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Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity

Sung Hee Um1, Francesca Frigerio, Mitsuhiro Watanabe

  • 1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.

Nature
|August 13, 2004
PubMed

Insights

S6 Kinase 1 (S6K1) deficiency protects against obesity by enhancing fat breakdown. However, S6K1 negatively regulates insulin signaling, particularly under high-fat conditions, offering new therapeutic targets for diabetes.

Area of Science:

  • Metabolic signaling pathways
  • Obesity and diabetes research
  • Mammalian Target of Rapamycin (mTOR) pathway

Background:

  • Obesity impairs insulin action, contributing to diabetes.
  • S6 Kinase 1 (S6K1) integrates nutrient and insulin signals.
  • S6K1 deficiency in mice shows complex metabolic phenotypes, including glucose intolerance and altered insulin sensitivity.

Purpose of the Study:

  • To investigate the role of S6K1 in metabolic regulation and insulin sensitivity.
  • To determine the impact of S6K1 deficiency on obesity and response to high-fat diets.
  • To elucidate the molecular mechanisms linking S6K1 to insulin resistance.

Main Methods:

  • Analysis of S6K1-deficient mice under normal and high-fat diet conditions.
  • Assessment of glucose homeostasis, free fatty acid levels, and beta-oxidation.
  • Investigation of insulin receptor substrate 1 (IRS1) phosphorylation at key insulin resistance sites (S307 and S636/S639).

Main Results:

  • S6K1-deficient mice are protected against diet-induced obesity due to enhanced beta-oxidation.
  • Despite protection, high-fat diets lead to hyperglycemia and insulin receptor desensitization in S6K1-deficient mice.
  • S6K1 deficiency prevents IRS1 phosphorylation at S307 and S636/S639, indicating preserved insulin sensitivity via a disrupted negative feedback loop.
  • Obese wild-type and genetic obesity models exhibit elevated S6K1 activity and increased IRS1 phosphorylation.

Conclusions:

  • S6K1 plays a critical role in negatively regulating insulin signaling under nutrient-rich conditions.
  • Disruption of the S6K1-IRS1 negative feedback loop contributes to insulin sensitivity.
  • Targeting S6K1 activity may offer therapeutic strategies for obesity and type 2 diabetes.

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