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

Shannon M Reilly, Maryam Ahmadian, Brian F Zamarron, Louise Chang, Maeran Uhm, BreAnne Poirier, Xiaoling Peng, Danielle M Krause, Evgenia Korytnaya, Adam Neidert, Christopher Liddle, Ruth T Yu, Carey N Lumeng, Elif A Oral, Michael Downes, Ronald M Evans, Alan R Saltiel

Index: Nat. Commun. 6 , 6047, (2015)

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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.