Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing

Shi, Sally Yu; Luk, Cynthia T.; Brunt, Jara J.; Sivasubramaniyam, Tharini; Lu, Shun-Yan; Schroer, Stephanie A.; Woo, Minna

doi:10.1007/s00125-014-3185-0

Cited by 55 publications

(59 citation statements)

References 45 publications

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“…Indeed, consistent with impaired BAT function, our previous work showed extensive adipose expansion and the development of progressive obesity in A-Jak2 KO mice even on a chow diet [25]. At 1 month of age, when there was no difference in body weight, A-Jak2 KO mice had decreased BAT Ucp1 mRNA abundance that was associated with lower whole-body energy expenditure (Fig.…”

Section: Resultssupporting

confidence: 78%

“…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: 50%

“…Impaired BAT function in A-Jak2 KO mice To test whether adipose JAK2 has an essential regulatory role in adaptive thermogenesis, we used mice with an adipocyte-specific Jak2 deficiency (A-Jak2 KO) that we had generated previously [25]. Given the pivotal role of β-adrenergic signalling in both diet-and cold-induced thermogenesis [11,12], we first tested the impact of Jak2 deficiency on the thermogenic response to adrenergic stimulation by monitoring the metabolic rate before and after injection of the selective β 3 -adrenergic agonist CL316,243.…”

Section: Resultsmentioning

confidence: 99%

“…Animal model A-Jak2 KO mice in which the Cre gene is driven by the adipocyte protein 2 (Ap2) promoter (Ap2Cre + Jak2 fl/fl ) were described previously [25]. Jak2 fl/fl mice (Jak2 tm1Kuw ) were kindly provided by K.-U.…”

Section: Methodsmentioning

confidence: 99%

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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: Resultssupporting

confidence: 78%

Section: Discussionsupporting

confidence: 50%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…The precise cascade of events whereby GH stimulates adipose tissue lipolysis is incompletely understood, and there is a lack of human in vivo studies examining these events. Administration of GH to normal subjects increases STAT-5b phosphorylation and SOCS3 mRNA in adipose tissue (10) and a recent study in JAK2 knockout mice reported impaired lipolysis (18). The biological function of the SOCS/CISH proteins is mainly to feedback inhibit the JAK/STAT signaling pathway (1).…”

Section: European Journal Of Endocrinologymentioning

confidence: 99%

GH signaling in human adipose and muscle tissue during ‘feast and famine’: amplification of exercise stimulation following fasting compared to glucose administration

Vendelbo

Christensen

Grønbæk

et al. 2015

European Journal of Endocrinology

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Objective: Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression. Design and methods: Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise. Results: GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days. Conclusions: This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.

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Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

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Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID‐19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

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Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing

Abstract: Our results suggest that adipocyte JAK2 plays a critical role in the regulation of adipocyte biology and whole-body metabolism. Targeting of the JAK-STAT pathway could be a novel therapeutic option for the treatment of obesity and type 2 diabetes.

Cited by 55 publications

References 45 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

GH signaling in human adipose and muscle tissue during ‘feast and famine’: amplification of exercise stimulation following fasting compared to glucose administration

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

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