4A, middle panel). In contrast, as compared with regular chow (CHD), none of the fatty liver–inducing diets (HSD, HFD, and MCD) affected the level of ATGL mRNA expression (Fig. 4A, right panel). It is noteworthy that although MCD diet induced the largest TG accumulation in the liver compared with feeding with other diets (Table 1), it did not have any effect on the mRNA HM781-36B expression of the three different patatin-like

family members (Fig. 4A). In any case, there was no evidence of compensatory adjustment in hepatic Pnpla5 or ATGL expression in the absence of Pnpla3 in the liver (Fig. 4A, middle and right panels). We next examined the mRNA expression of PNPLA family genes in perigonadal Everolimus ic50 WAT in wild-type and Pnpla3−/− mice. As reported previously22 and confirmed by us, Pnpla3 expression in the WAT of wild-type mice was significantly induced by HSD diet (∼2.5-fold) and slightly up-regulated by HFD diet (∼1.5-fold,

not significant; Fig. 4B, left panel). Under the same conditions, the expression of Pnpla5 was not significantly affected (Fig. 4B, open bars, middle panel). The mRNA expression of ATGL was not altered under the different diets in the wild-type WAT; furthermore, the diets did not affect ATGL mRNA in WAT in the two genotypes (Fig. 4B, right panel). Interestingly, the mRNA level of Pnpla5, normally expressed in WAT at very low level compared with the other two paralogs (Lake et al.23 and our own data), was up-regulated by ∼5-fold in Pnpla3−/− mice fed regular chow (CHD). This up-regulation of Pnpla5 was also observed in the gonadal fat of

Pnpla3−/− mice fed HSD or HFD, although a little less in the HFD group (Fig. 4B, solid bars, middle panel). It thus appears that increased mRNA expression of another patatin-like family member, Pnpla5, may partly compensate for the loss of Pnpla3 in mice, specifically in WAT, but not in liver. Genome-wide association studies have identified the Pnpla3/adiponutrin gene to be associated with obesity and insulin sensitivity,13, 21, 24 and more recently with nonalcoholic,3-5 as well as alcoholic, fatty liver disease6 and elevated AST and ALT,3, 5 implicating PNPLA3 in the control of body fat, liver fat, and whole-body glucose and lipid homeostasis. However, 上海皓元医药股份有限公司 to our surprise, we found that loss of Pnpla3 in mice does not have any effect on body weight, adiposity, or plasma lipid or glucose levels (Fig. 1 and Supporting Table 1), nor does it cause detectable alterations in hepatic TG content or serum ALT and AST levels (Table 1). Furthermore, the whole-body glucose homeostasis and insulin sensitivity remained normal. These were evident whether the Pnpla3-null mice were fed CHD, HFD, HSD, or MCD regimens or in mice bred into a genetic obesity Lepob/ob background. We conclude that Pnpla3 appears dispensable for liver TG metabolism and normal adipose development in mice.