Increased spontaneous physical activity in female MEST-deficient mice protects against diet-induced obesity

Mesoderm-specific transcript (Mest), a paternally expressed imprinted gene, is involved in the modulation of adipose tissue expansion. Mest is also highly expressed in the developing and adult brain, suggesting a role in behavioral phenotypes. Previously, we showed that female mice with paternal Mest inactivation (Mest ^pKO) exhibit no discernible behavioral impairments compared to wild-type mice. In this study, we performed metabolic phenotyping of female Mest ^pKO mice in response to a dietary challenge.

Eight-week-old female and male wild-type and Mest ^pKO mice were fed a control or Western diet (40 kcal% fat) until 24 weeks of age. Body weight, body composition, and metabolic parameters were measured during the course of the feeding regimens, and gene expression and type-2-deiodinase (DIO2) activity were examined in white adipose tissue and brain at the end of the study.

Mest ^pKO female mice fed a Western diet were protected against diet-induced obesity. Strikingly, these mice showed increased ambulatory activity and speed, coupled with reduced resting parameters, suggesting a role for MEST in the regulation of spontaneous physical activity, a form of nonexercise activity thermogenesis. When considering body mass (control diet) and lean mass (Western diet), energy expenditure was increased in the female Mest ^pKO mice. Male Mest ^pKO mice did not exhibit these changes. Analyses of hypothalamic gene expression revealed upregulation of Dio2, and RNA-seq highlighted differential expression of numerous thyroid hormone-responsive genes in Mest ^pKO female mice.

Mechanistically, our results suggest that MEST directly or indirectly regulates thyroid hormone-responsive genes in the hypothalamus, thereby modulating the neurobiological control of nonexercise activity thermogenesis in Western diet-fed female mice.