Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Open accessAbstract
Lipodystrophy is characterized by the complete or partial absence of adipose tissue, insulin resistance, hepatic steatosis, and leptin deficiency. Here, we show that low-dose central leptin corrects the insulin resistance and fatty liver of lipodystrophic aP2-nSREBP-1c mice, while the same dose given peripherally does not. Central leptin also repressed stearoyl-CoA desaturase-1 (SCD-1) RNA and enzymatic activity, which were increased in livers of lipodystrophic mice. aP2-nSREBP-1c mice homozygous for an SCD-1 deletion had markedly reduced hepatic steatosis, increased saturated fatty acids, decreased acetyl-CoA carboxylase activity, and decreased malonyl-CoA levels in the liver. Despite the reduction in hepatic steatosis, these mice remained diabetic. A leptin dose-response curve showed that subcutaneous leptin improved hyperglycemia and hyperinsulinemia in aP2-nSREBP-1c mice at doses that did not substantially alter hepatic steatosis or hepatic SCD enzymatic activity. Leptin treatment at this dose improved insulin-stimulated insulin receptor and insulin receptor substrate 2 (IRS-2) phosphorylation, IRS-2–associated PI3K activity, and Akt activity in liver. Together, these data suggest that CNS-mediated repression of SCD-1 contributes to leptin's antisteatotic actions. Intracerebroventricular leptin improves glucose homeostasis by improving insulin signal transduction in liver, but in this case the effect appears to be independent of SCD-1.
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Low-dose intracerebroventricular administration of leptin corrects the insulin resistance and diabetes phenotype of both leptin-deficient ob/ob and lipodystrophic mice.
“low-dose i.c.v. administration of leptin corrects the insulin resistance and diabetes phenotype of both leptin deficient ob/ob and lipodystrophic mice (2).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [2]
In rodent models, leptin increased expression of AMP-activated protein kinase and PPARα, activating enzymes of fatty acid oxidation and inhibiting enzymes of lipogenesis.
“In rodent models, leptin increased expression of AMP-activated protein kinase (28) and peroxisome proliferator-activated receptor (PPAR) ␣ (29), activating enzymes of fatty acid oxidation, including carnitine palmitoyl transferase-1 and acyl-CoA oxidase, and inhibiting enzymes of lipogenesis, including acyl-CoA carboxylase and stearoyl-CoA desaturase-1 (28,30).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [30]
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- Authors
- Asilmaz, E., Cohen, P., Miyazaki, M., Dobrzyn, P., Ueki, K., Fayzikhodjaeva, G., Soukas, A. A., Kahn, C. R., Ntambi, J. M., Socci, N. D., & Friedman, J. M.
- Affiliations
- Rockefeller University (US)
- University of Wisconsin System (US)
- Joslin Diabetes Center (US)
- Albert Einstein College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Friedman, Jeffrey M.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2004-02-01
- Volume
- 113
- Issue
- 3
- Pages
- 414-424
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2104945088
- Cited by
- 210
- References
- 51
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 9 · 2022: 2 · 2021: 5 · 2020: 6 · 2019: 8 · 2018: 3 · 2017: 9 · 2016: 13 · 2015: 8 · 2014: 13 · 2013: 12 · 2012: 5
- FWCI
- 6.74
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (GM07739, MSTPGM07739)
- National Institute of General Medical Sciences (GM 07739, T32GM007739)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK-41096, R01DK062388, R01-DK-62388, R01DK041096)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- leptin, congenital lipodystrophy, insulin resistance, hepatic steatosis, stearoyl-CoA desaturase 1, glucose homeostasis, insulin receptor substrate 2, PI3K/Akt signaling, acetyl-CoA carboxylase, malonyl-CoA
- MeSH terms
- Animals, Disease Models, Animal, Female, Lipodystrophy, Liver, Male, Mice, Inbred C57BL, Phylogeny, Stearoyl-CoA Desaturase, Muscle, Skeletal, Leptin, Gene Expression Profiling, Mice
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