Cited by 879Adipokines, Inflammation, and Metabolic DiseasesRegulation of Appetite and ObesityLipid metabolism and biosynthesis

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Lipotoxic Diseases

Unger, Roger H.·2002·Annual Review of Medicine

DOI 10.1146/annurev.med.53.082901.104057

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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 beta-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 lipid-laden cells, such as beta-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.

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Authors: Unger, R. H.
Affiliations: Dallas VA Medical Center (US)
Corresponding author: Unger, Roger H.
Venue: Annual Review of Medicine
Publisher: Annual Reviews
Published: 2002-02
Volume: 53
Issue: 1
Pages: 319-336
ISSN: 0066-4219 (ISSN-L)
1545-326X
DOI: 10.1146/annurev.med.53.082901.104057
OpenAlex: W4254261652
Cited by: 875
References: 71
Citations by year: 2026: 9 · 2025: 14 · 2024: 25 · 2023: 15 · 2022: 18 · 2021: 31 · 2020: 22 · 2019: 21 · 2018: 22 · 2017: 30 · 2016: 32 · 2015: 30 · 2014: 29 · 2013: 49 · 2012: 34
FWCI: 10.58
Type: journal article
Language: en
Open access: closed
Locations: Annual Review of Medicine (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords: leptin, lipotoxicity, lipid homeostasis, lipoapoptosis, leptin resistance, leptin deficiency, lipodystrophy, leptin receptor mutation, diet-induced obesity, type 2 diabetes, cardiomyopathy, insulin resistance, metabolic syndrome, ceramide, nitric oxide, caloric restriction, thiazolidinediones, obesity complications
MeSH terms: Adipose Tissue, Animals, Homeostasis, Humans, Lipids, Myocardium, Obesity, Risk Factors, Leptin, Metabolic Syndrome

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