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An Adipocyte Cell Culture Model to Study the Impact of Protein and Micro-RNA Modulation on Adipocyte Function
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The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene

Tetsuya Hosooka1, Yusei Hosokawa1, Kaku Matsugi1

  • 1Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.

Proceedings of the National Academy of Sciences of the United States of America
|May 13, 2020
PubMed

Insights

Insulin signaling in fat cells regulates leukotriene B4 (LTB4) production. This pathway, involving PDK1 and FoxO1, is crucial for maintaining systemic insulin sensitivity and preventing metabolic dysfunction.

Area of Science:

  • Metabolic disease research
  • Endocrinology
  • Molecular biology

Background:

  • Insulin's role in adipocytes is vital for metabolic homeostasis.
  • The precise mechanisms by which impaired insulin action in adipocytes affects overall metabolism are not fully understood.

Purpose of the Study:

  • To investigate the impact of impaired insulin signaling in adipocytes on metabolic homeostasis.
  • To elucidate the molecular pathways involved in insulin resistance originating from adipose tissue.

Main Methods:

  • Generation and analysis of adipocyte-specific PDK1-deficient (A-PDK1KO) and A-PDK1/FoxO1KO mice.
  • Assessment of metabolic parameters including insulin resistance, glucose intolerance, and hepatic steatosis.
  • Lipidomics, microarray analysis, and genetic/pharmacological targeting of the LTB4 pathway.

Main Results:

  • A-PDK1KO mice exhibited insulin resistance, glucose intolerance, and hepatic steatosis.
  • Ablation of FoxO1 in adipocytes partially rescued the metabolic phenotype.
  • Elevated leukotriene B4 (LTB4) levels and 5-lipoxygenase (5-LO) expression in A-PDK1KO mice were normalized in A-PDK1/FoxO1KO mice.
  • Targeting the LTB4 pathway ameliorated insulin resistance in A-PDK1KO mice.
  • Insulin signaling inhibits LTB4 production via PDK1-FoxO1 mediated down-regulation of 5-LO in adipocytes.

Conclusions:

  • Adipocyte insulin signaling negatively regulates LTB4 production through the PDK1-FoxO1 pathway.
  • This regulatory mechanism is essential for maintaining systemic insulin sensitivity.
  • Disruption of this pathway contributes to the development of metabolic dysfunction.
Keywords:
5-lipoxygenaseFoxO1PDK1insulin resistanceleukotriene B4

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