Journal
NATURE COMMUNICATIONS
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms7047
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Funding
- US National Institutes of Health [DK60597, 60591, F32DK09685101, R24DK090962, DK98776]
- Leona M. and Harry B. Helmsley Charitable Trust
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK060591, R01DK060597, R01DK100319, P30DK063491, R24DK090962, R01DK061618, T32DK094775, F31DK103524, P30DK089503, R21DK098776] Funding Source: NIH RePORTER
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The search for effective treatments for obesity and its comorbidities is of prime importance. We previously identified IKK-epsilon and TBK1 as promising therapeutic targets for the treatment of obesity and associated insulin resistance. Here we show that acute inhibition of IKK-epsilon 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.
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