Bombesin receptor-activated protein homolog deficiency reduces food intake and alleviates metabolic dysfunction in high-fat diet treated mice.

In our previous study, we found that both bombesin receptor-activated protein (BRAP) and its mouse homolog, BC004004, are expressed in the central nervous system, although their functions remain unclear. In feeding experiments, BRAP homolog knockout mice (BC004004-/-) showed reduced preference for a high-fat diet (HFD) compared with wild-type controls. After four months of HFD treatment, BC004004-/- mice had lower food intake and weight gain, along with reduced fasting blood glucose, insulin, triglycerides, and low-density lipoprotein cholesterol levels. Histological analysis revealed less hepatic steatosis, renal injury, and white adipose tissue (WAT) hypertrophy in the BC004004-/- mice. qPCR analysis of inguinal fat tissues showed increased expression of thermogenic markers (UCP1, Prdm16, Tfam) in BC004004-/- mice, indicating enhanced WAT "browning". Oil red O staining showed that overexpression of the BC004004 gene in cultured mouse microglia BV2 cells increased palmitic acid-induced lipid deposition and higher levels of the proinflammatory cytokines IL-1β and TNF-α, as measured by ELISA of culture supernatants. Additionally, qPCR showed lower agouti-related peptide (AgRP) and neuropeptide Y (NPY) expression and higher proopiomelanocortin (POMC) and melanocortin receptors 4 (MC4R) expression in the hypothalamus of BC004004-/- mice, possibly contributed to their reduced food intake and weight gain. These results suggest that BRAP homolog deficiency protects against HFD-induced metabolic dysfunction through multiple mechanisms, including alterations in hypothalamic neuronal circuits and adipose tissue biology.