Abstract 016: Sex-Specific Effects of Neuropeptide Y2 Receptor (y2) Deletion in Adipose Tissue From Mice Exposed to Early Life Stress

Abstract

Neuropeptide Y (NPY) plays a critical role in the regulation of energy homeostasis acting in the central nervous system as an orexigenic agent. Peripherally, NPY is co-released by catecholaminergic neurons and stimulates adipocyte precursor proliferation, differentiation, via NPY receptor 2 (Y2), and inhibit lipolysis, via the cAMP/PKA pathway. We have shown that female mice exposed to a model of early life stress, maternal separation and early weaning (MSEW), display greater increases in fat mass in response to high fat diet (HF). Thus, we hypothesized that Y2 deletion in adipose tissue could prevent fat expansion in female MSEW mice. MSEW was performed by separating pups from the dam during postnatal days 2 to 16, and weaned early on day 17. Control (C) mice remained undisturbed and were weaned on day 21. Genotyping was completed to determine WT (Y2 fl/fl) and Y2 KO (Y2 fl/fl) littermates. All groups were placed on a HF (60% kcal from fat) for 18 weeks. Following, mice were subjected to 6-weeks of chronic restraint stress (1 hr/day) combined with high fat/high sucrose diet (RS+HFS). No differences in fat mass were found between male WT MSEW and C mice (37.5±2.0 vs. 41.9±2.3 % body fat, respectively), although Y2 KO reduced fat mass in both groups (23.2±2.3 vs. 38.1±2.9 % body fat, p MSEW=0.084, p genotype=0.011, p interaction=0.401). Conversely, female WT MSEW mice displayed increased fat mass compared to C (26.4±2.6 vs. 19.1±2.6 % body fat), and Y2 KO further increased fat deposition in MSEW female mice compared to C (36.1±4.3 vs. 15.8±1.2 % body fat, p MSEW=0.0001, p genotype=0.047, p interaction=0.007). In addition, female WT MSEW mice displayed reduced free fatty acid release in response to an in vivo lipolysis test in compared to C (101±21 vs. 167±12 uM/ml, p=0.066). After RS+HFS, MSEW increased fat mass in male WT mice more than in female WT mice, while Y2 KO attenuated this effect in both sexes. These data suggests that Y2 in adipose tissue may contribute to reduced lipolysis in HF-fed female mice exposed to MSEW. However, Y2-mediated effects of chronic stress on fat expansion in adult life are greater in male than in female MSEW mice. Overall, our data shows that there is possibly a sex-specific imbalance between adipogenesis and lipolysis in response to different stressors.