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Interindividual variation of white adipose tissue (WAT) expression of mesoderm specific transcript ( Mest ), a paternally-expressed imprinted gene belonging to the α/β-hydrolase fold protein family, becomes apparent among genetically inbred mice fed high fat diet (HFD) and is positively associated with adipose tissue expansion (ATE). To elucidate a role for MEST in ATE, mice were developed with global and adipose tissue inactivation of  Mest . Mice with homozygous ( Mest   gKO  ) and paternal allelic ( Mest   pKO  ) inactivation of  Mest  were born at expected Mendelian frequencies, showed no behavioral or physical abnormalities, and did not perturb expression of the  Mest  locus-derived microRNA miR-335.  Mest   pKO   mice fed HFD showed reduced ATE and adipocyte hypertrophy, improved glucose tolerance, and reduced WAT expression of genes associated with hypoxia and inflammation compared to littermate controls. Remarkably, caloric intake and energy expenditure were unchanged between genotypes. Mice with adipose tissue inactivation of  Mest  were phenotypically similar to  Mest   pKO  , supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and  Mest   pKO   mice detected few differences between genotypes; nevertheless, genes with reduced expression in  Mest   pKO   mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from  Mest   gKO   mice showed no differences in adipogenic differentiation compared to control cells unless challenged by shRNA knockdown of  Gpat4 , an enzyme that mediates lipid accumulation in adipocytes. Reduced adipogenic capacity of EMSC from  Mest   gKO   after  Gpat4  knockdown suggests that MEST facilitates lipid accumulation in adipocytes. Our data suggests that reduced diet-induced ATE in MEST-deficient mice diminishes hypoxia and inflammation in WAT leading to improved glucose tolerance and insulin sensitivity. Since inactivation of  Mest  in mice has minimal additional effects aside from reduction of ATE, an intervention that mitigates MEST function in adipocytes is a plausible strategy to obviate obesity and type-2-diabetes.

Diet-induced adipose tissue expansion is mitigated in mice with a targeted inactivation of mesoderm specific transcript (Mest)