Abstract
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 of 14C from glucose into TAG and CO2 was 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.
Highlights
Brown adipose tissue uptake of glucose and fatty acids is very high during nonshivering thermogenesis
We studied the profile of mRNA expression for both DGATs, compared with the differentiation marker aP2 during brown adipocyte differentiation
In view of the preferential activation of the esterification of de novo synthesized FA into TAG labeled from glucose, we studied the possibility that DGAT1 and DGAT2 may have different roles in the esterification of newly synthesized FA into TAG after 3-stimulation of IMBAT-1 cells
Summary
Brown adipose tissue uptake of glucose and fatty acids is very high during nonshivering thermogenesis. DGAT2 participates in the maintenance of the TAG pool(s) in lipid droplets through the lipolysis-reesterification cycling that occurs between TAG and DG [4], the esterification between preformed FA and partial glycerides is primarily performed by DGAT1 in HepG2 cells [1] and in murine liver [5] This is consistent with the observations that Dgat 1 / and Dgat 2 / mice have very different phenotypes, with Dgat 1 / animals having a metabolically favorable phenotype (including lower plasma and tissue TAG) [6], whereas Dgat 2 / animals die within several hours after birth and are devoid of TAG (lipopenic) [7]. The wider applicability of this functional specialization of DGAT2 to other tissues and conditions remains to be determined [8, 9]
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