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Nat Commun. 2015 Jan 12;6:6047. doi: 10.1038/ncomms7047.

A subcutaneous adipose tissue-liver signalling axis controls hepatic gluconeogenesis.

Author information

1
Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
2
Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA.
3
Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA.
4
Department of Internal Medicine, Metabolism, Endocrine and Diabetes Division, University of Michigan, Ann Arbor, Michigan 48109, USA.
5
1] Gene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, California 92037, USA [2] Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia.
6
Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.

Abstract

The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-ε and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-ε and TBK1 with amlexanox treatment increases cAMP levels in subcutaneous adipose depots of obese mice, promoting the synthesis and secretion of the cytokine IL-6 from adipocytes and preadipocytes, but not from macrophages. IL-6, in turn, stimulates the phosphorylation of hepatic Stat3 to suppress expression of genes involved in gluconeogenesis, in the process improving glucose handling in obese mice. Preliminary data in a small cohort of obese patients show a similar association. These data support an important role for a subcutaneous adipose tissue-liver axis in mediating the acute metabolic benefits of amlexanox on glucose metabolism, and point to a new therapeutic pathway for type 2 diabetes.

PMID:
25581158
PMCID:
PMC4324568
DOI:
10.1038/ncomms7047
[Indexed for MEDLINE]
Free PMC Article

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