Diacylglycerol acyltransferase 2 links glucose utilization to fatty acid oxidation in the brown adipocytes.
Brown adipose tissue uptake of glucose and fatty acids is very high during nonshivering thermogenesis. Adrenergic stimulation markedly increases glucose uptake, de novo lipogenesis, and FA oxidation simultaneously. The mechanism that enables this concerted response has hitherto been unknown. Here, we find that in primary brown adipocytes and brown adipocyte-derived cell line (IMBAT-1), acute inhibition and longer-term knockdown of DGAT2 links the increased de novo synthesis of fatty acids from glucose to a pool of TAG that is simultaneously hydrolyzed, providing FA for mitochondrial oxidation. DGAT1 does not contribute to this pathway, but uses exogenous FA and glycerol to synthesize a functionally distinct pool of TAG to which DGAT2 also contributes. The DGAT2-dependent channelling of14C from glucose into TAG and CO2was reproduced in β3-agonist-stimulated primary brown adipocytes. Knockdown of DGAT2 in IMBAT-1 affected the mRNA levels of UCP1 and genes important in FA activation and esterification. Therefore, in β3-agonist activated brown adipocytes, DGAT2 specifically enables channelling of de novo synthesized FA into a rapidly mobilized pool of TAG, which is simultaneously hydrolyzed to provide substrates for mitochondrial fatty acid oxidation.
Translational and Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, CV4 7AL, United Kingdom.
Zehra
Z
Irshad
Translational and Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, CV4 7AL, United Kingdom.
Federica
F
Dimitri
Translational and Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, CV4 7AL, United Kingdom.
Mark
M
Christian
Translational and Experimental Medicine, Division of Biomedical Sciences, Warwick Medical School, CV4 7AL, United Kingdom v.a.zammit@warwick.ac.uk.
Victor A
VA
Zammit
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000378:metabolism; D000102:Acetyl-CoA C-Acyltransferase / Q000378:metabolism; D052437:Adipocytes, Brown / Q000378:metabolism*; D000818:Animals; D019748:Carbon-Carbon Double Bond Isomerases / Q000378:metabolism; D002460:Cell Line; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics*; D004746:Enoyl-CoA Hydratase / Q000378:metabolism; D004951:Esterification; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D050155:Lipogenesis / Q000235:genetics; D051379:Mice; D010084:Oxidation-Reduction; D019998:Racemases and Epimerases / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000235:genetics
D005227:Fatty Acids; D014280:Triglycerides; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C038784:fatty acid oxidation complex; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; C516957:DGAT2 protein, mouse; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D004746:Enoyl-CoA Hydratase; D019998:Racemases and Epimerases; D019748:Carbon-Carbon Double Bond Isomerases; D005947:Glucose
DGAT; adipocytes; adipose tissue; brown adipose tissue; de novo lipogenesis; fatty acid/metabolism; lipolysis; substrate channelling; thermogenesis; β3-agonist