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Publication
Differential roles of FOXO transcription factors on insulin action in brown and
white adipose tissue.
Authors Homan EP, Brandão BB, Softic S, El Ouaamari A, O'Neill BT, Kulkarni RN, Kim JK,
Kahn CR
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal The Journal of clinical investigation
Year 2021
Date Published 10/1/2021
Volume : Pages 131 : Not Specified
PubMed Reference 34428182
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 ß
cells.




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