Cited by 790Adipose Tissue and MetabolismPeroxisome Proliferator-Activated ReceptorsAdipokines, Inflammation, and Metabolic Diseases

Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy

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Shimomura, Iichiro, Hammer, Robert E., Richardson, James A., Ikemoto, Shinji, Bashmakov, Yuriy, Goldstein, Joseph L., Brown, Michael S.·1998·Genes & Development

Abstract

Overexpression of the nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c/ADD1) in cultured 3T3-L1 preadipocytes was shown previously to promote adipocyte differentiation. Here, we produced transgenic mice that overexpress nSREBP-1c in adipose tissue under the control of the adipocyte-specific aP2 enhancer/promoter. A syndrome with the following features was observed: (1) Disordered differentiation of adipose tissue. White fat failed to differentiate fully, and the size of white fat depots was markedly decreased. Brown fat was hypertrophic and contained fat-laden cells resembling immature white fat. Levels of mRNA encoding adipocyte differentiation markers (C/EBPα, PPARγ, adipsin, leptin, UCP1) were reduced, but levels of Pref-1 and TNFα were increased. (2) Marked insulin resistance with 60-fold elevation in plasma insulin. (3) Diabetes mellitus with elevated blood glucose (>300 mg/dl) that failed to decline when insulin was injected. (4) Fatty liver from birth and elevated plasma triglyceride levels later in life. These mice exhibit many of the features of congenital generalized lipodystrophy (CGL), an autosomal recessive disorder in humans.

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  • Transgenic animals developed to study MASH pathogenesis include those overexpressing MUP-uPA or SREBP1.

    “Several transgenic animals have been developed to study MASH pathogenesis, including those that overexpress urokinase-type plasminogen activator (MUP-uPA) (221) or sterol regulatory element-binding protein 1 (SREBP1) (222, 223).”
  • Leptin deficiency contributes to insulin resistance and diabetes in lipodystrophy.

    “Several lines of evidence from both humans and rodent models suggest that leptin deficiency contributes to insulin resistance and diabetes in this setting (139, 168, 169).”

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  1. Foster, D.W. 1992. Eating disorders: Obesity, anorexia nervosa, and bulimia nervosa. In Williams textbook of endocrinology (ed. J.D. Wilson and D.W. Foster), pp. 1335-1365.

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Authors
Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., & Brown, M. S.
Affiliations
Howard Hughes Medical Institute (US)
Venue
Genes & Development
Published
1998-10-15
Volume
12
Issue
20
Pages
3182-3194
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
OpenAlex
W2155846381
Cited by
790
References
50
Citations by year
2026: 3 · 2025: 8 · 2024: 18 · 2023: 20 · 2022: 17 · 2021: 11 · 2020: 15 · 2019: 21 · 2018: 26 · 2017: 21 · 2016: 18 · 2015: 23 · 2014: 16 · 2013: 27 · 2012: 26
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Manpei Suzuki Diabetes Foundation
  • National Institutes of Health (HL20948)
  • National Heart, Lung, and Blood Institute (HL-20948, P01HL020948)
Topics
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
  • Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
Keywords
congenital generalized lipodystrophy, SREBP-1c, ADD1, insulin resistance, diabetes mellitus, adipose tissue differentiation, transgenic mice, adipogenesis, hepatic steatosis, hypertriglyceridemia
MeSH terms
Adipose Tissue, Animals, Animals, Newborn, Blood Glucose, Cell Differentiation, Diabetes Mellitus, Experimental, Diabetes Mellitus, Lipoatrophic, Disease Models, Animal, DNA-Binding Proteins, Female, Insulin, Insulin Resistance, Liver, Male, Mice, Transgenic, Nuclear Proteins, Phenotype, RNA, Messenger, Transcription Factors, Transgenes, CCAAT-Enhancer-Binding Proteins, Mice, Sterol Regulatory Element Binding Protein 1

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