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.
View: Text | PDF
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

×

Figure 1

Partial recovery of subcutaneous WAT and recovery of functional BAT with fat-specific deletion of Foxo1, -3, and -4 in F-Quint–KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Partial recovery of subcutaneous WAT and recovery of functional BAT with...
(A–C) Ad lib–fed CONT, FIGIR-KO, and F-Quint–KO mice were sacrificed at 3 months of age, and visceral (perigonadal) WAT (A), subcutaneous (inguinal) WAT (B), and BAT (C) were removed and weighed. Results represent 4 to 11 mice per group. Statistics were performed using a 1-way ANOVA, where *P < 0.05, ***P < 0.001, and ****P < 0.0001. (D) H&E-stained sections of subcutaneous tissues from the mice in panel B. Scale bar: 0.1 mm. Arrows indicate areas of lymphocyte infiltration. (E) Average adipocyte area was measured in subcutaneous tissues from mice in panel B. Statistics were performed using a 2-way ANOVA, where ****P < 0.0001. (F) H&E-stained sections of BAT tissues from the mice in panel C. Scale bar: 0.1 mm. (G) Rectal temperature was measured in 3-month-old mice every 30 minutes for 3 hours during exposure to a 6°C environment. Results represent 4 to 11 mice per group. Statistics were performed using a 2-way ANOVA with repeated measures, where #P < 0.05 CONT vs. FIGIR-KO, and $P < 0.05 CONT vs. FIGIR-KO and FIGIR-KO vs. F-Quint–KO. (H) Images of subcutaneous adipose–derived CONT, DKO, and QKO adipocyte cell lines stained with Oil Red O after in vitro adipogenic differentiation. Each image is 1 representative well of a 6-well plate.