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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis
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Mechanism of Regulation of Adipocyte Numbers in Adult Organisms Through Differentiation and Apoptosis Homeostasis

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Novel repressor regulates insulin sensitivity through interaction with Foxo1

Jun Nakae1, Yongheng Cao, Fumihiko Hakuno

  • 1Frontier Medicine on Metabolic Syndrome, Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. jnakae35@sc.itc.keio.ac.jp

The EMBO Journal
|April 19, 2012
PubMed

Insights

A novel protein, Foxo1-CoRepressor (FCoR), regulates insulin sensitivity and energy metabolism. FCoR fine-tunes Forkhead box-containing protein o (Foxo) 1 activity in adipose tissue, impacting glucose metabolism and adipocyte function.

Area of Science:

  • Metabolic regulation
  • Adipose tissue biology
  • Molecular endocrinology

Background:

  • Forkhead box-containing protein o (Foxo) 1 is a critical regulator of insulin and glucose metabolism.
  • Understanding the precise mechanisms controlling Foxo1 activity is essential for metabolic health.

Purpose of the Study:

  • To identify novel regulators of Foxo1 activity in adipose tissue.
  • To elucidate the role of a newly identified Foxo1-CoRepressor (FCoR) in metabolic regulation.

Main Methods:

  • Identification and characterization of FCoR in mouse adipose tissue.
  • Investigating FCoR's interaction with Foxo1 and Sirt1.
  • Phosphorylation site analysis of FCoR.
  • Cellular studies using 3T3-F442A cells (knockdown and overexpression).
  • In vivo studies using Lepr(db/db) mice, high-fat diet models, and Fcor knockout mice.

Main Results:

  • FCoR inhibits Foxo1 activity by promoting its acetylation and disrupting its interaction with Sirt1.
  • FCoR is phosphorylated by protein kinase A and translocates to the nucleus to bind Foxo1.
  • FCoR knockdown in adipocytes enhances Foxo target gene expression and inhibits differentiation.
  • FCoR overexpression in mice improves insulin sensitivity, reduces adipocyte size, and decreases Foxo target gene expression.
  • Fcor knockout mice exhibit leanness, glucose intolerance, decreased insulin sensitivity, enlarged adipocytes, and increased Foxo target gene expression.

Conclusions:

  • FCoR is a novel repressor of Foxo1 activity in adipose tissue.
  • FCoR plays a significant role in regulating insulin sensitivity and energy metabolism.
  • FCoR acts as a fine-tuner of Foxo1 activity, influencing adipocyte function and overall metabolic homeostasis.

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