nach oben

Erschienen in:

01.05.2014 | Article

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

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

Erschienen in: Diabetologia | Ausgabe 5/2014

Einloggen, um Zugang zu erhalten

Abstract

Aims/hypothesis

The growing obesity epidemic necessitates a better understanding of adipocyte biology and its role in metabolism. The Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway mediates signalling by numerous cytokines and hormones that regulate adipocyte function, illustrating the physiological importance of adipose JAK–STAT. The aim of this study was to investigate potential roles of adipocyte JAK2, an essential player in the JAK–STAT pathway, in adipocyte biology and metabolism.

Methods

We generated adipocyte-specific Jak2 knockout (A-Jak2 KO) mice using the Cre-loxP system with Cre expression driven by the Ap2 (also known as Fabp4) promoter.

Results

Starting at 2–3 months of age, male and female A-Jak2 KO mice gradually gained more body weight than control littermates primarily due to increased adiposity. This was associated with reduced energy expenditure in A-Jak2 KO mice. In perigonadal adipose tissue, the expression of numerous genes involved in lipid metabolism was differentially regulated. In addition, adipose tissue from A-Jak2 KO mice displayed impaired lipolysis in response to isoprenaline, growth hormone and leptin stimulation, suggesting that adipose JAK2 directly modulates the lipolytic program. Impaired lipid homeostasis was also associated with disrupted adipokine secretion. Accordingly, while glucose metabolism was normal at 2 months of age, by 5–6 months of age, A-Jak2 KO mice had whole-body insulin resistance.

Conclusions/interpretation

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.

Nur mit Berechtigung zugänglich

Sun K, Kusminski CM, Scherer PE (2011) Adipose tissue remodeling and obesity. J Clin Invest 121:2094–2101PubMedCentralPubMedCrossRef

Guilherme A, Virbasius JV, Puri V, Czech MP (2008) Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat Rev Mol Cell Biol 9:367–377PubMedCentralPubMedCrossRef

Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481PubMedCentralPubMedCrossRef

Swinburn BA, Sacks G, Hall KD et al (2011) The global obesity pandemic: shaped by global drivers and local environments. Lancet 378:804–814PubMedCrossRef

Richard AJ, Stephens JM (2011) Emerging roles of JAK–STAT signaling pathways in adipocytes. Trends Endocrinol Metab 22:325–332PubMedCentralPubMedCrossRef

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 287:10277–10288PubMedCentralPubMedCrossRef

Sos BC, Harris C, Nordstrom SM et al (2011) Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte-specific deletion of JAK2. J Clin Invest 121:1412–1423PubMedCentralPubMedCrossRef

Stewart WC, Morrison RF, Young SL, Stephens JM (1999) Regulation of signal transducers and activators of transcription (STATs) by effectors of adipogenesis: coordinate regulation of STATs 1, 5A, and 5B with peroxisome proliferator-activated receptor-gamma and C/AAAT enhancer binding protein-alpha. Biochim Biophys Acta 1452:188–196PubMedCrossRef

Hellgren G, Albertsson-Wikland K, Billig H, Carlsson LM, Carlsson B (2001) Growth hormone receptor interaction with Jak proteins differs between tissues. J Interferon Cytokine Res 21:75–83PubMedCrossRef

10.

Gomez-Ambrosi J, Catalan V, Diez-Caballero A et al (2004) Gene expression profile of omental adipose tissue in human obesity. FASEB J 18:215–217PubMed

11.

Zhang K, Guo W, Yang Y, Wu J (2011) JAK2/STAT3 pathway is involved in the early stage of adipogenesis through regulating C/EBPbeta transcription. J Cell Biochem 112:488–497PubMedCrossRef

12.

Yarwood SJ, Sale EM, Sale GJ, Houslay MD, Kilgour E, Anderson NG (1999) Growth hormone-dependent differentiation of 3T3-F442A preadipocytes requires Janus kinase/signal transducer and activator of transcription but not mitogen-activated protein kinase or p70 S6 kinase signaling. J Biol Chem 274:8662–8668PubMedCrossRef

13.

Floyd ZE, Stephens JM (2003) STAT5A promotes adipogenesis in nonprecursor cells and associates with the glucocorticoid receptor during adipocyte differentiation. Diabetes 52:308–314PubMedCrossRef

14.

Shang CA, Waters MJ (2003) Constitutively active signal transducer and activator of transcription 5 can replace the requirement for growth hormone in adipogenesis of 3T3-F442A preadipocytes. Mol Endocrinol 17:2494–2508PubMedCrossRef

15.

Nanbu-Wakao R, Morikawa Y, Matsumura I et al (2002) Stimulation of 3T3-L1 adipogenesis by signal transducer and activator of transcription 5. Mol Endocrinol 16:1565–1576PubMedCrossRef

16.

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

17.

Trujillo ME, Sullivan S, Harten I, Schneider SH, Greenberg AS, Fried SK (2004) Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro. J Clin Endocrinol Metab 89:5577–5582PubMedCrossRef

18.

van Hall G, Steensberg A, Sacchetti M et al (2003) Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 88:3005–3010PubMedCrossRef

19.

Memon RA, Feingold KR, Moser AH, Doerrler W, Grunfeld C (1992) In vivo effects of interferon-alpha and interferon-gamma on lipolysis and ketogenesis. Endocrinology 131:1695–1702PubMed

20.

Goodman HM (1968) Multiple effects of growth hormone on lipolysis. Endocrinology 83:300–308PubMedCrossRef

21.

Fielder PJ, Talamantes F (1987) The lipolytic effects of mouse placental lactogen II, mouse prolactin, and mouse growth hormone on adipose tissue from virgin and pregnant mice. Endocrinology 121:493–497PubMedCrossRef

22.

Buettner C, Muse ED, Cheng A et al (2008) Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 14:667–675PubMedCentralPubMedCrossRef

23.

Zvonic S, Cornelius P, Stewart WC, Mynatt RL, Stephens JM (2003) The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. J Biol Chem 278:2228–2235PubMedCrossRef

24.

Hogan JC, Stephens JM (2005) Effects of leukemia inhibitory factor on 3T3-L1 adipocytes. J Endocrinol 185:485–496PubMedCrossRef

25.

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–R8PubMedCrossRef

26.

Song HY, Kim MR, Lee MJ et al (2007) Oncostatin M decreases adiponectin expression and induces dedifferentiation of adipocytes by JAK3- and MEK-dependent pathways. Int J Biochem Cell Biol 39:439–449PubMedCrossRef

27.

Thompson BR, Mazurkiewicz-Munoz AM, Suttles J, Carter-Su C, Bernlohr DA (2009) Interaction of adipocyte fatty acid-binding protein (AFABP) and JAK2: AFABP/aP2 as a regulator of JAK2 signaling. J Biol Chem 284:13473–13480PubMedCentralPubMedCrossRef

28.

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 27:1333–1342PubMedCrossRef

29.

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 40:52–57PubMedCrossRef

30.

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 24:5510–5520PubMedCentralPubMedCrossRef

31.

Lemonnier D (1972) Effect of age, sex, and sites on the cellularity of the adipose tissue in mice and rats rendered obese by a high-fat diet. J Clin Invest 51:2907–2915PubMedCentralPubMedCrossRef

32.

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

33.

Bluher M, Michael MD, Peroni OD et al (2002) Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance. Dev Cell 3:25–38PubMedCrossRef

34.

He W, Barak Y, Hevener A et al (2003) Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A 100:15712–15717PubMedCentralPubMedCrossRef

35.

Urs S, Harrington A, Liaw L, Small D (2006) Selective expression of an aP2/fatty acid binding protein 4-Cre transgene in non-adipogenic tissues during embryonic development. Transgenic Res 15:647–653PubMedCrossRef

36.

List EO, Berryman DE, Funk K et al (2013) The role of GH in adipose tissue: lessons from adipose-specific GH receptor gene-disrupted mice. Mol Endocrinol 27:524–535PubMedCentralPubMedCrossRef

37.

Cernkovich ER, Deng J, Bond MC, Combs TP, Harp JB (2008) Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity. Endocrinology 149:1581–1590PubMedCentralPubMedCrossRef

38.

Huan JN, Li J, Han Y, Chen K, Wu N, Zhao AZ (2003) Adipocyte-selective reduction of the leptin receptors induced by antisense RNA leads to increased adiposity, dyslipidemia, and insulin resistance. J Biol Chem 278:45638–45650PubMedCrossRef

39.

List EO, Palmer AJ, Berryman DE, Bower B, Kelder B, Kopchick JJ (2009) Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes. Diabetologia 52:1647–1655PubMedCrossRef

40.

Stewart WC, Pearcy LA, Floyd ZE, Stephens JM (2011) STAT5A expression in Swiss 3T3 cells promotes adipogenesis in vivo in an athymic mice model system. Obesity (Silver Spring) 19:1731–1734CrossRef

41.

Teglund S, McKay C, Schuetz E et al (1998) Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841–850PubMedCrossRef

42.

Hunt CR, Ro JH, Dobson DE, Min HY, Spiegelman BM (1986) Adipocyte P2 gene: developmental expression and homology of 5'-flanking sequences among fat cell-specific genes. Proc Natl Acad Sci U S A 83:3786–3790PubMedCentralPubMedCrossRef

43.

Fain JN, Ihle JH, Bahouth SW (1999) Stimulation of lipolysis but not of leptin release by growth hormone is abolished in adipose tissue from Stat5a and b knockout mice. Biochem Biophys Res Commun 263:201–205PubMedCrossRef

44.

Girard J, Perdereau D, Foufelle F, Prip-Buus C, Ferre P (1994) Regulation of lipogenic enzyme gene expression by nutrients and hormones. FASEB J 8:36–42PubMed

45.

Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806PubMedCrossRef

Titel: Adipocyte-specific deficiency of Janus kinase (JAK) 2 in mice impairs lipolysis and increases body weight, and leads to insulin resistance with ageing
verfasst von: Sally Yu Shi
Cynthia T. Luk
Jara J. Brunt
Tharini Sivasubramaniyam
Shun-Yan Lu
Stephanie A. Schroer
Minna Woo
Publikationsdatum: 01.05.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 5/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3185-0

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

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

Kostenlos registrieren

Neu im Fachgebiet Innere Medizin

Echinokokkose medikamentös behandeln oder operieren?

06.05.2024 DCK 2024 Kongressbericht

Die Therapie von Echinokokkosen sollte immer in spezialisierten Zentren erfolgen. Eine symptomlose Echinokokkose kann – egal ob von Hunde- oder Fuchsbandwurm ausgelöst – konservativ erfolgen. Wenn eine Op. nötig ist, kann es sinnvoll sein, vorher Zysten zu leeren und zu desinfizieren.

Umsetzung der POMGAT-Leitlinie läuft

03.05.2024 DCK 2024 Kongressbericht

Seit November 2023 gibt es evidenzbasierte Empfehlungen zum perioperativen Management bei gastrointestinalen Tumoren (POMGAT) auf S3-Niveau. Vieles wird schon entsprechend der Empfehlungen durchgeführt. Wo es im Alltag noch hapert, zeigt eine Umfrage in einem Klinikverbund.

Proximale Humerusfraktur: Auch 100-Jährige operieren?

01.05.2024 DCK 2024 Kongressbericht

Mit dem demographischen Wandel versorgt auch die Chirurgie immer mehr betagte Menschen. Von Entwicklungen wie Fast-Track können auch ältere Menschen profitieren und bei proximaler Humerusfraktur können selbst manche 100-Jährige noch sicher operiert werden.

Die „Zehn Gebote“ des Endokarditis-Managements

30.04.2024 Endokarditis Leitlinie kompakt

Worauf kommt es beim Management von Personen mit infektiöser Endokarditis an? Eine Kardiologin und ein Kardiologe fassen die zehn wichtigsten Punkte der neuen ESC-Leitlinie zusammen.

Update Innere Medizin

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

Newsletter bestellen

Springer Medizin

Abstract

Aims/hypothesis

Methods

Results

Conclusions/interpretation

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2014

Striatal dopamine receptor binding in morbidly obese women before and after gastric bypass surgery and its relationship with insulin sensitivity

The effects of ezetimibe on non-alcoholic fatty liver disease and glucose metabolism: a randomised controlled trial

In vivo activation of the PI3K–Akt pathway in mouse beta cells by the EGFR mutation L858R protects against diabetes

A PGC-1α- and muscle fibre type-related decrease in markers of mitochondrial oxidative metabolism in skeletal muscle of humans with inherited insulin resistance

Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes