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 8

Mechanism of improved glucose handling and insulin sensitivity.

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Mechanism of improved glucose handling and insulin sensitivity. (A) Day ...
(A) Day 3 fasting blood glucose levels in obese Il6-KO and WT littermate control mice. n = 5 animals per treatment per genotype. (B–F, H, and I) Obese SLKO and WT mice. (B) Day 3 weight loss. n = 10 vehicle-treated mice and n = 9 amlexanox-treated mice per genotype. (C) Day 3 fasting blood glucose levels. n = 6 vehicle-treated WT mice, n = 7 amlexanox-treated WT mice, n = 11 vehicle-treated SLKO mice, and n = 12 amlexanox-treated SLKO mice. Day 3 liver expression of (D) Socs3 and (E) G6pc. n = 5 animals per genotype per treatment. (F) Pyruvate tolerance test after 3 days of treatment. n = 6 vehicle-treated WT mice, n = 7 amlexanox-treated WT mice, n = 11 vehicle-treated SLKO mice, and n = 12 amlexanox-treated SLKO mice. (G) Day 3 fasting blood glucose levels in obese FAKO and WT littermate control animals. n = 9 vehicle-treated mice and n = 8 amlexanox-treated mice per genotype. (H) Insulin tolerance test after 4 weeks of treatment. n = 8 vehicle-treated mice and n = 7 amlexanox-treated mice per genotype. (I) Weight loss after 4 weeks of treatment. n = 9 mice per treatment per genotype. (J and K) Fasting serum insulin levels in obese mice after 4 weeks of treatment. (J) Serum insulin levels in WT and Fgf21-KO mice. n = 9 WT mice per treatment, n = 8 vehicle-treated Fgf21-KO mice, and n = 6 amlexanox-treated Fgf21-KO mice. (K) Serum insulin levels in WT and Ucp1-KO mice. n = 6 mice per treatment per genotype. (L) Insulin tolerance test after 4 weeks of treatment in obese Fgf21-KO and WT littermate control mice. n = 10 vehicle-treated mice per genotype, n = 9 WT mice, and n = 8 amlexanox-treated Fgf21-KO mice. (M) Insulin tolerance test after 4 weeks of treatment in obese Ucp1-KO and WT littermate control mice. n = 10 vehicle-treated mice per genotype, n = 9 WT mice, and n = 8 amlexanox-treated Ucp1-KO mice. *P < 0.05, by Holm-Šidák post hoc test after significant 2-way ANOVA for the vehicle versus amlexanox treatment groups. #P < 0.05, by Holm-Šidák post hoc test after significant 2-way ANOVA for vehicle versus amlexanox treatment in both the WT and KO groups. ~P < 0.05, by Holm-Šidák post hoc test after significant 2-way ANOVA for WT versus KO animals within the amlexanox treatment group. Data are presented as the mean ± SEM.