Phosphodiesterase 4 Inhibition Attenuates Diet-Induced Obesity and Activates BAT Thermogenic Pathways Through Central Mechanisms

Obesity is marked by chronic low-grade inflammation and impaired thermogenic function of brown adipose tissue (BAT), contributing to decreased energy expenditure. BAT dissipates energy through uncoupling protein 1 (UCP1)-mediated thermogenesis, a process suppressed in obesity. Phosphodiesterase 4 (PDE4) inhibition reduces inflammation by decreasing TNF-α release, and it has been linked to protection against metabolic dysfunction. Here, we investigated the effects of rolipram, a selective PDE4 inhibitor, in a model of diet-induced obesity. Male C57Bl/6 mice were fed a chow or high-fat diet (HFD; 60% fat) for 10 weeks and treated daily with rolipram (2 mg/kg, subcutaneous) or vehicle from week 8 on. Rolipram reduced body weight and adiposity in HFD-fed mice. It also enhanced BAT function, increasing thermogenic gene expression, UCP1 protein, noradrenaline content, and BAT temperature. PDE4 inhibition increased energy expenditure and heat production without altering locomotor activity. Corroborating these data, rolipram elevated cFOS expression and increased membrane excitability in neurons of the hypothalamic paraventricular nucleus, suggesting activation of hypothalamic pathways involved in energy balance and thermoregulation. These findings show that PDE4 inhibition attenuates diet-induced obesity by stimulating BAT thermogenesis and energy expenditure at least partially through central mechanisms, supporting PDE4 as a promising target for obesity treatment. ARTICLE HIGHLIGHTS Metabolic alterations in obesity encompass impaired thermogenesis and sympathetic activity, underscoring the need for new metabolic targets to treat this disease. This study tested whether inhibition of PDE4 by rolipram enhances energy expenditure and brown adipose tissue activity. Rolipram reduced body weight and adiposity and increased brown adipose tissue temperature, UCP1 protein levels, noradrenaline levels, and enhanced excitability of hypothalamic paroventricular nucleus neurons. These findings suggest that central PDE4 inhibition promotes brown adipose tissue thermogenic activity and contributes to the metabolic effects of rolipram.