FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition

Abstract

The protein kinases IKKe and TBK1 are activated in liver and fat in mouse models of obesity.We have previously demonstrated that treatment with the IKKe/TBK1 inhibitor, amlexanox, produces weight loss and relieves insulin resistance in obese animals and patients. While amlexanox treatment caused a transient reduction in food intake, long-term weight loss was attributable to increased energy expenditure via FGF21-dependent beiging of WAT. Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, while hepatic secretion determined circulating levels, it was dispensable for regulating energy expenditure. In contrast, adipocyte-secreted FGF21 may have acted as an autocrine factor that leads to adipose tissue browning and weight loss in obese mice. Moreover, increased energy expenditure was an important determinant of improved insulin sensitivity by amlexanox. Conversely, the immediate reductions in fasting blood glucose observed with acute amlexanox treatment were mediated by suppression of hepatic glucose production via the activation of STAT3 by adipocyte-secreted IL-6. These findings demonstrate that amlexanox improved metabolic health via FGF21 action in adipocytes to increase energy expenditure via WAT beiging, and an endocrine role of adipocytederived IL-6 to decrease gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.

Adipocyte-secreted IL-6 sensitizes macrophages to IL-4 signaling

“…Indeed, there are likely multiple pathways by which amlexanox affects adipose tissue inflammation of obese animals. Amlexanox-induced weight loss is a likely contributor to reduced adipose tissue inflammation with long-term amlexanox treatment [2,5].…”

“…Indeed, there are likely multiple pathways by which amlexanox affects adipose tissue inflammation of obese animals. Amlexanox-induced weight loss is a likely contributor to reduced adipose tissue inflammation with long-term amlexanox treatment [2, 5]. Interestingly, cAMP-driven adipocyte FGF21 secretion promotes adipose tissue beiging and contributes to amlexanox induced weight loss [5, 21].…”

“…Treatment of obese mice with amlexanox, a dual specific inhibitor of IKKε and TBK1, results in improved metabolic health via weight loss and resolution of adipose tissue inflammation [2]. By restoring cAMP signaling in adipocytes, amlexanox promotes the expression of IL-6 [5]. Adipocyte-secreted IL-6 activates hepatic STAT3 to suppress the expression of G6pc and gluconeogenesis [6].…”

Exercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness

“…The study demonstrated that exercise induced an increase in plasma FGF21. In another study, the increase of FGF21 can mediate the browning of WAT to increase energy consumption [ 11 ]. FGF21 is secreted mainly by the liver, which regulates the circulating levels of FGF21.…”

“…This indicates that IL-6 is very important for the browning of WAT. Another paper [ 11 ], also demonstrated that the secretion of IL-6 from adipose tissue can activate STAT3 and inhibit glucose production in the liver. In addition, Tong Liu et al [ 44 ] extracted fat from scWAT in the thighs or abdomen of five patients and transplanted it into the dorsal side of 6- to 8-week-old female nude mice.…”