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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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Research Article Endocrinology Metabolism

Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue

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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 8

Restoration of liver insulin sensitivity in the context of whole-body insulin resistance in F-Quint–KO mice.

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Restoration of liver insulin sensitivity in the context of whole-body in...
(A) Glucose infusion rate adjusted every 10 to 20 minutes over the course of a hyperinsulinemic-euglycemic clamp in 3-month-old CONT, FIGIR-KO, and F-Quint–KO mice. Results represent 5 to 8 mice per group. Statistics were analyzed using a 2-way ANOVA with repeated measures, where #P < 0.05 CONT vs. FIGIR-KO and CONT vs. F-Quint–KO. (B–F) Whole-body glucose turnover (B), whole-body glycogen plus lipid synthesis (C), insulin-stimulated glucose uptake in skeletal muscle (gastrocnemius) (D), basal and clamp HGP (E), and hepatic insulin action (F) measured during a hyperinsulinemic-euglycemic clamp in 3-month-old CONT, FIGIR-KO, and F-Quint–KO mice. Results represent 5 to 8 mice per group. Statistics were analyzed using a 1-way ANOVA, where *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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