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Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats
Open accessAbstract
Short-term overfeeding blunts the central effects of fatty acids on food intake and glucose production. This acquired defect in nutrient sensing could contribute to the rapid onset of hyperphagia and insulin resistance in this model. Here we examined whether central inhibition of lipid oxidation is sufficient to restore the hypothalamic levels of long-chain fatty acyl-CoAs (LCFA-CoAs) and to normalize food intake and glucose homeostasis in overfed rats. To this end, we targeted the liver isoform of carnitine palmitoyltransferase-1 (encoded by the CPT1A gene) by infusing either a sequence-specific ribozyme against CPT1A or an isoform-selective inhibitor of CPT1A activity in the third cerebral ventricle or in the mediobasal hypothalamus (MBH). Inhibition of CPT1A activity normalized the hypothalamic levels of LCFA-CoAs and markedly inhibited feeding behavior and hepatic glucose fluxes in overfed rats. Thus central inhibition of lipid oxidation is sufficient to restore hypothalamic lipid sensing as well as glucose and energy homeostasis in this model and may be an effective approach to the treatment of diet-induced obesity and insulin resistance.
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“Hypothalamic levels of long-chain fatty acyl-Coenzyme As have been shown to regulate rodent feeding behaviour and glucose homeostasis37”
From Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies (2010) · cites this paper as [37]
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“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [77-80].”
BackgroundResult
Metadata
- Authors
- Pocai, A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Corresponding author
- Pocai, A.
- ORCID
- Pocai, A.
- Venue
- Journal of Clinical Investigation
- Published
- 2006-03-23
- Volume
- 116
- Issue
- 4
- Pages
- 1081-1091
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1395479
- OpenAlex
- W2156594005
- Cited by
- 211
- References
- 52
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 4 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 3 · 2017: 9 · 2016: 15 · 2015: 9 · 2014: 6 · 2013: 17 · 2012: 23
- FWCI
- 8.68
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- Skirball Foundation
- National Institutes of Health
- Albert Einstein College of Medicine, Yeshiva University
- National Institute on Aging (P01AG021654, AG 21654, T32AG023475)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-48321, R01DK045024, R01DK048321, R37DK048321, DK20541, P60DK020541, DK-45024, P30DK020541)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- overfeeding, CPT1A, carnitine palmitoyltransferase 1, long-chain fatty acyl-CoA, lipid oxidation, hyperphagia, insulin resistance, diet-induced obesity, glucose homeostasis, energy homeostasis, hepatic glucose production, ribozymes, mediobasal hypothalamus, fatty acid signaling
- MeSH terms
- Animals, Carnitine O-Palmitoyltransferase, Energy Metabolism, Glucose, Homeostasis, Hyperphagia, Hypothalamus, Liver, Male, Models, Biological, Oxidation-Reduction, Rats, Sprague-Dawley, Lipid Metabolism, Rats
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