Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy
Open accessAbstract
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).”
From Found in translation—Fibrosis in metabolic dysfunction–associated steatohepatitis (MASH) (2023) · cites this paper as [222]
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).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [169]
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M<scp>ETABOLIC</scp> L<scp>ESSONS FROM</scp> G<scp>ENETICALLY</scp> L<scp>EAN</scp> M<scp>ICE</scp>
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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)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-10-15
- Volume
- 12
- Issue
- 20
- Pages
- 3182-3194
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317215
- 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
- bronze
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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