title: Pharmacological glycerol-3-phosphate acyltransferase inhibition decreases food intake and adiposity and increases insulin sensitivity in diet-induced obesity.
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.
authors.affiliation: Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, 855 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Kuhajda
authors.forename: Susan
authors.initials: S
authors.lastname: Aja
authors.forename: Yajun
authors.initials: Y
authors.lastname: Tu
authors.forename: Wan Fang
authors.initials: WF
authors.lastname: Han
authors.forename: Susan M
authors.initials: SM
authors.lastname: Medghalchi
authors.forename: Rajaa
authors.initials: R
authors.lastname: El Meskini
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Landree
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Peterson
authors.forename: Khadija
authors.initials: K
authors.lastname: Daniels
authors.forename: Kody
authors.initials: K
authors.lastname: Wong
authors.forename: Edward A
authors.initials: EA
authors.lastname: Wydysh
authors.forename: Craig A
authors.initials: CA
authors.lastname: Townsend
authors.forename: Gabriele V
authors.initials: GV
authors.lastname: Ronnett
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000502:physiology*; D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D013851:Thinness / Q000378:metabolism / Q000503:physiopathology; D014280:Triglycerides / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D009478:Neuropeptide Y; D014280:Triglycerides; D005992:Glycerol-3-Phosphate O-Acyltransferase