The prevalence of obesity is the leading cause of metabolic syndrome in ageing people. The NPY system plays a critical role in controlling energy balance, centrally and peripherally, but its role in the development of obesity in ageing populations is not clear. To investigate this we treated 20 week-old wild type mice with high fat diet with/without the non-brain-penetrable highly selective Y1 receptor (Y1R) antagonist BIBO3304 (0.5uM) daily for 3 weeks and compared this also to a cohort of younger mice.
Short-term pharmacological inhibition of peripheral Y1R did not affect body weight in HFD-fed older mice compared to age-matched controls, but reduced body weight gain in HFD-fed younger mice. However, despite no change in body weight, fat weights of inguinal and mesenteric depots were markedly reduced in BIBO3304-treated older mice, whereas all fat depots in younger mice were markedly reduced by the antagonism of Y1R. This is associated with a significant increase in UCP1 mRNA expression in inguinal WAT of BIBO3304-treated DIO mice, suggesting the induction of browning of white fat by the inhibition of Y1R. There was no difference in lean mass in either age group. More importantly, despite its different extents in decreasing fat weights, Y1R antagonism by BIBO3304 was able to improve glucose tolerance in both younger and older mice. Elevated basal insulin level was observed in both age groups.
These data demonstrates that short-term peripheral Y1R blockade is effective to induce metabolic benefits in both younger and ageing DIO mice. This is achieved, at least in part by increasing WAT browning. Increased dosage of BIBO3304 or treatment duration in ageing mice may be required to achieve further improved metabolic outcomes. These findings demonstrate that NPY-Y1R signalling in peripheral tissues plays an important role in HFD-induced age-related obesity, and the blockade of Y1R will promote healthier ageing.