Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue
Erica P. Homan, Bruna B. Brandão, Samir Softic, Abdelfattah El Ouaamari, Brian T. O’Neill, Rohit N. Kulkarni, Jason K. Kim, C. Ronald Kahn
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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Research Article Endocrinology Metabolism

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 3

β Cell hyperplasia remains despite loss of FOXO1, -3, and -4 in F-Quint–KO mice.

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β Cell hyperplasia remains despite loss of FOXO1, -3, and -4 in F-Quint–...
(A) H&E and immunofluorescence staining for insulin, Ki67, and DAPI in pancreatic sections of CONT, FIGIR-KO, and F-Quint–KO mice at 12 weeks of age. Scale bars: 200 μm for H&E staining and 50 μm for immunofluorescence. White arrows indicate Ki67+ β cells. (B) Mass of β cells relative to total pancreas mass and (C) the percentage of Ki67+ β cells were measured. Results represent 5–7 mice per group. Statistics were analyzed using a 1-way ANOVA, where *P < 0.05. (D) In vitro GSIS results represent 3 per group. Statistics were analyzed using a 2-way ANOVA, where *P < 0.05, and **P < 0.01. (E) Densitometric quantification of SERPINB1 serum protein levels in the fed state determined by Western blot analysis in 12-week-old mice. Results represent 4 to 5 mice per group. Statistics were analyzed using a 1-way ANOVA, where **P < 0.01.