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

The protein kinases IKK-epsilon and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKK-epsilon/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 adipocyte-derived IL-6 to decrease gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.