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Sökning: WFRF:(Wernstedt Asterholm Ingrid)

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  • Brännmark, Cecilia, et al. (författare)
  • Adiponectin is secreted via caveolin 1-dependent mechanisms in white adipocytes
  • 2020
  • Ingår i: Journal of Endocrinology. - : BIOSCIENTIFICA LTD. - 0022-0795 .- 1479-6805. ; 247:1, s. 25-38
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we have investigated the role of the protein caveolin 1 (Cav1) and caveolae in the secretion of the white adipocyte hormone adiponectin. Using mouse primary subcutaneous adipocytes genetically depleted of Cav1, we show that the adiponectin secretion, stimulated either adrenergically or by insulin, is abrogated while basal (unstimulated) release of adiponectin is elevated. Adiponectin secretion is similarly affected in wildtype mouse and human adipocytes where the caveolae structure was chemically disrupted. The altered ex vivo secretion in adipocytes isolated from Cav1 null mice is accompanied by lowered serum levels of the high-molecular weight (HMW) form of adiponectin, whereas the total concentration of adiponectin is unaltered. Interestingly, levels of HMW adiponectin are maintained in adipose tissue from Cav1-depleted mice, signifying that a secretory defect is present. The gene expression of key regulatory proteins known to be involved in cAMP/adrenergically triggered adiponectin exocytosis (the beta-3-adrenergic receptor and exchange protein directly activated by cAMP) remains intact in Cav1 null adipocytes. Microscopy and fractionation studies indicate that adiponectin vesicles do not co-localise with Cav1 but that some vesicles are associated with a specific fraction of caveolae. Our studies propose that Cav1 has an important role in secretion of HMW adiponectin, even though adiponectin-containing vesicles are not obviously associated with this protein. We suggest that Cav1, and/or the caveolae domain, is essential for the organisation of signalling pathways involved in the regulation of HMW adiponectin exocytosis, a function that is disrupted in Cav1/caveolae-depleted adipocytes.
  • Vergari, Elisa, et al. (författare)
  • Insulin inhibits glucagon release by SGLT2-induced stimulation of somatostatin secretion
  • 2019
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 10:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoglycaemia (low plasma glucose) is a serious and potentially fatal complication of insulin-treated diabetes. In healthy individuals, hypoglycaemia triggers glucagon secretion, which restores normal plasma glucose levels by stimulation of hepatic glucose production. This counterregulatory mechanism is impaired in diabetes. Here we show in mice that therapeutic concentrations of insulin inhibit glucagon secretion by an indirect (paracrine) mechanism mediated by stimulation of intra-islet somatostatin release. Insulin's capacity to inhibit glucagon secretion is lost following genetic ablation of insulin receptors in the somatostatin-secreting δ-cells, when insulin-induced somatostatin secretion is suppressed by dapagliflozin (an inhibitor of sodium-glucose co-tranporter-2; SGLT2) or when the action of secreted somatostatin is prevented by somatostatin receptor (SSTR) antagonists. Administration of these compounds in vivo antagonises insulin's hypoglycaemic effect. We extend these data to isolated human islets. We propose that SSTR or SGLT2 antagonists should be considered as adjuncts to insulin in diabetes therapy.
  • Benrick, Anna, 1979, et al. (författare)
  • Adiponectin protects against development of metabolic disturbances in a PCOS mouse model
  • 2017
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 114:34, s. E7187-E7196
  • Tidskriftsartikel (refereegranskat)abstract
    • Adiponectin, together with adipocyte size, is the strongest factor associated with insulin resistance in women with polycystic ovary syndrome (PCOS). This study investigates the causal relationship between adiponectin levels and metabolic and reproductive functions in PCOS. Prepubertal mice overexpressing adiponectin from adipose tissue (APNtg), adiponectin knockouts (APNko), and their wild-type (WT) littermate mice were continuously exposed to placebo or dihydrotestosterone (DHT) to induce PCOS-like traits. As expected, DHT exposure led to reproductive dysfunction, as judged by continuous anestrus, smaller ovaries with a decreased number of corpus luteum, and an increased number of cystic/atretic follicles. A two-way between-groups analysis showed that there was a significant main effect for DHT exposure, but not for genotype, indicating adiponectin does not influence follicle development. Adiponectin had, however, some protective effects on ovarian function. Similar to in many women with PCOS, DHT exposure led to reduced adiponectin levels, larger adipocyte size, and reduced insulin sensitivity in WTs. APNtg mice remained metabolically healthy despite DHT exposure, while APNko-DHT mice were even more insulin resistant than their DHT-exposed littermate WTs. DHT exposure also reduced the mRNA expression of genes involved in metabolic pathways in gonadal adipose tissue of WT and APNko, but this effect of DHT was not observed in APNtg mice. Moreover, APNtg-DHT mice displayed increased pancreatic mRNA levels of insulin receptors, Pdx1 and Igf1R, suggesting adiponectin stimulates beta cell viability/hyperplasia in the context of PCOS. In conclusion, adiponectin improves metabolic health but has only minor effects on reproductive functions in this PCOS-like mouse model.
  • Mishra, Devesh, et al. (författare)
  • Parabrachial Interleukin-6 Reduces Body Weight and Food Intake and Increases Thermogenesis to Regulate Energy Metabolism
  • 2019
  • Ingår i: Cell Reports. - 2211-1247. ; 26:11, s. 3011-
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic low-grade inflammation and increased serum levels of the cytokine IL-6 accompany obesity. For brain-produced IL-6, the mechanisms by which it controls energy balance and its role in obesity remain unclear. Here, we show that brain-produced IL-6 is decreased in obese mice and rats in a neuro-anatomically and sex-specific manner. Reduced IL-6 mRNA localized to lateral parabrachial nucleus (IPBN) astrocytes, microglia, and neurons, including paraventricular hypothalamus-innervating IPBN neurons. IL-6 microinjection into IPBN reduced food intake and increased brown adipose tissue (BAT) thermogenesis in male lean and obese rats by increasing thyroid and sympathetic outflow to BAT. Parabrachial IL-6 interacted with leptin to reduce feeding. siRNA-mediated reduction of IPBN IL-6 leads to increased weight gain and adiposity, reduced BAT thermogenesis, and increased food intake. Ambient cold exposure partly normalizes the obesity-induced suppression of IPBN IL-6. These results indicate that IPBN-produced IL-6 regulates feeding and metabolism and pinpoints (patho)physiological contexts interacting with IPBN IL-6.
  • Wu, Yanling, 1985, et al. (författare)
  • Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice
  • 2021
  • Ingår i: FASEB Journal. - : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 35:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Hyperandrogenism is the main characteristic of polycystic ovary syndrome, which affects placental function and fetal growth, and leads to reproductive and metabolic dysfunction in female offspring. Adiponectin acts on the placenta and may exert endocrine effects on the developing fetus. This study aims to investigate if maternal and/or fetal adiponectin can prevent metabolic and reproductive dysfunction in prenatal androgenized (PNA) female offspring. Adiponectin transgenic (APNtg) and wild-type dams received dihydrotestosterone/vehicle injections between gestational days 16.5-18.5 to induce PNA offspring, which were followed for 4 months. Offspring from APNtg dams were smaller than offspring from wild-type dams, independent of genotype. Insulin sensitivity was higher in wild-type mice from APNtg dams compared to wild-types from wild-type dams, and insulin sensitivity correlated with fat mass and adipocyte size. PNA increased visceral fat% and adipocyte size in wild-type offspring from wild-type dams, while wild-type and APNtg offspring from APNtg dams were protected against this effect. APNtg mice had smaller adipocytes than wild-types and this morphology was associated with an increased expression of genes regulating adipogenesis (Ppard, Pparg, Cebpa, and Cebpb) and metabolism (Chrebp and Lpl). Anogenital distance was increased in all PNA-exposed wild-type offspring, but there was no increase in PNA APNtg offspring, suggesting that adiponectin overexpression protects against this effect. In conclusion, elevated adiponectin levels in utero improve insulin sensitivity, reduce body weight and fat mass gain in the adult offspring and protect against PNA-induced visceral adiposity. In conclusion, these data suggest that PNA offspring benefit from prenatal adiponectin supplementation.
  • An, Y. A., et al. (författare)
  • Dysregulation of amyloid precursor protein impairs adipose tissue mitochondrial function and promotes obesity
  • 2019
  • Ingår i: Nature Metabolism. ; 1:12, s. 1243-57
  • Tidskriftsartikel (refereegranskat)abstract
    • Mitochondrial function in white adipose tissue (WAT) is an important yet understudied aspect of adipocyte biology. Here, we report a role for amyloid precursor protein (APP) in compromising WAT mitochondrial function through a high-fat diet (HFD)-induced, unconventional mis-localization to mitochondria that further promotes obesity. In humans and mice, obese conditions induce substantial APP production in WAT and APP enrichment in mitochondria. Mechanistically, HFD-induced dysregulation of signal recognition particle subunit 54c is responsible for the mis-targeting of APP to adipocyte mitochondria. Mis-localized APP blocks the protein import machinery, leading to mitochondrial dysfunction in WAT. Mice overexpressing adipocyte-specific and mitochondria-targeted APP display increased body mass and reduced insulin sensitivity, along with dysfunctional WAT, owing to a dramatic hypertrophic program in adipocytes. Elimination of adipocyte APP rescues HFD-impaired mitochondrial function with considerable protection from weight gain and systemic metabolic deficiency. Our data highlight an important role for APP in modulating WAT mitochondrial function and obesity-associated metabolic dysfunction.
  • Anderberg, Rozita H, et al. (författare)
  • Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight
  • 2017
  • Ingår i: Diabetes. - 0012-1797. ; 66:4, s. 1062-1073
  • Tidskriftsartikel (refereegranskat)abstract
    • Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT2A) and 5-HT2C serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT2A, but surprisingly not the 5-HT2C, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT2A receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.
  • Benrick, Anna, 1979, et al. (författare)
  • Elevated interlukin-6 levels as a consequence, not the cause of obesity and insulin resistance
  • 2013
  • Ingår i: Interleukin-6: Genetics, Clinical Applications and Role in Disease. - : Nova Science Publishers, Inc.. - 9781624175923 ; , s. 197-210
  • Bokkapitel (refereegranskat)abstract
    • Several population-based studies have reported that serum interleukin-6 (IL-6) levels are positively correlated with obesity and insulin resistance. This has lead to the hypothesis of a causal relationship between elevated IL-6 levels and insulin resistance. This notion is further strengthened by the observation that obesity is associated with a chronic low-grade inflammation in adipose tissue, which is postulated to be causal in the development of insulin resistance and type-2 diabetes. A recent study of weight gain demonstrates however that insulin resistance develops even in the absence of a significant signs of adipose inflammation. This suggests that inflammation in adipose tissue occurs subsequent to peripheral insulin resistance in humans. More and more data also supports the hypothesis that increased adiposity in itself, independent of the increased IL-6 levels, is a predictor of diabetes risk. IL-6 levels tend to also increase with age and since the incidence of insulin resistance and type-2 diabetes also increases with age, this could explain some of the observed correlations. Taken together, the above studies provide an association of metabolic disorder with IL-6, but not causation. An emerging concept is that IL-6 appears to have different effects on different tissues, and the effects depend on whether the IL-6 levels are acutely or chronically elevated. Given the opposing views of the impact of IL-6 on glucose homeostasis, many investigations have aimed at clarifying the effects of IL-6 on insulin action. A recent study shows that IL-6, either released from skeletal muscle or adipose tissue, induces GLP-1 release, leading to insulin secretion, improved beta-cell function and glycemic control. Still, the causal relationships between IL-6, obesity and type-2 diabetes remain a matter of debate. This review summarizes the current data on IL-6, supporting an association, but not a causative relationship, between IL-6 and metabolic disturbances. © 2013 Nova Science Publishers, Inc. All rights reserved.
  • Benrick, Anna, 1979, et al. (författare)
  • Interleukin-6 gene knockout influences energy balance regulating peptides in the hypothalamic paraventricular and supraoptic nuclei.
  • 2009
  • Ingår i: Journal of neuroendocrinology. - 1365-2826. ; 21:7, s. 620-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Interleukin (IL)-6 is a pro-inflammatory cytokine that also affects metabolic function because IL-6 depleted (IL-6(-/-)) mice develop late-onset obesity. IL-6 appears to act in the central nervous system, presumably in the hypothalamus, to increase energy expenditure that appears to involve stimulation of the sympathetic nervous system. In the present study, we explored possible central mechanisms for the effects exerted by IL-6 on body fat. Therefore, we measured the effects of IL-6 depletion in IL-6(-/-) mice on expression of key hypothalamic peptide genes involved in energy balance by the real time polymerase chain reaction. Additionally, co-localisation between such peptides and IL-6 receptor alpha was investigated by immunohistochemistry. IL-6 deficiency decreased the expression of several peptides found in the paraventricular nucleus (PVN), which is a nucleus that has been attributed an adipostatic function. For example, corticotrophin-releasing hormone (CRH), which is reported to stimulate the sympathetic nervous system, was decreased by 40% in older IL-6(-/-) mice. Oxytocin, which is reported to prevent obesity, was also decreased in older IL-6(-/-) animals, as was arginine vasopressin (AVP). The IL-6 receptor alpha was abundantly expressed in the PVN, but also in the supraoptic nucleus, and was shown to be co-expressed to a high extent with CRH, AVP, oxytocin and thyrotrophin-releasing hormone. These data indicate that depletion of endogenous IL-6, a body fat suppressing cytokine, is associated with the decreased expression of CRH and oxytocin (i.e. energy balance regulating peptides) as well as AVP in the PVN. Because IL-6 receptor alpha is co-expressed with CRH, oxytocin and AVP, IL-6 could stimulate the expression of these peptides directly.
  • Benrick, Anna, 1979, et al. (författare)
  • Interleukin-6 mediates exercise-induced increase in insulin sensitivity in mice.
  • 2012
  • Ingår i: Experimental physiology. - 1469-445X. ; 97:11 SI, s. 1224-1235
  • Tidskriftsartikel (refereegranskat)abstract
    • Interleukin-6 (IL-6) is released from working skeletal muscle during exercise. We investigated the acute and the long-term beneficial effects of IL-6 on exercise-induced glucose uptake in skeletal muscle and insulin sensitivity. The acute effect on exercise-induced glucose uptake was measured in IL-6 deficient (-/-) mice and wild type controls using a tracer technique. There was no difference in serum disappearance of 3H-2-deoxyglucose after a bolus dose of exercise between IL-6 -/- and wild type mice (13565 ± 426 vs. 14343 ± 1309 dpm*min/ml, p=0.5). The glucose uptake rate in the EDL muscle was however lower in IL-6 -/- compared to wildtype mice (398 ± 44 vs. 657 ± 41 nmol/g/min, p<0.01). In the long-term study, we monitored insulin sensitivity, serum retinol-binding protein-4 (RBP-4) levels, running activity, food intake, body weight and body composition in IL-6 -/- and wild type mice on a high-fat diet (HFD), with or without access to running wheels. In sedentary IL-6 -/- and wild type mice, HFD decreased insulin sensitivity (glucose AUC increased about 20% during an insulin tolerance test (ITT), p<0.05 for both genotypes vs. baseline) and led to a 30% increase in serum RBP-4 levels (p <0.01 for both genotypes vs. baseline). Wild type runners were protected against these effects of HFD and maintained their baseline insulin sensitivity and serum RBP-4 levels. In contrast, IL-6 -/- mice did not, to the same extent as wild types, benefit from running. IL-6 -/- runners had a similar decrease in insulin sensitivity as their sedentary littermates (glucose AUC during an ITT in runners vs. sedentary IL-6-/- HFD mice: 312 ± 14 vs. 340 ± 22 mmol*min/L, p=0.4) and displayed a 14% increase in serum RBP-4 as compared to baseline levels (p<0.01). Our results indicate that endogenous IL-6 contributes to the exercise-induced increase in insulin sensitivity, but only plays a minor role for glucose uptake into skeletal muscle during exercise.
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