Abstract
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 (MestgKO) and paternal allelic (MestpKO) 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. MestpKO 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 MestpKO, supporting a role for WAT MEST in ATE. Global profiling of WAT gene expression of HFD-fed control and MestpKO mice detected few differences between genotypes; nevertheless, genes with reduced expression in MestpKO mice were associated with immune processes and consistent with improved glucose homeostasis. Ear-derived mesenchymal stem cells (EMSC) from MestgKO 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 MestgKO 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.
Highlights
The global rise in obesity rates are caused by interactions between an individual’s genetic predisposition, the environment and epigenetic factors
An imprinted gene that is almost exclusively expressed from the paternal allele in adult mice [42,43,44,45] and highly expressed in white adipose tissue (WAT) [10, 16, 46], is completely abrogated in mice with a paternal allelic inactivation of mesoderm specific transcript (Mest) (MestpKO), but shows fully intact mRNA and protein levels when the maternal allele of Mest is selectively inactivated (MestmKO; Fig 1B and 1C)
Unlike previous observations showing abnormal maternal behavior and high incidence of postnatal mortality in mice with global or paternal inactivation of Mest on a mixed B6/129 background (Lefebvre et al 1998), our studies indicate normal litter sizes reared by dams with inactivated Mest (~8.2 pups/litter); and non-skewed gender (29 female/30 male) and genotype ratios with 14 wildtype (WT), 30 MestmKO or MestpKO and 15 MestgKO born from crosses between heterozygous females and males
Summary
The global rise in obesity rates are caused by interactions between an individual’s genetic predisposition, the environment and epigenetic factors. Recent genome wide association studies (GWAS) of 97 body mass index (BMI)-associated loci in >300K individuals was shown to account for only
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