Monoacylglycerol Acyltransferase (MGAT) 1 and 2 Play Divergent Roles in Adipogenesis/Lipogenesis in Mice

Abstract

Monoacylglyerol acyltransferase (MGAT) catalyzes the synthesis of diacylglycerol, the precursor of triacylglycerol. Mogat1‐3 genes have been identified to code for the enzymes MGAT1‐3, respectively. Among them, MGAT1 and MGAT2 are expressed in mice and humans. Both MGATs share similarity in protein sequences and biochemical activities in vitro; however, they have different tissue expression patterns. In mice, MGAT2 is mainly expressed in intestine and its physiological roles are well established: mice deficient in MGAT2 have greatly reduced intestinal MGAT activity, show delayed fat absorption and increased energy expenditure, and are protected from obesity and associated metabolic disorders. MGAT1, on the other hand, is expressed in tissues where MGAT activity is not prominent, including stomach, kidney, and adipose tissue. Its hepatic expression is induced in models of non‐alcoholic fatty livers. However, the functions of MGAT1 in vivo remain unclear. To determine the physiological role of MGAT1, we examined mice deficient in the enzyme. Mogat1−/− mice appeared normal during suckling and when fed with regular chow diet; however, none of their tissues examined exhibited significant reduction in MGAT activity. When fed with high‐fat diet or crossed with the hyperphagic Agouti mice, Mogat1−/− mice had reduced energy expenditure with decreased locomotor activity, and accrued more fat mass with enlarged lipid droplets in both white and brown adipocytes. Excessive fat accumulation in Mogat1−/− mice was associated with glucose intolerance and insulin resistance. Thus, in response to excess calories, Mogat1−/− have phenotypes opposite to Mogat2−/− mice in body weight and fat mass. To further address whether either MGAT deficiency can affect the development of adipocytes, in which MGAT1 and MGAT2 are found, we examined ear mesenchymal stem cells (EMSCs) from both Mogat1−/− and Mogat2−/− mice. With both MGATs expressed in EMSCs, Mogat1 expression is induced over time upon adipogenesis induction with the differentiation cocktail containing insulin, dexamethasone, and 3‐isobutyl‐1‐methylxanthine; whereas Mogat2 expression is only detected without induction. Before induction, both Mogat1−/− and Mogat2−/− EMSCs exhibited high expression levels of the late stage adipogenesis regulator, CEBPα, and several lipogenic genes. Upon induction, Mogat1−/− and Mogat2−/− EMSCs had divergent responses to the differentiation cocktail. Mogat1−/− EMSCs exhibited enhanced lipogenesis as indicated by an increase in lipid droplet formation and expression of the lipid droplet protein, perilipin1. Mogat2−/− EMSCs, however, exhibited limited adipogenesis/lipogenesis as indicated by a decrease in lipid droplets and in the induction of adipocyte marker aP2, perilipin1, and lipogenic genes. Thus, parts of the effects of either MGAT deficiency on adiposity are possibly cell‐autonomous. Despite the MGAT activities in vitro, MGATs might play as different physiological roles in the adipose tissue.Support or Funding InformationThis work was funded by the National Institutes of Health Grant DK088210 and US Department of Agriculture Grant WIS01442.