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Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy
Abstract
Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by a paucity of adipose (fat) tissue which is evident at birth and is accompanied by a severe resistance to insulin, leading to hyperinsulinaemia, hyperglycaemia and enlarged fatty liver. We have developed a mouse model that mimics these features of CGL: the syndrome occurs in transgenic mice expressing a truncated version of a nuclear protein known as nSREBP-1c (for sterol-regulatory-element-binding protein-1c) under the control of the adipose-specific aP2 enhancer. Adipose tissue from these mice was markedly deficient in messenger RNAs encoding several fat-specific proteins, including leptin, a fat-derived hormone that regulates food intake and energy metabolism. Here we show that insulin resistance in our lipodystrophic mice can be overcome by a continuous systemic infusion of low doses of recombinant leptin, an effect that is not mimicked by chronic food restriction. Our results support the idea that leptin modulates insulin sensitivity and glucose disposal independently of its effect on food intake, and that leptin deficiency accounts for the insulin resistance found in CGL.
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In the citing paper
“Shimomura et al. have demonstrated that leptin treatment reversed insulin resistance in a fat-specific aP2-SREBP-1c knockout mouse model of congenital generalized lipodystrophy (4).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [4]
In the citing paper
“Taken together, these data suggest that intrahepatic and intramyocellular lipid lowering effects of leptin were mediated mostly by a reduction in energy intake, as opposed to a leptininduced increase in energy expenditure, although a lipolytic effect of leptin on these tissues cannot be ruled out (4, 28).”
From Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy (2002) · cites this paper as [4]
In the citing paper
“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 [168]
In the citing paper
“the diabetes phenotype of these lipodystrophic mice is also ameliorated by leptin administration via a mechanism that is, at least in part, independent of its effect on food intake and body weight (64, 168).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [168]
In the citing paper
“First in rodent models (5) and then in preliminary short-term studies in humans (6), it was shown that recombinant leptin administration could ameliorate dyslipidemia, insulin resistance, and diabetes.”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [5]
In the citing paper
“Moreover, leptin dramatically improves insulin sensitivity in human lipodystrophy and in lipodystrophic mouse models which are characterized by low serum leptin levels and by severe insulin resistance (Oral et al., 2002; Petersen et al., 2002; Shimomura et al., 1999).”
From Leptin-Dependent Control of Glucose Balance and Locomotor Activity by POMC Neurons (2009) · cites this paper as Shimomura et al., 1999
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Metadata
- Authors
- Shimomura, I., Hammer, R. E., Ikemoto, S., Brown, M. S., & Goldstein, J. L.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Brown, Michael S.
- Goldstein, Joseph L.
- Venue
- Nature
- Published
- 1999-09
- Volume
- 401
- Issue
- 6748
- Pages
- 73-76
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1492605893
- Cited by
- 1,038
- References
- 15
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 22 · 2023: 24 · 2022: 19 · 2021: 20 · 2020: 20 · 2019: 23 · 2018: 31 · 2017: 29 · 2016: 30 · 2015: 38 · 2014: 36 · 2013: 39 · 2012: 43
- FWCI
- 23.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Keywords
- leptin, congenital generalized lipodystrophy, insulin resistance, diabetes mellitus, transgenic mouse model, adipose tissue, hyperinsulinemia, hyperglycemia, hepatic steatosis, glucose disposal, dietary restriction, energy metabolism
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Disease Models, Animal, DNA-Binding Proteins, Female, Food Deprivation, Humans, Insulin Resistance, Lipodystrophy, Liver, Male, Mice, Obese, Mice, Transgenic, Nuclear Proteins, Promoter Regions, Genetic, Proteins, Transcription Factors, Adipocytes, Leptin, CCAAT-Enhancer-Binding Proteins, Mice, Sterol Regulatory Element Binding Protein 1
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