Disruption of JAK2 in Adipocytes Impairs Lipolysis and Improves Fatty Liver in Mice With Elevated GH

Nordstrom, Sarah M.; Tran, Jennifer L.; Sos, Brandon C.; Wagner, Kay Uwe; Weiss, Ethan J.

doi:10.1210/me.2013-1110

Cited by 56 publications

(79 citation statements)

References 31 publications

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“…Of note, A-Jak2 KO mice were obese even when maintained at 20°C. This difference compared with Ucp1 −/− mice may be attributable to the suppression of lipolysis in white adipose tissue as a result of JAK2 deficiency, as we and others have previously shown [25,36]. In this work, we showed that JAK2 is required for full activation of the thermogenic response to a β 3 -adrenergic agonist, suggesting that JAK2 acts downstream of β-adrenergic signalling in adipocytes.…”

Section: Discussionsupporting

confidence: 49%

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

et al. 2015

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Aims/hypothesis Non-shivering thermogenesis in adipose tissue can be activated by excessive energy intake or following cold exposure. The molecular mechanisms regulating this activation have not been fully elucidated. The Janus kinase (JAK) -signal transducer and activator of transcription (STAT) pathway mediates the signal transduction of numerous hormones and growth factors that regulate adipose tissue development and function, and may play a role in adaptive thermogenesis. Methods We analysed mRNA and protein levels of uncoupling protein 1 (UCP1) and JAK2 in different adipose depots in response to metabolic and thermal stress. The in vivo role of JAK2 in adaptive thermogenesis was examined using mice with adipocyte-specific Jak2 deficiency (A-Jak2 KO). Results We show in murine brown adipose tissue (BAT) that JAK2 is upregulated together with UCP1 in response to highfat diet (HFD) feeding and cold exposure. In contrast to white adipose tissue, where JAK2 was dispensable for UCP1 induction, we identified an essential role for BAT JAK2 in diet-and cold-induced thermogenesis via mediating the thermogenic response to β-adrenergic stimulation. Accordingly, A-Jak2 KO mice were unable to upregulate BAT UCP1 following a HFD or after cold exposure. Therefore, A-Jak2 KO mice were cold intolerant and susceptible to HFD-induced obesity and diabetes. Conclusions/interpretation Taken together, our results suggest that JAK2 plays a critical role in BAT function and adaptive thermogenesis. Targeting the JAK-STAT pathway may be a novel therapeutic approach for the treatment of obesity and related metabolic disorders.

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Section: Discussionsupporting

confidence: 49%

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

et al. 2015

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“…Adipocytes were found to be smaller in the SIGFRKO mice and genes involved in lipid breakdown, including LPL and ATGL, were expressed at higher levels than those in control mice. This is consistent with mice, which bear an adipocyte-specific deletion of JAK2 leading to GH resistance; there is increased body fat and decreased lipolysis [20]. This mouse model, however, had no changes in energy intake or expenditure and inguinal adiposity predominated.…”

Section: Discussionsupporting

confidence: 83%

“…Several studies, which demonstrate GH stimulation of lipolysis as well as a decrease in fatty acid synthesis have been performed in both rodents and humans [6-12]. In addition, transgenic animal models in which GH production or action have been altered provide further insight into the complexity of metabolic targets for GH [13-20]. Therefore, a physiologic mechanism(s) by which GH can either limit fat deposition and/or reverse obesity still requires further investigation.…”

Section: Introductionmentioning

confidence: 99%

Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice

et al. 2016

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Several transgenic mouse models with disruption in the growth hormone (GH) axis support the role of GH in augmenting metabolic homeostasis. Specifically, interest has focused on GH's lipolytic properties and ability to affect adipose deposition. Furthermore, both GH and insulin growth factor 1 (IGF-1) may also play a direct or indirect role in adipose development. The somatotroph insulin-like growth factor-1 receptor knockout (SIGFRKO) mouse with only a modest increase in serum GH and IGF-1 demonstrates less adipose tissue than controls. In order to characterize the metabolic phenotype of SIGFRKO mice, histologic analysis of fat depots confirmed a smaller average diameter of adipocytes in the SIGFRKO mice compared to controls. These changes were accompanied by an increase in lipolytic gene expression in fat depots. Indirect calorimetry performed on 6-8 week old male mice and again at 25 weeks of age demonstrated that SIGFRKO mice, at both ages, had a higher VO 2 and increased energy expenditure when compared with controls. The calculated respiratory exchange ratio (RER) was lower in the younger SIGFRKO mice compared to controls. No differences in food consumption or in either ambulatory or total activity were seen between SIGFRKO and control mice in either age group. These studies highlight the role of GH in adipose deposition and its influence on the expression of lipolytic genes resulting in an altered metabolic state, thus providing a mechanism for the decrease in weight gain seen in the SIGFRKO mouse model.

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“…Liver-specific deletion of GHR in mice results in a marked decrease in serum IGF-1 levels, significant increases in fat mass and serum lipids, and severe hepatic steatosis associated with systemic insulin resistance (22). A similar metabolic phenotype is observed in mice with liver-specific disruption of the GHR mediators Janus kinase-2 (JAK2) (23) or STAT5 (24). GH treatment in mice reduced diet-induced hepatosteatosis (21,25), and overexpression of a GHR antagonist increased hepatic steatosis (26).…”

Section: Introductionmentioning

confidence: 59%

“…However, ablation of JAK2 both in liver and adipose tissue resulted in significant reductions in hepatic TG levels as compared with JAK2L mice (23), but was still ∼2.5-fold greater than controls. Ablation of CD36 in the JAK2L mice (DKO-JAK2/CD36) improved hepatic TG content (5) as compared with JAK2L, but was still ∼20-fold higher than control mice.…”

Section: Discussionmentioning

confidence: 90%

Growth Hormone Control of Hepatic Lipid Metabolism

et al. 2016

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In humans, low levels of growth hormone (GH) and its mediator, IGF-1, associate with hepatic lipid accumulation. In mice, congenital liver-specific ablation of the GH receptor (GHR) results in reductions in circulating IGF-1 and hepatic steatosis, associated with systemic insulin resistance. Due to the intricate relationship between GH and IGF-1, the relative contribution of each hormone to the development of hepatic steatosis is unclear. Our goal was to dissect the mechanisms by which hepatic GH resistance leads to steatosis and overall insulin resistance, independent of IGF-1. We have generated a combined mouse model with liver-specific ablation of GHR in which we restored liver IGF-1 expression via the hepatic IGF-1 transgene. We found that liver GHR ablation leads to increases in lipid uptake, de novo lipogenesis, hyperinsulinemia, and hyperglycemia accompanied with severe insulin resistance and increased body adiposity and serum lipids. Restoration of IGF-1 improved overall insulin sensitivity and lipid profile in serum and reduced body adiposity, but was insufficient to protect against steatosis-induced hepatic inflammation or oxidative stress. We conclude that the impaired metabolism in states of GH resistance results from direct actions of GH on lipid uptake and de novo lipogenesis, whereas its actions on extrahepatic tissues are mediated by IGF-1.

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Disruption of JAK2 in Adipocytes Impairs Lipolysis and Improves Fatty Liver in Mice With Elevated GH

Cited by 56 publications

References 31 publications

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice

Altered somatotroph feedback regulation improves metabolic efficiency and limits adipose deposition in male mice

Growth Hormone Control of Hepatic Lipid Metabolism

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