306-OR: PEA15 Regulates Metabolism and Adiposity in a Sex-Dependent Manner through Alterations in Metabolic Flexibility

Phosphoprotein enriched in astrocytes 15kDa (PEA15) is a ubiquitously expressed cytosolic protein with high expression in the brain, and enhanced expression in the hypothalamus. Humans with type 2 diabetes mellitus have increased expression of PEA15 in adipose tissue and skeletal muscle, and overexpression of PEA15 in transgenic mice and pigs results in peripheral insulin resistance. Despite these findings, studies of PEA15 in high fat diet (HF)-mediated obesity are limited. Male and female Pea15-/- mice (KO) and littermate controls (WT) were fed a control diet (CD) or HF for 20 weeks, with a GTT at 19 weeks and metabolic cage data at 20 weeks, just prior to serum and tissue collection. The effects of PEA15 on metabolic parameters varied based on sex. Female KO mice fed HF had a significant increase in body weight due to increased inguinal adipose and liver weight, and impaired insulin sensitivity compared to HF-fed WT females. The KO mice had similar food intake but decreased activity during the light cycle compared to HF-fed WT female mice. In contrast, a genotypic effect in male mice was noted in CD-fed mice with KO mice having an increased body weight and corresponding increases in inguinal and gonadal adipose compared to WT with no significant change in insulin sensitivity, food intake or energy expenditure. KO males on CD were significantly more active during the light phase than WT controls despite increased body weight. Substrate utilization and its associated diurnal switch were altered in both sexes of KO mice compared to WT, with KO male mice having increased preference towards carbohydrate utilization while female KO mice had increased lipid utilization. These findings suggest that PEA15 regulates metabolism in a sex-dependent manner through alterations in metabolic flexibility, energy substrate utilization, and diurnal rhythms. Further work will investigate the sex-dependent role of PEA15 on central and peripheral regulators of diurnal rhythm and metabolism.