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Pharmacological Glycerol-3-phosphate Acyltransferase Inhibition Decreases Food Intake and Adiposity and Increases Insulin Sensitivity in Diet-induced Obesity
American Journal of Physiology : Regulatory, Integrative and Comparative Physiology (2011)
  • Francis P. Kuhajda, Johns Hopkins University School of Medicine
  • Susan Aja, Johns Hopkins University School of Medicine
  • Yajun Tu, Johns Hopkins University School of Medicine
  • Wan Fang Han, Johns Hopkins University School of Medicine
  • Susan M. Medghalchi, Johns Hopkins University School of Medicine
  • Rajaa El Meskini, Johns Hopkins University School of Medicine
  • Leslie E. Landree, Johns Hopkins University School of Medicine
  • Jonathan M. Peterson, Johns Hopkins University School of Medicine
  • Khadija Daniels, Johns Hopkins University School of Medicine
  • Kody Wong, Johns Hopkins University School of Medicine
  • Edward A. Wydysh, Johns Hopkins University School of Medicine
  • Craig A. Townsend, Johns Hopkins University School of Medicine
  • Gabriele V. Ronnett, Johns Hopkins University School of Medicine
Abstract
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 μmol/kg) produced gradual 12% weight loss in DIO mice beyond that due to transient 9- to 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 a high-fat diet, FSG67-treated mice showed further decreased respiratory exchange ratio, 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 intracerebroventricularly (100 and 320 nmol icv) produced 24-h weight loss and feeding suppression, indicating contributions from direct central nervous system sites of action. Together, these data point to GPAT as a new potential therapeutic target for the management of obesity and its comorbidities.
Keywords
  • pharmacological,
  • glycerol-3-phosphate,
  • acyltransferase,
  • inhibition,
  • food intake,
  • adiposity,
  • insulin sensitivity,
  • diet,
  • obesity
Publication Date
July 1, 2011
DOI
10.1152/ajpregu.00147.2011
Citation Information
Francis P. Kuhajda, Susan Aja, Yajun Tu, Wan Fang Han, et al.. "Pharmacological Glycerol-3-phosphate Acyltransferase Inhibition Decreases Food Intake and Adiposity and Increases Insulin Sensitivity in Diet-induced Obesity" American Journal of Physiology : Regulatory, Integrative and Comparative Physiology Vol. 301 Iss. 1 (2011) p. R116 - R130 ISSN: 0002-9513
Available at: http://works.bepress.com/jonathan-peterson/12/