Ambient Temperature Modulates the Effects of Peripheral Y1R Antagonism on Diet-induced Obesity and Glucose...

The neuropeptide Y1 receptor (Y1R) plays a key role in metabolic regulation, and its peripheral antagonism has shown promise in promoting weight loss and improving glucose metabolism. However, most studies are conducted at room temperature (RT, 21-22°C), where mild cold stress stimulates sympathetic nervous system (SNS) activation. The impact of Y1R blockade under thermoneutral (TN, 30°C) conditions, which eliminate cold stress, remains unclear. In this study, we investigated the effects of BIBO3304 on body weight, energy expenditure (EE), and glucose metabolism in chow- and high-fat diet (HFD)-fed mice housed at TN and compared the results with RT. We found that at RT, BIBO3304 significantly reduced body weight gain and fat mass while increasing EE and fat oxidation. These effects were abolished under TN, where SNS activation is minimized, leading to no changes in body composition or EE. Despite this, BIBO3304 improved glucose tolerance at TN, particularly in the early phase (week 2), independent of insulin sensitivity. However, these glucose-lowering effects diminished by week 6, suggesting a potential SNS-dependent mechanism for long-term benefits. TN-housed mice exhibited greater glucose excursions and reduced insulin sensitivity compared to RT-housed mice, highlighting the impact of ambient temperature on metabolic regulation. In summary, these findings suggest that BIBO3304's effects on energy balance are SNS-dependent, whereas its glucose-lowering benefits persist transiently at TN. This highlights the need to consider environmental temperature in the evaluation of pharmacological interventions for obesity and diabetes, with potential implications for climate-adjusted dosing strategies.

Peripheral Y1R blockade-induced reductions in body weight and enhancements in energy expenditure at room temperature are abolished under thermoneutrality, irrespective of dietary fat content.Glucose-lowering effects of peripheral Y1R antagonism persist under thermoneutrality, independent of changes in body weight and insulin sensitivity.Chronic thermoneutrality blunts the ability of peripheral Y1R blockade to ameliorate fat-induced glucose intoleranceThese findings emphasize the temperature-dependent efficacy of metabolic drugs and the need for climate-adjusted therapeutic strategies.