FGF21 is required for the metabolic benefits of IKKε/TBK1 inhibition
Shannon M. Reilly, … , Matthew J. Potthoff, Alan R. Saltiel
Shannon M. Reilly, … , Matthew J. Potthoff, Alan R. Saltiel
Published April 6, 2021
Citation Information: J Clin Invest. 2021;131(10):e145546. https://doi.org/10.1172/JCI145546.
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Research Article Metabolism

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

Abstract

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.

Authors

Shannon M. Reilly, Mohammad Abu-Odeh, Magdalene Ameka, Julia H. DeLuca, Meghan C. Naber, Benyamin Dadpey, Nima Ebadat, Andrew V. Gomez, Xiaoling Peng, BreAnne Poirier, Elyse Walk, Matthew J. Potthoff, Alan R. Saltiel

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Figure 1

Amlexanox transiently reduces food intake.

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Amlexanox transiently reduces food intake. (A) Weekly body weights of ob...
(A) Weekly body weights of obese mice treated with 25 mg/kg amlexanox or vehicle control. n = 7 vehicle-treated mice and n = 8 amlexanox-treated mice. (B–F) Metabolic cage experiment. n = 8 animals per treatment group. Vertical lines indicate treatment initiation and, in B and D, the time of daily treatment administration administration (day –1 vehicle control was administered to all). The dark cycle (6 pm to 6 am) is indicated in B and D by gray shading. (B) Oxygen consumption rate (VO2). (C) Average oxygen consumption rate during the light or dark cycle. (D) Carbon dioxide production rate (VCO2). (E) Average carbon dioxide production rate during the light or dark cycle. (F) Daily food intake. (G) Food intake 24–48 hours after treatment initiation for obese Il6-KO mice and littermate WT controls. WT versus Il6-KO values within treatment groups were not significantly different. n = 5 animals per genotype in each treatment group. (H–K) Daily food intake and body weights of obese mice treated with 25 mg/kg amlexanox or vehicle control. n = 9 vehicle-treated mice and n = 10 amlexanox-treated mice. (H) Body weight–normalized food intake. (I) Total food intake per mouse. (J) Body weight. (K) Body weight as a percentage of baseline body weight. *P < 0.05, by Holm-Šidák post hoc test after significant 2-way ANOVA. #P < 0.05, by Student’s t test, not corrected for multiple comparisons. Data are presented as the mean ± SEM.