Expression of DGAT2 in White Adipose Tissue Is Regulated by Central Leptin Action

Abstract

Acyl-CoA:diacylglycerol acyltransferase (DGAT) enzymes catalyze the final step in mammalian triglyceride synthesis, and their functions are considered to be involved in the mechanisms of obesity, insulin resistance, and leptin resistance. Insulin receptor substrate-2 (IRS-2)-deficient mice exhibit obesity-associated with hypertrophic adipocytes and leptin resistance. Screening for transcripts of genes involved in fatty acid and triglyceride synthesis to investigate the mechanism of the hypertrophic change in the adipocytes showed that expression of DGAT2 mRNA was up-regulated in the white adipose tissue (WAT) of Irs2 ؊/؊ mice, whereas that of DGAT1 was down-regulated. This reciprocal expression of DGAT1 and DGAT2 was also observed in WAT of leptin-deficient ob/ob mice. A high fat diet also resulted in increased DGAT2 and reduced DGAT1 in the WAT of C57BL/6 mice. Induction of adipocyte hypertrophy in vitro up-regulated both DGAT1 and DGAT2 expression in 3T3-L1 cells, suggesting that adipocyte non-autonomous mechanism in vivo is required for the reciprocal changes in expression of DGAT1 and DGAT2. In fact, intracerebroventricular infusion of leptin reduced DGAT2 expression in WAT of Irs2 ؊/؊ mice and ob/ob mice, independently of DGAT1 expression. We propose the hypothesis that leptin regulates adipocyte size by altering expression patterns of DGAT via central nervous system to determine the levels of triglyceride synthesis.We have hypothesized that the size of adipocytes is inversely correlated with insulin sensitivity; namely, that larger adipocytes are associated with insulin resistance and smaller adipocytes are associated with insulin sensitivity (1). Acyl-CoA:diacylglycerol acyltransferase (DGAT) 1 is a key enzyme that catalyzes the final step in mammalian triglyceride synthesis (2), and two DGAT enzymes have been identified (3-5). Although the genes encoding DGAT1 and DGAT2 belong to different gene families, both genes are ubiquitously expressed and the enzymes they encode have similar substrate specificity (5). Dgat1 Ϫ/Ϫ mice have been reported to exhibit normal growth on a chow diet, and to be resistant to diet-induced obesity (6). Interestingly, Dgat1Ϫ/Ϫ mice exhibit increased insulin sensitivity and a leptin-sensitive phenotype associated with decreased tissue triglyceride content, suggesting that DGAT1 is somehow involved in insulin and leptin action throughout the body (7, 8). Recently, Dgat2Ϫ/Ϫ mice have been reported to exhibit marked reduction of triglyceride and fatty acids in the body, suggesting a critical role of DGAT2 in lipogenesis; however, the physiological roles of DGAT2 in adult mice are still unknown because Dgat2 Ϫ/Ϫ mice die soon after birth (9). The insulin receptor substrate (IRS) proteins play a key role in signal transduction from the insulin receptor (10, 11) and are major intracellular phosphorylation targets of activated insulin receptor tyrosine kinase. Irs2 Ϫ/Ϫ mice develop diabetes because of inadequate ␤-cell proliferation combined with insulin resistance (12-14). Another n...

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

“…Since leptin was associated with subcutaneous fat cell size as well as insulin resistance in vitro in this study, leptin may serve as a marker and possibly be a link between fat cell size and insulin resistance. On the other hand, fat cell enlargement could also develop as a consequence of leptin resistance, which could lead to elevated diacylglycerol acyltransferase 2 activity and triacylglycerol assembly [31].…”

Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis

“…10 B and F). The downregulation of mRNA for DGAT1 and other genes involved in lipogenesis in ob/ob white adipose tissue has been reported and has been attributed to dedifferentiation of adipose tissue in ob/ob mice (19,20). In contrast to GPAT3, the expression levels of mtGPAT1 and DGAT1 did not change in the liver of ob/ob mice or in adipose tissue upon rosiglitazone treatment (SI Fig.…”

Fat-specific Protein 27 Undergoes Ubiquitin-dependent Degradation Regulated by Triacylglycerol Synthesis and Lipid Droplet Formation

“…The sequences of the sense siRNAs were DGAT1, 5Ј-GAUUCUUUGUUCAGCUCAGACTT-3Ј and DGAT2, 5Ј-GACAUCUUCUCUGUCACCUGGTT-3Ј (16). Forty-eight hours after siRNA transfection, total RNA was isolated using the TRIzol reagent (Invitrogen).…”