Abstract 12742: Leptin Links Acute Effects of Phosphodiesterase 4 Inhibition on Weight Loss and Energy Expenditure

Abstract

Objective: Leptin has been previously shown to play an important role in maintaining insulin sensitivity and energy balance via catecholamine and cAMP dependent pathways. Since inhibition of phosphodiesterase 4 (PDE4), an enzyme that potently modulates cAMP and widely expressed in innate immune cells, causes weight loss, we hypothesized that PDE4i may mediate its effects in part via shared pathways with Leptin. Methods and Results: Diet-induced obese C57Bl/6 (DIO) mice (12 weeks of high-fat diet, HFD, 60% fat) were treated with Roflumilast (3mg/kg/day, IP; HFD-Roflu), a high affinity inhibitor of PDE4 (PDE4i) or vehicle (HFD-Veh, n=6~10 in each group). Compared to HFD-Veh, HFD-Roflu mice showed rapid (<7 days) and substantial weight loss (% of fat content, 27.3±2.7 vs 14.5±1.6), increased energy expenditure (~20%↑ in VCO 2 ,VO 2 and heat production), upregulated thermogenic genes (↑expression of Pgc-1α , Ucp-1 , Cidea and Dio-2 ) and norepinephrine (9.5±2.0 vs 27.4±2.9 pg/g) in brown adipose tissue with corresponding upregulation of the “browning” genes in white adipose tissue (WAT). PDE4i decreased plasma leptin levels (Δ Leptin of 1.5±0.8 vs . 16.7±4.4 in HFD-Veh vs HFD-Roflu from baseline to the end of treatment), with corresponding improvement in insulin sensitivity (improved ITT), hepatic steatosis and WAT inflammation (↓19.9% of CD11b + /F4/80 + cells in subcutaneous WAT). However, these effects of PDE4i were not observed in Lep ob/ob mice when treated for the same duration with similar dose (n=6), suggesting the requisite role of leptin signaling for PDE4i effects. Simultaneous treatment of DIO mice with PDE4i and leptin-neutralizing antibody (0.4 μg/g/day, SC for 6 days) abrogated the aforementioned effects of PDE4i, while administration of Leptin (0.5 ug/g/day, IP) in addition to PDE4i in Lep ob/ob mice for consecutive 6 days restored weight loss and energy expenditure, improved ITT, and increased catecholamine in both WAT (6.2±0.4 vs 27.4±2.3) and BAT (14.3±1.4 vs 24.8±2.4 pg/g) previously seen in HFD-Roflu mice (n=6). Conclusions: Our results suggest that leptin signaling is requisite for PDE4i-induced weight loss, energy expenditure and catecholamine production in obesity.