Abstract
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.
Highlights
Glycerol-3-phosphate acyltransferase-4 (GPAT4) is a major glycerol-3-phosphate acyltransferase (GPAT) isoform in brown adipose tissue (BAT)
These data suggest that mice lacking GPAT4 grow poorly when fat is the predominant macronutrient in the diet, both during the suckling period and with high fat feeding
The initial report describing Gpat4Ϫ/Ϫ mice suggested that they were protected from diet and genetically induced obesity, and that their higher metabolic rate at 2 months resulted from an inadequate insulating subdermal adipose tissue layer [5]
Summary
GPAT4 is a major glycerol-3-phosphate acyltransferase (GPAT) isoform in brown adipose tissue (BAT). Mice deficient in GPAT4 are protected from diet and genetically induced obesity, and, compared with controls, their metabolic rate was reported to be 5% higher [5]. This metabolic phenotype had been attributed to the absence of a subdermal adipose layer at 12 weeks of age [7]. To determine whether Gpat4Ϫ/Ϫ mice are resistant to adipose tissue accumulation because of a broader influence on energy metabolism and to investigate the mechanism whereby GPAT4-deficient mice are protected from obesity, we characterized the growth and weight gain of littermate control and. Our studies provide evidence that the lack of GPAT4 protects mice from obesity because GPAT4 normally limits the oxidation of exogenously provided FA by brown adipocytes
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