PPARα is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue
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Adenovirus-induced hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)α expression, which was increased during the rapid loss of fat, we infused adenovirus–leptin into PPARα −/− and PPARα +/+ mice. Despite similar degrees of hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPARα −/− mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR −/− mice. Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPARα −/− mice. PPARγ coactivator-1α rose 3-fold in the fat and 46% in the liver of wild-type mice but was unchanged in PPARα −/− mice. Although AMP-activated protein kinase could not be implicated in the lipopenic actions of hyperleptinemia, acetyl CoA carboxylase protein was reduced in the liver of wild-type but not in PPARα −/− mice. Thus, in PPARα −/− mice, up-regulation of carnitine palmitoyl transferase-1 mRNA in fat, down-regulation of acetyl CoA carboxylase in liver, and up-regulation of PPARγ coactivator-1α mRNA in both tissues are abolished, as is the reduction in their triacylglycerol content.
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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 [29]
Leptin upregulates mitochondria biogenesis through expression of PPARγ coactivator-1α.
“Additionally, leptin upregulates mitochondria biogenesis through expression of PPAR␥ coactivator-1␣ (29,31).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [29]
Recent rodent studies suggest that leptin resistance can be potentially overcome with a high enough dose.
“Recent rodent studies suggest that this can be potentially overcome with a high enough dose, 22,24 a theory similar to insulin resistance.”
From Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy† (2005) · cites this paper as [22]
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- Authors
- Lee, Y., Yu, X., Gonzales, F., Mangelsdorf, D. J., Wang, M.-Y., Richardson, C., Witters, L. A., & Unger, R. H.
- Affiliations
- Dartmouth College (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-08-23
- Volume
- 99
- Issue
- 18
- Pages
- 11848-11853
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC129357
- OpenAlex
- W1975015881
- Cited by
- 181
- References
- 20
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 6 · 2016: 2 · 2015: 7 · 2014: 8 · 2013: 8 · 2012: 7
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- U.S. Department of Veterans Affairs
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK058398, DK-35712, DK-58398, DK 02700, K08DK002700, R01DK035712, R01DK002700)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- PPARα, hyperleptinemia, leptin, adipose tissue, liver, fatty acid oxidation, PPARγ coactivator-1α, acetyl-CoA carboxylase, triglycerides, AMPK, adipocyte lipolysis, adipose tissue atrophy
- MeSH terms
- Adipose Tissue, Animals, Base Sequence, Lipolysis, Liver, Multienzyme Complexes, Oxidation-Reduction, Phosphorylation, Transcription Factors, Triglycerides, Gene Expression Regulation, Enzymologic, Polymerase Chain Reaction, Protein Serine-Threonine Kinases, DNA Primers, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Leptin, Mice, AMP-Activated Protein Kinases
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