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

Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIRKO) exhibit complete loss of white and brown fat (WAT/BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIRKO mice with fat-specific knockout of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint KO). Unlike FIGIRKO 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/IGF1 action in different adipose depots, being more important in BAT > subcutaneous WAT > visceral WAT. Disruption of FOXOs in fat also leads 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.

• Publication year

  2021

• Venue

  Journal of Clinical Investigation

• Publication date

  2021-08-24

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1172/JCI143328PMID 34428182PMCID PMC8483763
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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