Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue
Erica P. Homan, … , Jason K. Kim, C. Ronald Kahn
Erica P. Homan, … , Jason K. Kim, C. Ronald Kahn
Published August 24, 2021
Citation Information: J Clin Invest. 2021;131(19):e143328. https://doi.org/10.1172/JCI143328.
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Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue

Abstract

Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor–KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint–KO). Unlike FIGIR-KO mice, F-Quint–KO mice had normal BAT, glucose tolerance, insulin-regulated hepatic glucose production, and cold tolerance. However, loss of FOXOs only partially rescued subcutaneous WAT and hepatosteatosis, did not rescue perigonadal WAT or systemic insulin resistance, and led to even more marked hyperinsulinemia. Thus, FOXOs play different roles in insulin/IGF-1 action in different adipose depots, being most important in BAT, followed by subcutaneous WAT and then by visceral WAT. Disruption of FOXOs in fat also led to a reversal of insulin resistance in liver, but not in skeletal muscle, and an exacerbation of hyperinsulinemia. Thus, adipose FOXOs play a unique role in regulating crosstalk between adipose depots, liver, and β cells.

Authors

Erica P. Homan, Bruna B. Brandão, Samir Softic, Abdelfattah El Ouaamari, Brian T. O’Neill, Rohit N. Kulkarni, Jason K. Kim, C. Ronald Kahn

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Figure 2

Recovery of glucose homeostasis and worsening of hyperinsulinemia in F-Quint–KO mice.

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Recovery of glucose homeostasis and worsening of hyperinsulinemia in F-Q...
(A) Blood glucose in 12-week-old fed and fasting mice. Results represent 10 to 32 mice per group. Statistics were analyzed using a 1-way ANOVA, where *P < 0.05, **P < 0.01, and ***P < 0.001. (B) Glucose tolerance tests of control, FIGIR-KO, and F-Quint–KO mice at 12 weeks of age. Results represent 5 to 15 mice per group. Statistics were analyzed using a 2-way ANOVA with repeated measures, where #P < 0.05 between CONT vs. FIGIR-KO and FIGIR-KO vs. F-Quint–KO. (C and D) Serum insulin (C) and C-peptide (D) levels in the fed or fasted state in 12-week old control, FIGIR-KO, and F-Quint–KO mice. Results represent 6 to 8 mice per group. Statistics were analyzed using a 1-way ANOVA, where *P < 0.05, and ****P < 0.0001. (E) HOMA-IR was calculated for CONT, FIGIR-KO, and F-Quint–KO mice at 12 weeks old. Results represent 5 to 7 mice per group. Statistics were analyzed using a 1-way ANOVA, where ***P < 0.001, and ****P < 0.0001. (F) ITT of CONT, FIGIR-KO, and F-Quint–KO mice at 12 weeks of age. Results represent 5–22 mice per group. Statistics were analyzed using a 2-way ANOVA with repeated measures, where $P < 0.05 between CONT vs. FIGIR-KO, CONT vs. F-Quint–KO, and FIGIR-KO vs. F-Quint–KO.