Effects of Npy1r limbic conditional knock-out on adipose tissue metabolism

Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacological target in obesity. While the orexigenic role of NPY in the hypothalamus is well established, its downstream effects on peripheral metabolism remain less defined, particularly when perturbations to the system are introduced. Previously, we observed that female mice with limbic NPY-Y1 receptor gene (Npy1r) knockout (KO) under different dietary conditions (standard, SD, or high-fat diet, HFD) accumulated more subcutaneous white adipose tissue (WAT) compared to wild-type in the absence of gonadal hormones, despite no changes in food intake. To deepen the mechanisms underlying these effects, we conducted molecular analyses on WAT of these mice. We found that Npy gene expression was upregulated in WAT of HFD-fed mice, regardless of genotype. However, NPY peptide levels were reduced in both KO and HFD groups, suggesting post-transcriptional regulation of NPY under metabolic stress. NPY-Y2 receptor gene (Npy2r) expression in WAT was significantly increased in both KO and HFD while Npy1r expression in WAT remained unchanged across groups. Genes involved in WAT metabolism were similarly upregulated in both KO and HFD mice, indicating that limbic Npy1r KO mimics some of the metabolic effects induced by HFD. Correlation analysis suggests that dysregulated NPY signalling may promote increased lipid storage and reduce energy expenditure. Overall, these findings highlight the complex interplay between central and peripheral NPY signalling emphasizing the importance of caution when investigating therapeutic strategies targeting single NPY receptors. Overall, these findings highlight the complex interplay between central Npy1r signalling and peripheral adipose tissue regulation. They also emphasize the importance of caution when investigating new therapeutic strategies targeting single NPY receptors, as central interventions may provoke maladaptive metabolic responses in peripheral tissues.