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Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice.

Abstract：

OBJECTIVE:Obesity is associated with increased activation of the c-Jun NH(2)-terminal kinase (JNK) in several metabolic organs, including adipose tissue, liver, and skeletal muscle. In this study, we aimed to define the role of JNK activation in adipose tissue in the development of obesity-related insulin resistance. RESEARCH DESIGN AND METHODS:Transgenic mice with adipose tissue-specific overexpression of dominant-negative JNK (ap2-dn-JNK) under the transcriptional control of the aP2 gene promoter were generated and subjected to metabolic characterization together with the wild-type littermates. RESULTS:On a high-fat diet (HFD), the ap2-dn-JNK mice displayed a marked suppression of both JNK1 and JNK2 activation in their adipose tissue, accompanied by a marked reduction in weight gain, fat mass, and size of the adipocytes. The transgenic mice were resistant to the deleterious impact of an HFD on systemic insulin sensitivity, glucose tolerance, and hepatic steatosis. Reduced hepatic gluconeogenesis was evident in in vivo and ex vivo studies and showed greater insulin-induced glucose uptake in skeletal muscles. These changes were accompanied by reduced macrophage infiltration in adipose tissue, decreased production of proinflammatory adipokines, and increased expression of adiponectin. Indirect calorimetry analysis showed that the transgenic mice had significant increases in oxygen consumption and reductions in respiration exchange rates compared with their wild-type littermates. CONCLUSIONS:Selective suppression of JNK activation in adipose tissue alone is sufficient to counteract HFD-induced obesity and its associated metabolic dysregulations, in part through an increase in energy expenditure and a decrease in systemic inflammation.

journal_name

Diabetes

journal_title

Diabetes

authors

Zhang X,Xu A,Chung SK,Cresser JH,Sweeney G,Wong RL,Lin A,Lam KS

doi

10.2337/db10-0650

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

486-95

issue

eissn

0012-1797

issn

1939-327X

pii

60/2/486

journal_volume

pub_type

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Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice.