| 1. |
- Norgren, Jakob, et al.
(författare)
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Capillary blood tests may overestimate ketosis : triangulation between three different measures of beta-hydroxybutyrate
- 2020
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:2, s. e184-E188
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Tidskriftsartikel (refereegranskat)abstract
- The ketone body beta-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.
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| 2. |
- Frank, Per, et al.
(författare)
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Acute exercise reverses starvation-mediated insulin resistance in humans.
- 2013
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 304:4, s. E436-43
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Tidskriftsartikel (refereegranskat)abstract
- Within 2-3 days of starvation, pronounced insulin resistance develops, possibly mediated by increased lipid load. Here, we show that one exercise bout increases mitochondrial fatty acid (FA) oxidation and reverses starvation-induced insulin resistance. Nine healthy subjects underwent 75-h starvation on two occasions: with no exercise (NE) or with one exercise session at the end of the starvation period (EX). Muscle biopsies were analyzed for mitochondrial function, contents of glycogen, and phosphorylation of regulatory proteins. Glucose tolerance and insulin sensitivity, measured with an intravenous glucose tolerance test (IVGTT), were impaired after starvation, but in EX the response was attenuated or abolished. Glycogen stores were reduced, and plasma FA was increased in both conditions, with a more pronounced effect in EX. After starvation, mitochondrial respiration decreased with complex I substrate (NE and EX), but in EX there was an increased respiration with complex I + II substrate. EX altered regulatory proteins associated with increases in glucose disposal (decreased phosphorylation of glycogen synthase), glucose transport (increased phosphorylation of Akt substrate of 160 kDa), and FA oxidation (increased phosphorylation of acetyl-CoA carboxylase). In conclusion, exercise reversed starvation-induced insulin resistance and was accompanied by reduced glycogen stores, increased lipid oxidation capacity, and activation of signaling proteins involved in glucose transport and FA metabolism.
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| 3. |
- Henning, Petra, 1974, et al.
(författare)
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The effect of estrogen on bone requires ER alpha in nonhematopoietic cells but is enhanced by ER alpha in hematopoietic cells
- 2014
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 307:7
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Tidskriftsartikel (refereegranskat)abstract
- The effects of estrogen on bone are mediated mainly via estrogen receptor (ER)alpha. ER alpha in osteoclasts (hematopoietic origin) is involved in the trabecular bone-sparing effects of estrogen, but conflicting data are reported on the role of ER alpha in osteoblast lineage cells (nonhematopoietic origin) for bone metabolism. Because Cre-mediated cell-specific gene inactivation used in previous studies might be confounded by nonspecific and/or incomplete cell-specific ER alpha deletion, we herein used an alternative approach to determine the relative importance of ER alpha in hematopoietic (HC) and nonhematopoietic cells (NHC) for bone mass. Chimeric mice with selective inactivation of ER alpha in HC or NHC were created by bone marrow transplantations of wild-type (WT) and ER alpha-knockout (ER alpha(-/-)) mice. Estradiol treatment increased both trabecular and cortical bone mass in ovariectomized WT/WT (defined as recipient/donor) and WT/ER alpha(-/-) mice but not in ER alpha(-/-)/WT or ER alpha(-/-)/ER alpha(-/-) mice. However, estradiol effects on both bone compartments were reduced (similar to 50%) in WT/ER alpha(-/-) mice compared with WT/WT mice. The effects of estradiol on fat mass and B lymphopoiesis required ER alpha specifically in NHC and HC, respectively. In conclusion, ER alpha in NHC is required for the effects of estrogen on both trabecular and cortical bone, but these effects are enhanced by ER alpha in HC.
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| 4. |
- Johansson, Julia, 1982, et al.
(författare)
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Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome.
- 2010
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Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 299:4
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Tidskriftsartikel (refereegranskat)abstract
- Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20-25 min five times/wk for 4-5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity.
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| 5. |
- Kopietz, Franziska, et al.
(författare)
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AMPK activation by A-769662 and 991 does not affect catecholamine-induced lipolysis in human adipocytes
- 2018
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Ingår i: American Journal of Physiology - Endocrinology and Metabolism. - : American Physiological Society. - 1522-1555 .- 0193-1849. ; 315:5, s. 1075-1085
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Tidskriftsartikel (refereegranskat)abstract
- Activation of AMP-activated protein kinase (AMPK) is considered an attractive strategy for the treatment of type 2 diabetes. Favorable metabolic effects of AMPK activation are mainly observed in skeletal muscle and liver tissue whereas the effects in human adipose tissue are only poorly understood. Previous studies, which largely employed the AMPK activator 5-aminoimidazole-4-carboxamide-1-D-ribofuranoside (AICAR), suggest an anti-lipolytic role of AMPK in adipocytes. The aim of this work was to re-investigate the role of AMPK in the regulation of lipolysis, using the novel allosteric small-molecule AMPK activators A-769662 and 991, with a focus on human adipocytes. For this purpose, human primary subcutaneous adipocytes were treated with A-769662, 991 or AICAR, as a control, before being stimulated with isoproterenol. AMPK activity status, glycerol release and the phosphorylation of hormone-sensitive lipase (HSL), a key regulator of lipolysis, was then monitored. Our results show that both A-769662 and 991 activated AMPK to a level which was similar to, or greater than that induced by AICAR. In contrast to AICAR, which as expected was anti-lipolytic, neither A-769662 nor 991 affected lipolysis in human adipocytes, although 991 treatment lead to altered HSL phosphorylation. Furthermore, we suggest that HSL Ser660 is an important regulator of lipolytic activity in human adipocytes. These data suggest that the anti-lipolytic effect observed with AICAR in previous studies is, at least to some extent, AMPK-independent.
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| 6. |
- Börjesson, Anna E, et al.
(författare)
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SERMs have substance-specific effects on bone, and these effects are mediated via ER alpha AF-1 in female mice
- 2016
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 310:11
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Tidskriftsartikel (refereegranskat)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.
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| 7. |
- Börjesson, Anna E, et al.
(författare)
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The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice
- 2012
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 302:11
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Tidskriftsartikel (refereegranskat)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.
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| 8. |
- Svensson, Johan, 1964, et al.
(författare)
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Liver-derived IGF-I regulates cortical bone mass but is dispensable for the osteogenic response to mechanical loading in female mice
- 2016
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 311:1
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Tidskriftsartikel (refereegranskat)abstract
- Low circulating IGF-I is associated with increased fracture risk. Conditional depletion of IGF-I produced in osteoblasts or osteocytes inhibits the bone anabolic effect of mechanical loading. Here, we determined the role of endocrine IGF-I for the osteogenic response to mechanical loading in young adult and old female mice with adult, liver-specific IGF-I inactivation (LI-IGF-I-/- mice, serum IGF-I reduced by approximate to 70%) and control mice. The right tibia was subjected to short periods of axial cyclic compressive loading three times/wk for 2 wk, and measurements were performed using microcomputed tomography and mechanical testing by three-point bending. In the nonloaded left tibia, the LI-IGF-I-/- mice had lower cortical bone area and increased cortical porosity, resulting in reduced bone mechanical strength compared with the controls. Mechanical loading induced a similar response in LI-IGF-I-/- and control mice in terms of cortical bone area and trabecular bone volume fraction. In fact, mechanical loading produced a more marked increase in cortical bone mechanical strength, which was associated with a less marked increase in cortical porosity, in the LI-IGF-I-/- mice compared with the control mice. In conclusion, liver-derived IGF-I regulates cortical bone mass, cortical porosity, and mechanical strength under normal (nonloaded) conditions. However, despite an similar to 70% reduction in circulating IGF-I, the osteogenic response to mechanical loading was not attenuated in the LI-IGF-I-/- mice.
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| 9. |
- Trokovic, N., et al.
(författare)
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Exosomal secretion of death bullets: a new way of apoptotic escape?
- 2012
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 303:8
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Tidskriftsartikel (refereegranskat)abstract
- Trokovic N, Pollanen R, Porola P, Stegaev V, Hetzel U, Tivesten A, Engdahl C, Carlsten H, Forsblad-D'Elia H, Fagman JB, Lagerquist M, Konttinen YT. Exosomal secretion of death bullets: a new way of apoptotic escape? Am J Physiol Endocrinol Metab 303: E1015-E1024, 2012. First published August 12, 2012; doi: 10.1152/ajpendo.00139.2012.-Ovariectomy/estrogen deficiency causes selective apoptosis of the serous epithelial cells of the submandibular glands (SMG) in female mice. Because such apoptosis does not occur in healthy, estrogen-deficient male mice, it was hypothesized that dihydrotestosterone (DHT) protects epithelial SMG cells against apoptosis. The antiapoptotic effect of DHT on human epithelial HSG cells exposed to tumor necrosis factor-alpha and cycloheximide was studied. Correspondingly, the proapoptotic effect of androgen deficiency was studied in orchiectomized (ORX) androgen-knockout (ARKO) and wild-type (WT) mice. The health state of the SMG cells was studied with Alcian blue-periodic acid Schiff (AB-PAS) and amylase staining and transmission electron microscopy (TEM). The eventual protective antiapoptotic effect of dehydroepiandrosterone (DHEA) treatment was tested in this model. Apoptosis was assessed using immunohistochemisty of cleaved effector caspase-3 and its activator caspase-8 and the TUNEL assay. To test for the bioavailability, intracrine metabolism and sex steroid effects of DHEA, cystein-rich secretory protein-3 (CRISP-3), and leucine-isoleucine-valine transport system 1 (LIV-1) were used as androgen-and estrogen-regulated biomarkers, respectively. DHT protected HSG cells against induced apoptosis. In mice, androgen deficiency resulted in extensive activation of apoptotic caspase-8/3 cascade in serous epithelial cells. However, in salivary glands, active caspases were not translocated to nuclei but secreted to salivary ducts in exosome-like particles, which are associated with weak AB-PAS and amylase staining of the androgen-deprived cells and reduced number of intracellular secretory granules. DHEA treatment suppressed induction of proapoptotic caspases and almost normalized mucins and amylase and ultramophology of the serous epithelial cells in WT ORX but not ARKO ORX mice. According to the CRISP-3 and LIV-1 markers, DHEA probably exerted its effects via intracrine conversion to DHT.
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| 10. |
- Apró, William, et al.
(författare)
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Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle.
- 2013
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 305:1, s. E22-32
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Tidskriftsartikel (refereegranskat)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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