期刊
DIABETOLOGIA
卷 57, 期 5, 页码 1016-1026出版社
SPRINGER
DOI: 10.1007/s00125-014-3185-0
关键词
Adipocyte; Glucose homeostasis; JAK2; Janus; kinase 2; Metabolism; Obesity
资金
- Canadian Institute of Health Research [MOP-81148, MOP-93707]
- Canadian Diabetes Association
- Canada Research Chair in Signal Transduction in Diabetes Pathogenesis
- Canadian Institutes of Health Research Doctoral Research Award
- Canadian Diabetes Association Doctoral Student Research Award
- Canadian Liver Foundation
- Eliot Phillipson Clinician Scientist Training Program
- Banting and Best Diabetes Centre Post-doctoral Fellowship
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.
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