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

• Published in: The Journal of clinical investigation 2021-05, Vol.131 (10), p.1-15
• Main Authors: Reilly, Shannon M, Abu-Odeh, Mohammad, Ameka, Magdalene, DeLuca, Julia H, Naber, Meghan C, Dadpey, Benyamin, Ebadat, Nima, Gomez, Andrew V, Peng, Xiaoling, Poirier, BreAnne, Walk, Elyse, Potthoff, Matthew J, Saltiel, Alan R
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipose tissue; Aminopyridines - pharmacology; Animal models; Animals; Autocrine signalling; Biomedical research; Blood glucose; Blood Glucose - genetics; Blood Glucose - metabolism; Body weight loss; Catecholamines; Chemokines; Cytokines; Diabetes; Diet; Eating - drug effects; Eating - genetics; Energy; Energy expenditure; Energy Metabolism - drug effects; Energy Metabolism - genetics; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Food; Food intake; Gene expression; Gluconeogenesis; Gluconeogenesis - drug effects; Gluconeogenesis - genetics; Glucose; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Inflammation; Insulin; Insulin resistance; Interleukin 6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Kinases; Liver; Liver - metabolism; Metabolism; Mice; Mice, Knockout; Obesity; Protein kinase; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Proteins; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Weight control
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI145546

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.