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Is reactivation of autophagy a possible therapeutic solution for obesity and metabolic syndrome?

Sebastiano Sciarretta1, Massimo Volpe, Junichi Sadoshima

  • 1Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA.

Autophagy
|May 12, 2012
PubMed

Insights

RAS homolog enriched in brain (RHEB) inhibition protects heart cells during energy stress. Impaired RHEB signaling in obesity worsens heart injury during ischemia, highlighting its role in metabolic syndrome.

Area of Science:

  • Cardiovascular Research
  • Molecular Mechanisms
  • Metabolic Syndrome

Background:

  • Cardiomyocyte response to energy stress is crucial for treating ischemic heart disease.
  • RAS homolog enriched in brain (RHEB) activity is inhibited by glucose deprivation (GD) in cardiomyocytes and during ischemia.
  • This inhibition is a survival mechanism, suppressing mTORC1 and activating autophagy.

Purpose of the Study:

  • To investigate the role of RHEB-MTORC1 signaling in cardiomyocyte adaptation to energy stress.
  • To examine how obesity and metabolic syndrome affect this protective mechanism.
  • To discuss the implications for ischemic heart disease and human disease.

Main Methods:

  • Studied RHEB activity in cardiomyocytes under glucose deprivation.
  • Investigated RHEB-MTORC1 signaling and autophagy in mouse models of myocardial ischemia.
  • Compared responses in lean and high-fat diet (HFD)-induced obese/metabolic syndrome models.

Main Results:

  • RHEB activity is physiologically inhibited during GD and ischemia, suppressing mTORC1 and activating autophagy for cell survival.
  • This protective RHEB-MTORC1 inhibition is impaired in obesity/metabolic syndrome (HFD feeding).
  • Impaired RHEB signaling leads to increased ischemic injury in obese hearts.

Conclusions:

  • RHEB is critical for regulating MTORC1 and autophagy during cardiac ischemia.
  • Dysregulation of RHEB-MTORC1 signaling and autophagy suppression in obesity exacerbates ischemic heart injury.
  • Targeting RHEB-MTORC1 signaling may offer therapeutic strategies for ischemic heart disease in metabolic syndrome.

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