MGAT2 deficiency increases energy expenditure even in the absence of dietary fat and protects against obesity in hyperphagic agouti mice

Acyl CoA: monoacylglycerol acyltransferase (MGAT) 2 is believed important in dietary fat absorption. Mice deficient in this enzyme (Mgat2 −/− ) are protected from obesity when fed a high‐fat diet. Surprisingly, these mice absorb normal quantities of fat but have increased energy expenditure (EE). To examine the role of dietary fat in metabolic alterations of Mgat2 −/− mice, we fed mice diets containing 10, 45, or 60% calories from fat. Mgat2 −/− mice exhibited 8–15% increases in EE compared to wildtype littermates with higher levels of dietary fat exacerbating the differences. Interestingly, dietary fat is not required, as Mgat2 −/− mice fed a fat‐free diet showed elevated EE similar to when they were fed the 10% fat diet. These differences were closely linked to the consumption of meals. Further, Mgat2 −/− mice expend energy and lose weight to similar degrees as wildtype mice during fasting. To examine if Mgat2 deficiency protects against obesity in the absence of high‐fat feeding, we crossed Mgat2 −/− mice with hyperphagic, genetically obese Agouti mice. Mgat2 deficiency increased EE and prevented Agouti mice from gaining excess weight, even when fed a low‐fat chow. Our results suggest that MGAT2 modulates EE through multiple mechanisms, including one independent of dietary fat, and that inhibiting MGAT2 may be useful in combating obesity and related metabolic disorders. Funding: UW‐Madison, AHA, USDA, and NIH.