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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
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 func...
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Published in: | Diabetologia 2014-05, Vol.57 (5), p.1016-1026 |
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Main Authors: | , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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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ISSN: | 0012-186X 1432-0428 |
DOI: | 10.1007/s00125-014-3185-0 |