fibers (r=-0.41; P<0.001). Muscle protein expression of endothelial nitric oxide synthase (eNOS), whose activation results in vasodilation, was measured in two subsets of subjects expressing a high percentage of type I fibers (59±6%; HR = 57±9 beats/min; SIgalvin = 1.8±0.7 units) or low percentage of type I fibers (30±6%; HR = 71±11; SIgalvin = 0.8±0.3 units; P<0.001 for all variables vs. first group). eNOS expression was: 1. higher in subjects with high type I expression; 2. almost two-fold higher in pools of type I vs. II fibers; 3. only detected in capillaries surrounding muscle fibers; and 4. linearly associated with SIgalvin. These data demonstrate that an altered function of the autonomic nervous system and a compromised capacity for vasodilation in the microvasculature occur early in the development of IR.
  •  
26.
  • Blackwood, Sarah J, et al. (author)
  • Insulin resistance after a 3-day fast is associated with an increased capacity of skeletal muscle to oxidize lipids.
  • 2023
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 324:5, s. E390-E401
  • Journal article (peer-reviewed)abstract
    • There is a debate on whether lipid-mediated insulin resistance derives from an increased or decreased capacity of muscle to oxidize fats. Here we examine the involvement of muscle fiber composition in the metabolic responses to a 3-day fast (starvation, which results in increases in plasma lipids and insulin resistance) in two groups of healthy young subjects: 1, area occupied by type I fibers = 61.0 ± 11.8%; 2, type I area = 36.0 ± 4.9% (P<0.001). Muscle biopsies and intravenous glucose tolerance tests were performed after an overnight fast and after starvation. Biopsies were analyzed for muscle fiber composition and mitochondrial respiration. Indices of glucose tolerance and insulin sensitivity were determined. Glucose tolerance was similar in both groups after an overnight fast and deteriorated to a similar degree in both groups after starvation. In contrast, whole-body insulin sensitivity decreased markedly after starvation in group 1 (P<0.01), whereas the decrease in group 2 was substantially smaller (P=0.06). Non-esterified fatty acids and β-hydroxybutyrate levels in plasma after an overnight fast were similar between groups and increased markedly and comparably in both groups after starvation, demonstrating similar degrees of lipid load. The capacity of permeabilized muscle fibers to oxidize lipids was significantly higher in group 1 vs. 2, whereas there was no significant difference in pyruvate oxidation between groups. The data demonstrate that loss of whole-body insulin sensitivity after short-term starvation is a function of muscle fiber composition and is associated with an elevated rather than a diminished capacity of muscle to oxidize lipids.
  •  
27.
  • Blackwood, Sarah J, et al. (author)
  • Role of nitration in control of phosphorylase and glycogenolysis in mouse skeletal muscle.
  • 2021
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:4, s. E691-E701
  • Journal article (peer-reviewed)abstract
    • Phosphorylase is one of the most carefully studied proteins in history, but knowledge of its regulation during intense muscle contraction is incomplete. Tyrosine nitration of purified preparations of skeletal muscle phosphorylase results in inactivation of the enzyme and this is prevented by antioxidants. Whether an altered redox state affects phosphorylase activity and glycogenolysis in contracting muscle is not known. Here, we investigate the role of redox state in control of phosphorylase and glycogenolysis in isolated mouse fast-twitch (extensor digitorum longus, EDL) and slow-twitch (soleus) muscle preparations during repeated contractions. Exposure of crude muscle extracts to H2O2 had little effect on phosphorylase activity. However, exposure of extracts to peroxynitrite (ONOO-), a nitrating/oxidizing agent, resulted in complete inactivation of phosphorylase (half maximal inhibition at ~200 µM ONOO-), which was fully reversed by the presence of an ONOO-scavanger, dithiothreitol (DTT). Incubation of isolated muscles with ONOO- resulted in nitration of phosphorylase and marked inhibition of glycogenolysis during repeated contractions. ONOO- also resulted in large decreases in high-energy phosphates (ATP and phosphocreatine) in the rested state and following repeated contractions. These metabolic changes were associated with decreased force production during repeated contractions (to ~60% of control). In contrast, repeated contractions did not result in nitration of phosphorylase, nor did DTT or the general antioxidant N-acetylcysteine alter glycogenolysis during repeated contractions. These findings demonstrate that ONOO- inhibits phosphorylase and glycogenolysis in living muscle under extreme conditions. However, nitration does not play a significant role in control of phosphorylase and glycogenolysis during repeated contractions.
  •  
28.
  • Blomqvist, G, et al. (author)
  • Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients
  • 2002
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 283:1, s. E20-E28
  • Journal article (peer-reviewed)abstract
    • Using R-β-[1-11C]hydroxybutyrate and positron emission tomography, we studied the effect of acute hyperketonemia (range 0.7–1.7 μmol/ml) on cerebral ketone body utilization in six nondiabetic subjects and six insulin-dependent diabetes mellitus (IDDM) patients with average metabolic control (HbA1c = 8.1 ± 1.7%). An infusion of unlabeled R-β-hydroxybutyrate was started 1 h before the bolus injection of R-β-[1-11C]hydroxybutyrate. The time course of the radioactivity in the brain was measured during 10 min. For both groups, the utilization rate of ketone bodies was found to increase nearly proportionally with the plasma concentration of ketone bodies (1.0 ± 0.3 μmol/ml for nondiabetic subjects and 1.3 ± 0.3 μmol/ml for IDDM patients). No transport of ketone bodies from the brain could be detected. This result, together with a recent study of the tissue concentration of R-β-hydroxybutyrate in the brain by magnetic resonance spectroscopy, indicate that, also at acute hyperketonemia, the rate-limiting step for ketone body utilization is the transport into the brain. No significant difference in transport and utilization of ketone bodies could be detected between the nondiabetic subjects and the IDDM patients.
  •  
29.
  • Blomstrand, Eva, et al. (author)
  • BCAA intake affects protein metabolism in muscle after but not during exercise in humans.
  • 2001
  • In: American Journal of Physiology. Endocrinology and Metabolism. - 0193-1849 .- 1522-1555. ; 281:2, s. E365-74
  • Journal article (peer-reviewed)abstract
    • Branched-chain amino acids (BCAA) or a placebo was given to seven subjects during 1 h of ergometer cycle exercise and a 2-h recovery period. Intake of BCAA did not influence the rate of exchange of the aromatic amino acids, tyrosine and phenylalanine, in the legs during exercise or the increase in their concentration in muscle. The increase was approximately 30% in both conditions. On the other hand, in the recovery period after exercise, a faster decrease in the muscle concentration of aromatic amino acids was found in the BCAA experiment (46% compared with 25% in the placebo condition). There was also a tendency to a smaller release (an average of 32%) of these amino acids from the legs during the 2-h recovery. The results suggest that BCAA have a protein-sparing effect during the recovery after exercise, either that protein synthesis has been stimulated and/or protein degradation has decreased, but the data during exercise are too variable to make any conclusions about the effects during exercise. The effect in the recovery period does not seem to be mediated by insulin.
  •  
30.
  • Boon, Hanneke, 1981-, et al. (author)
  • Influence of chronic and acute spinal cord injury on skeletal muscle Na+-K+-ATPase and phospholemman expression in humans
  • 2012
  • In: American Journal of Physiology. Endocrinology and Metabolism. - Bethesda, MD : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:7, s. E864-E871
  • Journal article (peer-reviewed)abstract
    • Na +-K +-ATPase is an integral membrane protein crucial for the maintenance of ion homeostasis and skeletal muscle contractibility. Skeletal muscle Na +-K +-ATPase content displays remarkable plasticity in response to long-term increase in physiological demand, such as exercise training. However, the adaptations in Na +-K +-ATPase function in response to a suddenly decreased and/or habitually low level of physical activity, especially after a spinal cord injury (SCI), are incompletely known. We tested the hypothesis that skeletal muscle content of Na +-K +-ATPase and the associated regulatory proteins from the FXYD family is altered in SCI patients in a manner dependent on the severity of the spinal cord lesion and postinjury level of physical activity. Three different groups were studied: 1) six subjects with chronic complete cervical SCI, 2) seven subjects with acute, complete cervical SCI, and 3) six subjects with acute, incomplete cervical SCI. The individuals in groups 2 and 3 were studied at months 1, 3, and 12 postinjury, whereas individuals with chronic SCI were compared with an able-bodied control group. Chronic complete SCI was associated with a marked decrease in [ 3H]ouabain binding site concentration in skeletal muscle as well as reduced protein content of the α 1-, α 1-, and (β1-subunit of the Na +-K +-ATPase. In line with this finding, expression of the Na +-K +-ATPase α 1-, α 1- subunits progressively decreased during the first year after complete but not after incomplete SCI. The expression of the regulatory protein phospholemman (PLM or FXYD1) was attenuated after complete, but not incomplete, cervical SCI. In contrast, FXYD5 was substantially upregulated in patients with complete SCI. In conclusion, the severity of the spinal cord lesion and the level of postinjury physical activity in patients with SCI are important factors controlling the expression of Na +-K +-ATPase and its regulatory proteins PLM and FXYD5. © 2012 the American Physiological Society.
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31.
  • Borgenvik, Marcus, et al. (author)
  • Intake of branched-chain amino acids influences the levels of MAFbx mRNA and MuRF-1 total protein in resting and exercising human muscle.
  • 2012
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:5, s. E510-21
  • Journal article (peer-reviewed)abstract
    • Resistance exercise and amino acids are two major factors that influence muscle protein turnover. Here, we examined the effects of resistance exercise and branched-chain amino acids (BCAA), individually and in combination, on the expression of anabolic and catabolic genes in human skeletal muscle. Seven subjects performed two sessions of unilateral leg press exercise with randomized supplementation with BCAA or flavored water. Biopsies were collected from the vastus lateralis muscle of both the resting and exercising legs before and repeatedly after exercise to determine levels of mRNA, protein phosphorylation, and amino acid concentrations. Intake of BCAA reduced (P < 0.05) MAFbx mRNA by 30 and 50% in the resting and exercising legs, respectively. The level of MuRF-1 mRNA was elevated (P < 0.05) in the exercising leg two- and threefold under the placebo and BCAA conditions, respectively, whereas MuRF-1 total protein increased by 20% (P < 0.05) only in the placebo condition. Phosphorylation of p70(S6k) increased to a larger extent (∼2-fold; P < 0.05) in the early recovery period with BCAA supplementation, whereas the expression of genes regulating mTOR activity was not influenced by BCAA. Muscle levels of phenylalanine and tyrosine were reduced (13-17%) throughout recovery (P < 0.05) in the placebo condition and to a greater extent (32-43%; P < 0.05) following BCAA supplementation in both resting and exercising muscle. In conclusion, BCAA ingestion reduced MAFbx mRNA and prevented the exercise-induced increase in MuRF-1 total protein in both resting and exercising leg. Further-more, resistance exercise differently influenced MAFbx and MuRF-1 mRNA expression, suggesting both common and divergent regulation of these two ubiquitin ligases.
  •  
32.
  • Borjesson, AE, et al. (author)
  • The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice
  • 2012
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 302:11, s. E1381-E1389
  • Journal article (peer-reviewed)abstract
    • High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/−mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/−mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.
  •  
33.
  • Bosselaar, Marlies, et al. (author)
  • Intra-arterial AICA-riboside administration induces NO-dependent vasodilation in vivo in human skeletal muscle
  • 2009
  • In: American Journal of Physiology. Endocrinology and Metabolism. - Bethesda, MD : American Physiological Society. - 0193-1849 .- 1522-1555. ; 297:3, s. E759-E766
  • Journal article (peer-reviewed)abstract
    • In animal models, administration of the adenosine analog AICA-riboside has shown beneficial effects on ischemia-reperfusion injury and glucose homeostasis. The vascular and/or metabolic effects of AICA-riboside administration in humans remain to be established. AICA-riboside was infused intra-arterially in four different dosages up to 8 mg·min-1·dl-1 in 24 healthy subjects. Forearm blood flow (FBF) and glucose uptake and plasma glucose, free fatty acid, and AICA-riboside concentrations were assessed. We also combined AICAriboside infusion (2 mg·min-1·dl -1) with the intra-arterial administration of the adenosine receptor antagonist caffeine (90 μg·min-1·dl-1; n = 6) and with the endothelial NO synthase inhibitor L-NMMA (0.4 mg·min-1·dl-1; n = 6). Additional in vitro experiments were performed to explain our in vivo effects of AICA-riboside in humans. AICA-riboside increased FBF dose dependently from 2.0 ± 0.2 to 13.2 ± 1.9 ml·min-1·dl-1 maximally (P < 0.05 for all dosages). The latter was not reduced by caffeine administration but was significantly attenuated by L-NMMA infusion. Despite high plasma AICA-riboside concentrations, forearm glucose uptake did not change. In vitro experiments showed rapid uptake of AICA-riboside by the equilibrative nucleoside transporter in erythrocytes and subsequent phosphorylation to AICA-ribotide. We conclude that AICA-riboside induces a potent vasodilator response in humans that is mediated by NO. Despite high local plasma concentrations, AICA-riboside does not increase skeletal muscle glucose uptake. Copyright © 2009 the American Physiological Society.
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34.
  • Boulet, Nathalie, et al. (author)
  • Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition
  • 2021
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:2, s. E359-E378
  • Journal article (peer-reviewed)abstract
    • Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical proinflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have, therefore, investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and proinflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Furthermore, the anti-inflammatory macrophage accretion was mediated via β1/β2-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.NEW & NOTEWORTHY A regulatory or mediatory role—positive or negative—for macrophages in the recruitment of brown adipose tissue is presently discussed. As the recruited state in the tissue is a dynamic process, maintenance of the recruited state would need persistent alterations in macrophage complement. Contrary to this expectation, we demonstrate here an absence of alterations in macrophage complement in thermogenically recruited brown—or brite/beige—adipose tissues. Macrophage regulation of thermogenic capacity is thus less likely.
  •  
35.
  • Bryzgalova, G, et al. (author)
  • Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice
  • 2008
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:4, s. E904-E912
  • Journal article (peer-reviewed)abstract
    • The high-fat diet (HFD)-fed mouse is a model of obesity, impaired glucose tolerance, and insulin resistance. The main objective of this study was to elucidate the molecular mechanisms underlying the antidiabetogenic and weight-lowering effects of 17β-estradiol (E2) in this mouse model. C57BL/6 female mice (8 wk old) were fed on a HFD for 10 mo. E2, given daily (50 μg/kg sc) during the last month of feeding, decreased body weight and markedly improved glucose tolerance and insulin sensitivity. Plasma levels of insulin, leptin, resistin, and adiponectin were decreased. We demonstrated that E2treatment decreased the expression of genes encoding resistin and leptin in white adipose tissue (WAT), whereas adiponectin expression was unchanged. Furthermore, in WAT we demonstrated decreased expression levels of sterol regulatory element-binding protein 1c (SREBP1c) and its lipogenic target genes, such as fatty acid synthase and stearoyl-CoA desaturase 1 (SCD1). In the liver, the expression levels of transcription factors such as liver X receptor α and SREBP1c were not changed by E2treatment, but the expression of the key lipogenic gene SCD1 was reduced. This was accompanied by decreased hepatic triglyceride content. Importantly, E2decreased the hepatic expression of glucose-6-phosphatase (G-6-Pase). We conclude that E2treatment exerts antidiabetic and antiobesity effects in HFD mice and suggest that this is related to decreased expression of lipogenic genes in WAT and liver and suppression of hepatic expression of G-6-Pase. Decreased plasma levels of resistin probably also play an important role in this context.
  •  
36.
  • Burgess, SC, et al. (author)
  • Effect of murine strain on metabolic pathways of glucose production after brief or prolonged fasting
  • 2005
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 289:1, s. 53-61
  • Journal article (peer-reviewed)abstract
    • Background strain is known to influence the way a genetic manipulation affects mouse phenotypes. Despite data that demonstrate variations in the primary phenotype of basic inbred strains of mice, there is limited data available about specific metabolic fluxes in vivo that may be responsible for the differences in strain phenotypes. In this study, a simple stable isotope tracer/NMR spectroscopic protocol has been used to compare metabolic fluxes in ICR, FVB/N (FVB), C57BL/6J (B6), and 129S1/SvImJ (129) mouse strains. After a short-term fast in these mice, there were no detectable differences in the pathway fluxes that contribute to glucose synthesis. However, after a 24-h fast, B6 mice retain some residual glycogenolysis compared with other strains. FVB mice also had a 30% higher in vivo phosphoenolpyruvate carboxykinase flux and total glucose production from the level of the TCA cycle compared with B6 and 129 strains, while total body glucose production in the 129 strain was similar to 30% lower than in either FVB or B6 mice. These data indicate that there are inherent differences in several pathways involving glucose metabolism of inbred strains of mice that may contribute to a phenotype after genetic manipulation in these animals. The techniques used here are amenable to use as a secondary or tertiary tool for studying mouse models with disruptions of intermediary metabolism.
  •  
37.
  • Börjesson, Anna E, et al. (author)
  • SERMs have substance-specific effects on bone, and these effects are mediated via ER alpha AF-1 in female mice
  • 2016
  • In: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 310:11
  • Journal article (peer-reviewed)abstract
    • The bone-sparing effect of estrogens is mediated primarily via estrogen receptor (ER)alpha, which stimulates gene transcription through activation function (AF)-1 and AF-2. The role of ER alpha AF-1 for the estradiol (E-2) effects is tissue specific. The selective ER modulators (SERMs) raloxifene (Ral), lasofoxifene (Las), and bazedoxifene (Bza) can be used to treat postmenopausal osteoporosis. They all reduce the risk for vertebral fractures, whereas Las and partly Bza, but not Ral, reduce the risk for nonvertebral fractures. Here, we have compared the tissue specificity of Ral, Las, and Bza and evaluated the role of ER alpha AF-1 for the effects of these SERMs, with an emphasis on bone parameters. We treated ovariectomized (OVX) wild-type (WT) mice and OVX mice lacking ER alpha AF-1 (ER alpha AF-1(0)) with E-2, Ral, Las, or Bza. All three SERMs increased trabecular bone mass in the axial skeleton. In the appendicular skeleton, only Las increased the trabecular bone volume/tissue volume and trabecular number, whereas both Ral and Las increased the cortical bone thickness and strength. However, Ral also increased cortical porosity. The three SERMs had only a minor effect on uterine weight. Notably, all evaluated effects of these SERMs were absent in ovx ER alpha AF-1(0) mice. In conclusion, all SERMs had similar effects on axial bone mass. However, the SERMs had slightly different effects on the appendicular skeleton since only Las increased the trabecular bone mass and only Ral increased the cortical porosity. Importantly, all SERM effects require a functional ER alpha AF-1 in female mice. These results could lead to development of more specific treatments for osteoporosis.
  •  
38.
  • Börjesson, Anna E, et al. (author)
  • The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice
  • 2012
  • In: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:11
  • Journal article (peer-reviewed)abstract
    • Borjesson AE, Windahl SH, Karimian E, Eriksson EE, Lagerquist MK, Engdahl C, Antal MC, Krust A, Chambon P, Savendahl L, Ohlsson C. The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am J Physiol Endocrinol Metab 302: E1381-E1389, 2012. First published March 13, 2012; doi:10.1152/ajpendo.00646.2011.-High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-alpha stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ER alpha and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ER alpha (ER alpha(-/-)) or ER alpha AF-1 (ER alpha AF-1(0)) were evaluated. Old (16- to 19-mo-old) female ER alpha(-/-) mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ER alpha AF-1(0) mice (tibia: -4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ER alpha AF-1(0) mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ER alpha(-/-) mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ER alpha or aromatase. In contrast, ER alpha AF-1 deletion results in a hyperactive ER alpha, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ER alpha that do not require AF-1 and that ER alpha AF-1 opposes growth plate closure.
  •  
39.
  • Carr, Richard D., et al. (author)
  • Incretin and islet hormonal responses to fat and protein ingestion in healthy men
  • 2008
  • In: American Journal of Physiology: Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 295:4, s. 779-784
  • Journal article (peer-reviewed)abstract
    • Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) regulate islet function after carbohydrate ingestion. Whether incretin hormones are of importance for islet function after ingestion of noncarbohydrate macronutrients is not known. This study therefore examined integrated incretin and islet hormone responses to ingestion of pure fat (oleic acid; 0.88 g/kg) or protein (milk and egg protein; 2 g/kg) over 5 h in healthy men, aged 20-25 yr (n = 12); plain water ingestion served as control. Both intact (active) and total GLP-1 and GIP levels were determined as was plasma activity of dipeptidyl peptidase-4 (DPP-4). Following water ingestion, glucose, insulin, glucagon, GLP-1, and GIP levels and DPP-4 activity were stable during the 5-h study period. Both fat and protein ingestion increased insulin, glucagon, GIP, and GLP-1 levels without affecting glucose levels or DPP-4 activity. The GLP-1 responses were similar after protein and fat, whereas the early (30 min) GIP response was higher after protein than after fat ingestion (P < 0.001). This was associated with sevenfold higher insulin and glucagon responses compared with fat ingestion (both P < 0.001). After protein, the early GIP, but not GLP-1, responses correlated to insulin (r(2) = 0.86; P = 0.0001) but not glucagon responses. In contrast, after fat ingestion, GLP-1 and GIP did not correlate to islet hormones. We conclude that, whereas protein and fat release both incretin and islet hormones, the early GIP secretion after protein ingestion may be of primary importance to islet hormone secretion.
  •  
40.
  • Chai, W. D., et al. (author)
  • Inhibiting myeloperoxidase prevents onset and reverses established high-fat diet-induced microvascular insulin resistance
  • 2019
  • In: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 317:6
  • Journal article (peer-reviewed)abstract
    • A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-ediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD's microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.
  •  
41.
  •  
42.
  • Chisalita, Simona Ioana, 1972-, et al. (author)
  • Insulin-like growth factor I receptors are more abundant than insulin receptors in human micro- and macrovascular endothelial cells
  • 2004
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 286, s. E896-E901
  • Journal article (peer-reviewed)abstract
    • Micro- and macroangiopathy are major causes of morbidity and mortality in patients with diabetes. Our aim was to characterize IGF-I receptor (IGF-IR) and insulin receptor (IR) in human micro- and macrovascular endothelial cells. Cultured human dermal microvascular endothelial cells (HMVEC) and human aortic endothelial cells (HAEC) were used. Gene expression was measured by quantitative real-time RT-PCR and receptor protein by ligand-binding assay. Phosphorylation of IGF-IR ß-subunit was analyzed by immunoprecipitation and Western blot. Glucose metabolism and DNA synthesis was assessed using [3H]glucose and [3H]thymidine incorporation, respectively. We detected gene expression of IGF-IR and IR in HAEC and HMVEC. IGF-IR gene expression was severalfold higher than that of IR. The specific binding of 125I-IGF-I was higher than that of 125I-insulin in HAEC and HMVEC. Insulin and the new, long-acting insulin analog glargine interacted with the IGF-IR with thousand- and hundred-fold less potency than IGF-I itself. Phosphorylation of the IGF-IR ß-subunit was shown in HAEC for IGF-I (10-8 M) and insulin (10-6 M) and in HMVEC for IGF-I and glargine (10-8 M, 10-6 M). IGF-I 10-7 M stimulated incorporation of [3H]thymidine into DNA, and 10-9–10-7 M also the incorporation of [3H]glucose in HMVEC, whereas glargine and insulin had no significant effects at 10-9–10-7 M. Human micro- and macrovascular endothelial cells express more IGF-IR than IR. IGF-I and high concentrations of glargine and insulin  ctivates the IGF-IR. Glargine has a higher affinity than insulin for the IGF-IR but probably has no effect on DNA synthesis at concentrations reached in vivo.
  •  
43.
  • Chittezhath, M, et al. (author)
  • Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes
  • 2019
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 317:6, s. E1108-E1120
  • Journal article (peer-reviewed)abstract
    • β-Cells respond to peripheral insulin resistance by first increasing circulating insulin during diabetes. Islet remodeling supports this compensation, but its drivers remain poorly understood. Infiltrating macrophages have been implicated in late-stage type 2 diabetes, but relatively little is known on islet resident macrophages, especially during compensatory hyperinsulinemia. We hypothesized that islet resident macrophages would contribute to islet vascular remodeling and hyperinsulinemia during diabetes, the failure of which results in a rapid progression to frank diabetes. We used chemical (clodronate), genetics (CD169-diphtheria toxin receptor mice), or antibody-mediated (colony-stimulating factor 1 receptor α) macrophage ablation methods in diabetic (db/db) and diet-induced models of compensatory hyperinsulinemia to investigate the role of macrophages in islet remodeling. We transplanted islets devoid of macrophages into naïve diabetic mice and assessed the impact on islet vascularization. With the use of the above methods, we showed that macrophage depletion significantly and consistently compromised islet remodeling in terms of size, vascular density, and insulin secretion capacity. Depletion of islet macrophages reduced VEGF-A secretion in both human and mouse islets ex vivo, and this functionally translated to delayed revascularization upon transplantation in vivo. We revealed that islet resident macrophages were associated with islet remodeling and increased insulin secretion during diabetes. This suggests utility in harnessing islet macrophages during this phase to promote islet vascularization, remodeling, and insulin secretion.
  •  
44.
  • Dahlman, I, et al. (author)
  • Comprehensive functional screening of miRNAs involved in fat cell insulin sensitivity among women
  • 2017
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 312:6, s. E482-E494
  • Journal article (peer-reviewed)abstract
    • The key pathological link between obesity and type 2 diabetes is insulin resistance, but the molecular mechanisms are not entirely identified. micro-RNAs (miRNA) are dysregulated in obesity and may contribute to insulin resistance. Our objective was to detect and functionally investigate miRNAs linked to insulin sensitivity in human subcutaneous white adipose tissue (scWAT). Subjects were selected based on the insulin-stimulated lipogenesis response of subcutaneous adipocytes. Global miRNA profiling was performed in abdominal scWAT of 18 obese insulin-resistance (OIR), 21 obese insulin-sensitive (OIS), and 9 lean women. miRNAs demonstrating differential expression between OIR and OIS women were overexpressed in human in vitro-differentiated adipocytes followed by assessment of lipogenesis and identification of miRNA targets by measuring mRNA/protein expression and 3′-untranslated region analysis. Eleven miRNAs displayed differential expression between OIR and OIS states. Overexpression of miR-143-3p and miR-652-3p increased insulin-stimulated lipogenesis in human in vitro differentiated adipocytes and directly or indirectly affected several genes/proteins involved in insulin signaling at transcriptional or posttranscriptional levels. Adipose expression of miR-143-3p and miR-652-3p was positively associated with insulin-stimulated lipogenesis in scWAT independent of body mass index. In conclusion, miR-143-3p and miR-652-3p are linked to scWAT insulin resistance independent of obesity and influence insulin-stimulated lipogenesis by interacting at different steps with insulin-signaling pathways.
  •  
45.
  • de Jong, Jasper M. A., et al. (author)
  • A stringent validation of mouse adipose tissue identity markers
  • 2015
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 308:12, s. E1085-E1105
  • Journal article (peer-reviewed)abstract
    • The nature of brown adipose tissue in humans is presently debated: whether it is classical brown or of brite/beige nature. The dissimilar developmental origins and proposed distinct functions of the brown and brite/beige tissues make it essential to ascertain the identity of human depots with the perspective of recruiting and activating them for the treatment of obesity and type 2 diabetes. For identification of the tissues, a number of marker genes have been proposed, but the validity of the markers has not been well documented. We used established brown (interscapular), brite (inguinal), and white (epididymal) mouse adipose tissues and corresponding primary cell cultures as validators and examined the informative value of a series of suggested markers earlier used in the discussion considering the nature of human brown adipose tissue. Most of these markers unexpectedly turned out to be noninformative concerning tissue classification (Car4, Cited1, Ebf3, Eva1, Fbxo31, Fgf21, Lhx8, Hoxc8, and Hoxc9). Only Zic1 (brown), Cd137, Epsti1, Tbx1, Tmem26 (brite), and Tcf21 (white) proved to be informative in these three tissues. However, the expression of the brite markers was not maintained in cell culture. In a more extensive set of adipose depots, these validated markers provide new information about depot identity. Principal component analysis supported our single-gene conclusions. Furthermore, Zic1, Hoxc8, Hoxc9, and Tcf21 displayed anteroposterior expression patterns, indicating a relationship between anatomic localization and adipose tissue identity (and possibly function). Together, the observed expression patterns of these validated marker genes necessitates reconsideration of adipose depot identity in mice and humans.
  •  
46.
  • de Jong, Jasper M. A., et al. (author)
  • The β3-adrenergic receptor is dispensable for browning of adipose tissues
  • 2017
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 312:6, s. E508-E518
  • Journal article (peer-reviewed)abstract
    • Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β3-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β3-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β3-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β3-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (Ucp1, Pgc1a, Dio2 and Cidea) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β3-adrenergic receptor. Experiments with the β3-adrenergic receptor agonist CL-316,243 verified the functional absence of β3-adrenergic signaling in these knockout mice. The β3-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus, our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β3-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells. This should be taken into account in the increasing number of studies on the induction of browning and their extrapolation to human physiology.
  •  
47.
  • Deshmukh, AS, et al. (author)
  • Role of the AMPKgamma3 isoform in hypoxia-stimulated glucose transport in glycolytic skeletal muscle
  • 2009
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 297:6, s. E1388-E1394
  • Journal article (peer-reviewed)abstract
    • Skeletal muscle glucose transport is regulated via the canonical insulin-signaling cascade as well as by energy-sensing signals. 5′-AMP-activated protein kinase (AMPK) has been implicated in the energy status regulation of glucose transport. We determined the role of the AMPKγ3 isoform in hypoxia-mediated energy status signaling and glucose transport in fast-twitch glycolytic extensor digitorum longus (EDL) muscle from AMPKγ3-knockout (KO) mice and wild-type mice. Although hypoxia increased glucose transport ( P < 0.001) in wild-type mice, this effect was attenuated in AMPKγ3-KO mice (45% reduction, P < 0.01). The role of Ca2+-mediated signaling was tested using the Ca2+/calmodulin competitive inhibitor KN-93. KN-93 exposure reduced hypoxia-mediated glucose transport in AMPKγ3-KO and wild-type mice ( P < 0.05). To further explore the underlying signaling mechanisms, phosphorylation of CaMKII, AMPK, ACC, and TBC1D1/D4 as well as isoform-specific AMPK activity was determined. Basal and hypoxia-mediated phosphorylation of CaMKII, AMPK, and ACC as well as α1- and α2-associated AMPK activity was comparable between AMPKγ3-KO and wild-type mice. KN-93 reduced hypoxia-mediated CaMKII phosphorylation in AMPKγ3-KO and wild-type mice ( P < 0.05), whereas phosphorylation of AMPK and ACC as well as α1- and α2-associated AMPK activity was unaltered. Hypoxia increased TBC1D1/D4 phosphorylation in AMPKγ3-KO and wild-type mice ( P < 0.001). KN-93 exposure prevented this effect in AMPKγ3-KO, but not in wild-type mice. Taken together, we provide direct evidence for a role of the AMPKγ3 isoform in hypoxia-mediated glucose transport in glycolytic muscle. Moreover, hypoxia-mediated TBC1D1/D4 phosphorylation was uncoupled from glucose transport in AMPKγ3-KO mice, indicating that TBC1D1/D4-independent mechanisms contribute to glucose transport in skeletal muscle.
  •  
48.
  • Di Gregorio, Gina B, et al. (author)
  • Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity.
  • 2004
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:4
  • Journal article (peer-reviewed)abstract
    • FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test (r = -0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA (P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-alpha, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.
  •  
49.
  • Drott, Carl Johan, et al. (author)
  • Ghrelin in rat pancreatic islets decreases islet blood flow
  • 2019
  • In: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 317:1, s. E139-E146
  • Journal article (peer-reviewed)abstract
    • The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the epsilon-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1 alpha). exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1 alpha receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1 alpha was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats. only, also improved the peak insulin response to glucose in vivo. thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.
  •  
50.
  • Efanov, AM, et al. (author)
  • Insulinotropic activity of the imidazoline derivative RX871024 in the diabetic GK rat
  • 2002
  • In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 282:1, s. E117-E124
  • Journal article (peer-reviewed)abstract
    • The insulinotropic activity of the imidazoline derivative RX871024 was compared in pancreatic islets from nondiabetic Wistar rats and spontaneously diabetic Goto-Kakizaki (GK) rats. RX871024 significantly stimulated insulin secretion in islets from both animal groups. The insulinotropic activity of RX871024 was higher than that of the sulfonylurea glibenclamide. This difference was more pronounced in islets from GK rats compared with Wistar rat islets. More importantly, RX871024 substantially improved glucose sensitivity in diabetic β-cells, whereas glibenclamide stimulated insulin secretion about twofold over a broad range of glucose concentrations in nondiabetic and diabetic rats. RX871024 induced a faster increase in cytosolic free Ca2+concentration and faster inhibition of ATP-dependent K+channel activity in GK rat islets compared with Wistar rat islets. RX871024 also induced a more pronounced increase in diacylglycerol concentration in GK rat islets. These data support the idea that imidazoline compounds can form the basis for the development of novel drugs for treatment of type 2 diabetes, which can restore glucose sensitivity in diabetic β-cells.
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