Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity.
Glycerol-3-phosphate acyltransferases (GPATs) catalyze the first step in the synthesis of glycerolipids and glycerophospholipids. Microsomal GPAT, the major GPAT activity, is encoded by at least two closely related genes, GPAT3 and GPAT4. To investigate the in vivo functions of GPAT3, we generated Gpat3-deficient (Gpat3(-/-)) mice. Total GPAT activity in white adipose tissue of Gpat3(-/-) mice was reduced by 80%, suggesting that GPAT3 is the predominant GPAT in this tissue. In liver, GPAT3 deletion had no impact on total GPAT activity but resulted in a 30% reduction in N-ethylmaleimide-sensitive GPAT activity. The Gpat3(-/-) mice were viable and fertile and exhibited no obvious metabolic abnormalities on standard laboratory chow. However, when fed a high-fat diet, female Gpat3(-/-) mice showed decreased body weight gain and adiposity and increased energy expenditure. Increased energy expenditure was also observed in male Gpat3(-/-) mice, although it was not accompanied by a significant change in body weight. GPAT3 deficiency lowered fed, but not fasted, glucose levels and tended to improve glucose tolerance in diet-induced obese male and female mice. On a high-fat diet, Gpat3(-/-) mice had enlarged livers and displayed a dysregulation in cholesterol metabolism. These data establish GPAT3 as the primary GPAT in white adipose tissue and reveal an important role of the enzyme in regulating energy, glucose, and lipid homeostasis.
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts cao_jingsong@yahoo.com.
Jingsong
J
Cao
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Sylvie
S
Perez
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Bryan
B
Goodwin
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Qingcong
Q
Lin
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Haibing
H
Peng
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Ariful
A
Qadri
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Yingjiang
Y
Zhou
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Ronald W
RW
Clark
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Mylene
M
Perreault
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
James F
JF
Tobin
Cardiovascular and Metabolic Disease Research Unit, Pfizer Worldwide Research and Development, Cambridge, Massachusetts.
Ruth E
RE
Gimeno
D052436:Adipose Tissue, White / Q000201:enzymology*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D004032:Diet / Q000009:adverse effects; D004734:Energy Metabolism / Q000235:genetics*; D005260:Female; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000235:genetics
D002784:Cholesterol; D005992:Glycerol-3-Phosphate O-Acyltransferase
GPAT; acyltransferase; lipid synthesis; phospholipid; triglyceride