Diseases of liporegulation: New perspective on obesity and related disorders

Roger H Unger, Lelio Orci

Research output: Contribution to journalReview article

353 Scopus citations

Abstract

Obesity-related diseases now threaten to reach epidemic proportions in the United States. Here we review in a rodent model of genetic obesity, the fa/fa Zucker diabetic fatty (ZDF) rat, the mechanisms involved in the most common complications of diet-induced human obesity, i.e., noninsulin-dependent diabetes mellitus, and myocardial dysfunction. In ZDF rats, hyperphagia leads to hyperinsulinemia, which upregulates transcription factors that stimulate lipogenesis. This causes ectopic deposition of triacylglycerol in nonadipocytes, providing fatty acid (FA) substrate for damaging pathways of nonoxidative metabolism, such as ceramide synthesis. In β cells and myocardium, the resulting functional impairment and apoptosis cause diabetes and cardiomyopathy. Interventions that lower ectopic lipid accumulation or block nonoxidative metabolism of FA and ceramide formation completely prevent these complications. Given the evidence for a similar etiology for the complications of human obesity, it would be appropriate to develop strategies to avert the predicted epidemic of lipotoxic disorders.

Original languageEnglish (US)
Pages (from-to)312-321
Number of pages10
JournalFASEB Journal
Volume15
Issue number2
DOIs
StatePublished - 2001

Keywords

  • Cardiomyopathy
  • Complications of obesity
  • Lipoapoptosis
  • Lipotoxicity
  • Noninsulin-dependent diabetes

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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