nach oben

Erschienen in:

01.01.2016 | Article

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

verfasst von: Sally Yu Shi, Wei Zhang, Cynthia T. Luk, Tharini Sivasubramaniyam, Jara J. Brunt, Stephanie A. Schroer, Harsh R. Desai, Alexandra Majerski, Minna Woo

Erschienen in: Diabetologia | Ausgabe 1/2016

Einloggen, um Zugang zu erhalten

Abstract

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 high-fat 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.

Nur mit Berechtigung zugänglich

Spiegelman BM, Flier JS (2001) Obesity and the regulation of energy balance. Cell 104:531–543CrossRefPubMed

Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359CrossRefPubMed

Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19:1252–1263CrossRefPubMed

Golozoubova V, Cannon B, Nedergaard J (2006) UCP1 is essential for adaptive adrenergic nonshivering thermogenesis. Am J Physiol Endocrinol Metab 291:E350–E357CrossRefPubMed

Vitali A, Murano I, Zingaretti MC, Frontini A, Ricquier D, Cinti S (2012) The adipose organ of obesity-prone C57BL/6J mice is composed of mixed white and brown adipocytes. J Lipid Res 53:619–629PubMedCentralCrossRefPubMed

Cypess AM, Lehman S, Williams G et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360:1509–1517PubMedCentralCrossRefPubMed

Saito M, Okamatsu-Ogura Y, Matsushita M et al (2009) High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58:1526–1531PubMedCentralCrossRefPubMed

Virtanen KA, Lidell ME, Orava J et al (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360:1518–1525CrossRefPubMed

Rothwell NJ, Stock MJ (1979) A role for brown adipose tissue in diet-induced thermogenesis. Nature 281:31–35CrossRefPubMed

10.

Ouellet V, Labbe SM, Blondin DP et al (2012) Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 122:545–552PubMedCentralCrossRefPubMed

11.

Bachman ES, Dhillon H, Zhang CY et al (2002) betaAR signaling required for diet-induced thermogenesis and obesity resistance. Science 297:843–845CrossRefPubMed

12.

Young JB, Saville E, Rothwell NJ, Stock MJ, Landsberg L (1982) Effect of diet and cold exposure on norepinephrine turnover in brown adipose tissue of the rat. J Clin Invest 69:1061–1071PubMedCentralCrossRefPubMed

13.

O’Shea JJ, Gadina M, Schreiber RD (2002) Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109(Suppl):S121–S131CrossRefPubMed

14.

Derecka M, Gornicka A, Koralov SB et al (2012) Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity. Cell Metab 16:814–824PubMedCentralCrossRefPubMed

15.

Moisan A, Lee YK, Zhang JD et al (2015) White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol 17:57–67PubMedCentralCrossRefPubMed

16.

Nguyen KD, Qiu Y, Cui X et al (2011) Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480:104–108PubMedCentralCrossRefPubMed

17.

Hioki C, Yoshida T, Kogure A et al (2004) Effects of growth hormone (GH) on mRNA levels of uncoupling proteins 1, 2, and 3 in brown and white adipose tissues and skeletal muscle in obese mice. Horm Metab Res 36:607–613CrossRefPubMed

18.

Li Y, Knapp JR, Kopchick JJ (2003) Enlargement of interscapular brown adipose tissue in growth hormone antagonist transgenic and in growth hormone receptor gene-disrupted dwarf mice. Exp Biol Med (Maywood) 228:207–215

19.

Viengchareun S, Servel N, Feve B, Freemark M, Lombes M, Binart N (2008) Prolactin receptor signaling is essential for perinatal brown adipocyte function: a role for insulin-like growth factor-2. PLoS One 3:e1535PubMedCentralCrossRefPubMed

20.

Siegrist-Kaiser CA, Pauli V, Juge-Aubry CE et al (1997) Direct effects of leptin on brown and white adipose tissue. J Clin Invest 100:2858–2864PubMedCentralCrossRefPubMed

21.

Sarmiento U, Benson B, Kaufman S et al (1997) Morphologic and molecular changes induced by recombinant human leptin in the white and brown adipose tissues of C57BL/6 mice. Lab Invest 77:243–256PubMed

22.

Li G, Klein RL, Matheny M, King MA, Meyer EM, Scarpace PJ (2002) Induction of uncoupling protein 1 by central interleukin-6 gene delivery is dependent on sympathetic innervation of brown adipose tissue and underlies one mechanism of body weight reduction in rats. Neuroscience 115:879–889CrossRefPubMed

23.

Wernstedt I, Edgley A, Berndtsson A et al (2006) Reduced stress-and cold-induced increase in energy expenditure in interleukin-6-deficient mice. Am J Physiol Regul Integr Comp Physiol 291:R551–R557CrossRefPubMed

24.

Ott V, Fasshauer M, Dalski A, Klein HH, Klein J (2002) Direct effects of ciliary neurotrophic factor on brown adipocytes: evidence for a role in peripheral regulation of energy homeostasis. J Endocrinol 173:R1–R8CrossRefPubMed

25.

Shi SY, Luk CT, Brunt JJ et al (2014) Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing. Diabetologia 57:1016–1026CrossRefPubMed

26.

Krempler A, Qi Y, Triplett AA, Zhu J, Rui H, Wagner KU (2004) Generation of a conditional knockout allele for the Janus kinase 2 (Jak2) gene in mice. Genesis 40:52–57CrossRefPubMed

27.

Wagner KU, Krempler A, Triplett AA et al (2004) Impaired alveologenesis and maintenance of secretory mammary epithelial cells in Jak2 conditional knockout mice. Mol Cell Biol 24:5510–5520PubMedCentralCrossRefPubMed

28.

Shi SY, Garcia Martin R, Duncan RE et al (2012) Hepatocyte-specific deletion of Janus kinase 2 (JAK2) protects against diet-induced steatohepatitis and glucose intolerance. J Biol Chem 287:10277–10288PubMedCentralCrossRefPubMed

29.

Wang L, Opland D, Tsai S et al (2014) Pten deletion in RIP-Cre neurons protects against type 2 diabetes by activating the anti-inflammatory reflex. Nat Med 20:484–492CrossRefPubMed

30.

Choi D, Schroer SA, Lu SY et al (2010) Erythropoietin protects against diabetes through direct effects on pancreatic beta cells. J Exp Med 207:2831–2842PubMedCentralCrossRefPubMed

31.

Enerback S, Jacobsson A, Simpson EM et al (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387:90–94CrossRefPubMed

32.

Lowell BB, S-Susulic V, Hamann A et al (1993) Development of obesity in transgenic mice after genetic ablation of brown adipose tissue. Nature 366:740–742CrossRefPubMed

33.

Lee MW, Odegaard JI, Mukundan L et al (2015) Activated type 2 innate lymphoid cells regulate beige fat biogenesis. Cell 160:74–87CrossRefPubMed

34.

Morrison SF, Madden CJ, Tupone D (2012) Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne) 3: pii: 00005

35.

Feldmann HM, Golozoubova V, Cannon B, Nedergaard J (2009) UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 9:203–209CrossRefPubMed

36.

Nordstrom SM, Tran JL, Sos BC, Wagner KU, Weiss EJ (2013) Disruption of JAK2 in adipocytes impairs lipolysis and improves fatty liver in mice with elevated GH. Mol Endocrinol 27:1333–1342PubMedCentralCrossRefPubMed

37.

Collins S, Surwit RS (2001) The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis. Recent Prog Horm Res 56:309–328CrossRefPubMed

38.

Marrero MB, Schieffer B, Paxton WG et al (1995) Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375:247–250CrossRefPubMed

39.

Mellado M, Rodriguez-Frade JM, Aragay A et al (1998) The chemokine monocyte chemotactic protein 1 triggers Janus kinase 2 activation and tyrosine phosphorylation of the CCR2B receptor. J Immunol 161:805–813PubMed

40.

Vila-Coro AJ, Rodriguez-Frade JM, Martin De Ana A, Moreno-Ortiz MC, Martinez AC, Mellado M (1999) The chemokine SDF-1alpha triggers CXCR4 receptor dimerization and activates the JAK/STAT pathway. FASEB J 13:1699–1710PubMed

41.

Commins SP, Watson PM, Padgett MA, Dudley A, Argyropoulos G, Gettys TW (1999) Induction of uncoupling protein expression in brown and white adipose tissue by leptin. Endocrinology 140:292–300PubMed

42.

Turkson J, Bowman T, Garcia R, Caldenhoven E, De Groot RP, Jove R (1998) Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18:2545–2552PubMedCentralCrossRefPubMed

Titel: JAK2 promotes brown adipose tissue function and is required for diet- and cold-induced thermogenesis in mice
verfasst von: Sally Yu Shi
Wei Zhang
Cynthia T. Luk
Tharini Sivasubramaniyam
Jara J. Brunt
Stephanie A. Schroer
Harsh R. Desai
Alexandra Majerski
Minna Woo
Publikationsdatum: 01.01.2016
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 1/2016
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3786-2

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

^{Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag}

Kostenlos registrieren

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

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