Lipotoxic diseases

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Abstract

I review evidence that leptin is a liporegulatory hormone that controls lipid homeostasis in nonadipose tissues during periods of overnutrition. When adipocytes store excess calories as triacylglycerol (TG), leptin secretion rises so as to prevent accumulation of lipids in nonadipose tissues, which are not adapted for TG storage. Whenever leptin action is lacking, whether through leptin deficiency or leptin resistance, overnutrition causes disease of nonadipose tissues with generalized steatosis, lipotoxicity, and lipoapoptosis. Examples of such disorders of liporegulation include generalized lipodystrophies, mutations of leptin and leptin receptor genes, and diet-induced obesity. Lipotoxicity of pancreatic β-cells, myocardium, and skeletal muscle leads, respectively, to type 2 diabetes, cardiomyopathy, and insulin resistance. In humans this constellation of abnormalities is referred to as the metabolic syndrome, a major health problem in the United States. When lipids overaccumulate in nonadipose tissues during overnutrition, fatty acids enter deleterious pathways such as ceramide production, which, through increased nitric oxide formation, causes apoptosis of lipidladen cells, such as β-cells and cardiomyocytes. Lipoapoptosis can be prevented by caloric restriction, by thiazolidinedione treatment, and by administration of nitric oxide blockers. There is now substantial evidence that complications of human obesity may reflect lipotoxicity similar to that described in rodents.

Original languageEnglish (US)
Pages (from-to)319-336
Number of pages18
JournalAnnual Review of Medicine
Volume53
DOIs
StatePublished - 2002

Fingerprint

Leptin
Overnutrition
Tissue
Medical problems
Lipids
Nitric Oxide
Triglycerides
Congenital Generalized Lipodystrophy
Obesity
Leptin Receptors
Caloric Restriction
Ceramides
Nutrition
Cardiomyopathies
Adipocytes
Cardiac Myocytes
Type 2 Diabetes Mellitus
Muscle
Insulin Resistance
Rodentia

Keywords

  • Apoptosis
  • Ceramide
  • Fatty acid homeostasis
  • Lipoapoptosis
  • Lipotoxicity
  • Metabolic syndrome

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Lipotoxic diseases. / Unger, Roger H.

In: Annual Review of Medicine, Vol. 53, 2002, p. 319-336.

Research output: Contribution to journalArticle

Unger, Roger H. / Lipotoxic diseases. In: Annual Review of Medicine. 2002 ; Vol. 53. pp. 319-336.
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