High-fat-diet-induced Obesity and Heart Dysfunction Are Regulated by the TOR Pathway in Drosophila

Cell Metab. 2010 Nov 3;12(5):533-44. doi: 10.1016/j.cmet.2010.09.014.

Abstract

High-fat-diet (HFD)-induced obesity is a major contributor to diabetes and cardiovascular disease, but the underlying genetic mechanisms are poorly understood. Here, we use Drosophila to test the hypothesis that HFD-induced obesity and associated cardiac complications have early evolutionary origins involving nutrient-sensing signal transduction pathways. We find that HFD-fed flies exhibit increased triglyceride (TG) fat and alterations in insulin/glucose homeostasis, similar to mammalian responses. A HFD also causes cardiac lipid accumulation, reduced cardiac contractility, conduction blocks, and severe structural pathologies, reminiscent of diabetic cardiomyopathies. Remarkably, these metabolic and cardiotoxic phenotypes elicited by HFD are blocked by inhibiting insulin-TOR signaling. Moreover, reducing insulin-TOR activity (by expressing TSC1-2, 4EBP or FOXO), or increasing lipase expression-only within the myocardium-suffices to efficiently alleviate cardiac fat accumulation and dysfunction induced by HFD. We conclude that deregulation of insulin-TOR signaling due to a HFD is responsible for mediating the detrimental effects on metabolism and heart function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Fats / adverse effects*
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Heart / physiopathology
  • Heart Diseases / complications
  • Heart Diseases / etiology*
  • Heart Diseases / metabolism
  • Humans
  • Insulin / metabolism
  • Metabolic Diseases / genetics
  • Mutation
  • Obesity / complications
  • Obesity / etiology*
  • Obesity / metabolism
  • Phenotype
  • Signal Transduction
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Triglycerides / metabolism

Substances

  • Dietary Fats
  • Drosophila Proteins
  • Insulin
  • Triglycerides
  • TOR Serine-Threonine Kinases