Glycerol-3-phosphate Acyltransferase Isoform-4 (GPAT4) Limits Oxidation of Exogenous Fatty Acids in Brown Adipocytes.
Glycerol-3-phosphate acyltransferase-4 (GPAT4) null pups grew poorly during the suckling period and, as adults, were protected from high fat diet-induced obesity. To determine why Gpat4(-/-) mice failed to gain weight during these two periods of high fat feeding, we examined energy metabolism. Compared with controls, the metabolic rate of Gpat4(-/-) mice fed a 45% fat diet was 12% higher. Core body temperature was 1 ºC higher after high fat feeding. Food intake, fat absorption, and activity were similar in both genotypes. Impaired weight gain in Gpat4(-/-) mice did not result from increased heat loss, because both cold tolerance and response to a β3-adrenergic agonist were similar in both genotypes. Because GPAT4 comprises 65% of the total GPAT activity in brown adipose tissue (BAT), we characterized BAT function. A 45% fat diet increased the Gpat4(-/-) BAT expression of peroxisome proliferator-activated receptor α (PPAR) target genes, Cpt1α, Pgc1α, and Ucp1, and BAT mitochondria oxidized oleate and pyruvate at higher rates than controls, suggesting that fatty acid signaling and flux through the TCA cycle were enhanced. To assess the role of GPAT4 directly, neonatal BAT preadipocytes were differentiated to adipocytes. Compared with controls, Gpat4(-/-) brown adipocytes incorporated 33% less fatty acid into triacylglycerol and 46% more into the pathway of β-oxidation. The increased oxidation rate was due solely to an increase in the oxidation of exogenous fatty acids. These data suggest that in the absence of cold exposure, GPAT4 limits excessive fatty acid oxidation and the detrimental induction of a hypermetabolic state.
From the Departments of Nutrition and.
Daniel E
DE
Cooper
From the Departments of Nutrition and.
Trisha J
TJ
Grevengoed
From the Departments of Nutrition and Medicine, University of North Carolina, Chapel Hill, North Carolina 27599.
Eric L
EL
Klett
From the Departments of Nutrition and rcoleman@unc.edu.
Rosalind A
RA
Coleman
D017667:Adipocytes / Q000201:enzymology / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005227:Fatty Acids / Q000378:metabolism*; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D022722:Thermogenesis / Q000235:genetics; D014280:Triglycerides / Q000378:metabolism; D015430:Weight Gain
D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; C529425:GPAT4 protein, mouse; D005992:Glycerol-3-Phosphate O-Acyltransferase
adipose tissue; energy metabolism; fatty acid metabolism; lipid droplet; lipid signaling