| Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity, and increases insulin sensitivity in diet-induced obesity. | |
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MedLine Citation:
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PMID: 21490364 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Storage of excess calories as triglycerides is central to obesity and its associated disorders. Glycerol-3-phosphate acyltransferases (GPATs) catalyze the initial step in acylglyceride syntheses, including triglyceride synthesis. We utilized a novel small molecule GPAT inhibitor, FSG67, to investigate metabolic consequences of systemic pharmacological GPAT inhibition in lean and diet-induced obese (DIO) mice. FSG67 administered intraperitoneally decreased body weight and energy intake, without producing conditioned taste aversion. Daily FSG67 (5 mg/kg (15.3 μmoles/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9-10-day hypophagia (6% weight loss in pair-fed controls). Continued FSG67 maintained the weight loss despite return to baseline energy intake. Weight was lost specifically from fat mass. Indirect calorimetry showed partial protection by FSG67 against decreased rates of oxygen consumption seen with hypophagia. Despite low respiratory exchange ratio due to high-fat diet, FSG67-treated mice showed further decreased RER, beyond pair-fed controls, indicating enhanced fat oxidation. Chronic FSG67 increased glucose tolerance and insulin sensitivity in DIO mice. Chronic FSG67 decreased gene expression for lipogenic enzymes in white adipose tissue and liver, and decreased lipid accumulation in white adipose, brown adipose, and liver tissues without signs of damage. RT-PCR showed decreased gene expression for orexigenic hypothalamic neuropeptides AgRP or NPY after acute and chronic systemic FSG67. FSG67 given icv (100, 320 ηmoles) produced 24-h weight loss and feeding suppression, indicating contributions from direct CNS sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities. |
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Authors:
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Francis Paul Kuhajda; Susan Aja; Yajun Tu; Wan Fang Han; Rajaa El Meskini; Leslie E Landree; Jonathan M Peterson; Khadija Daniels; Kody Wong; Edward A Wydysh; Craig A Townsend; Gabriele V Ronnett |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-13 |
Journal Detail:
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Title: American journal of physiology. Regulatory, integrative and comparative physiology Volume: - ISSN: 1522-1490 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-4-14 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 100901230 Medline TA: Am J Physiol Regul Integr Comp Physiol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1Johns Hopkins University School of Medicine. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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