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

The protein kinases IKKε and TBK1 are activated in liver and fat in mouse models of obesity. We have previously demonstrated that treatment with the IKKε/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 white adipose tissue (WAT). Amlexanox increased FGF21 synthesis and secretion in several tissues. Interestingly, although 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 led 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 the suppression of hepatic glucose production via 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 that adipocyte-derived IL-6 has an endocrine role in decreasing gluconeogenesis via hepatic STAT3 activation, thereby producing a coordinated improvement in metabolic parameters.

Catecholamines suppress fatty acid re-esterification and increase oxidation in white adipocytes via STAT3.

Catecholamines stimulate the mobilization of stored triglycerides in adipocytes to provide fatty acids (FAs) for other tissues. However, a large proportion is taken back up and either oxidized or re-esterified. What controls the disposition of these FAs in adipocytes remains unknown. Here, we report that catecholamines redirect FAs for oxidation through the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Adipocyte STAT3 is phosphorylated upon activation of ß-adrenergic receptors, and in turn suppresses FA re-esterification to promote FA oxidation. Adipocyte-specific Stat3 KO mice exhibit normal rates of lipolysis, but exhibit defective lipolysis-driven oxidative metabolism, resulting in reduced energy expenditure and increased adiposity when they are on a high-fat diet. This previously unappreciated, non-genomic role of STAT3 explains how sympathetic activation can increase both lipolysis and FA oxidation in adipocytes, revealing a new regulatory axis in metabolism.

Adipsin preserves beta cells in diabetic mice and associates with protection from type 2 diabetes in humans.

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.

Inhibition of IKKɛ and TBK1 Improves Glucose Control in a Subset of Patients with Type 2 Diabetes.

Numerous studies indicate an inflammatory link between obesity and type 2 diabetes. The inflammatory kinases IKKɛ and TBK1 are elevated in obesity; their inhibition in obese mice reduces weight, insulin resistance, fatty liver and inflammation. Here we studied amlexanox, an inhibitor of IKKɛ and TBK1, in a proof-of-concept randomized, double-blind, placebo-controlled study of 42 obese patients with type 2 diabetes and nonalcoholic fatty liver disease. Treatment of patients with amlexanox produced a statistically significant reduction in Hemoglobin A1c and fructosamine. Interestingly, a subset of drug responders also exhibited improvements in insulin sensitivity and hepatic steatosis. This subgroup was characterized by a distinct inflammatory gene expression signature from biopsied subcutaneous fat at baseline. They also exhibited a unique pattern of gene expression changes in response to amlexanox, consistent with increased energy expenditure. Together, these data suggest that dual-specificity inhibitors of IKKɛ and TBK1 may be effective therapies for metabolic disease in an identifiable subset of patients.

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

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.