Abstract P192: Trpc6 Deficiency Causes Obesity, Impaired Glucose Tolerance and Leptin Resistance

Abstract

Transient receptor potential cation channel subfamily C member 6 (TPRC6) is a receptor-operated cation channel that contributes to changes in cytosolic free Ca 2+ concentration. TRPCs have been suggested to play a role in the regulation of neurite outgrowth, synapse formation, and neuronal survival. However, the role of TRPC6 in controlling metabolic and cardiovascular functions is still unclear. We therefore investigated the impact of TRPC6 on regulation of energy balance, metabolic and cardiovascular functions and anorexic responses to leptin in male and female TRPC6 knockout mice and control B6/129 mice, including assessment of body weight (BW), food intake (FI), body fat/lean composition, responses to acute leptin injection, glucose tolerance tests (GTTs), and blood pressure (BP) and heart rate (HR). TRPC6 null mice of both sexes were heavier than control mice from 6 to 16 weeks of age when fed a standard diet (39.5 ± 1.5 vs 31.1 ± 1.2 g in males and 31.1 ± 1.2 vs 22.9 ± 1.0 in females at 16 weeks of age, n=7, p <0.05). EchoMRI scans showed that the higher body weight in TRPC6 null mice was mainly due to increased body fat compared to controls (30.0 % vs 22.6 % of fat mass/BW in males and 32.7 % vs 21.0 % in females at 16 weeks of age), and was associated with increased daily FI (3.4 ± 0.1 vs 2.7 ± 0.2 g in males and 2.7 ± 0.1 vs 2.0 ± 0.1 in females at 16 weeks of age, n=7, p <0.05). Acute leptin injections (5 mg/kg, i.p. at 18 weeks of age, n=7) significantly reduced 24-hr FI by 41 % and 32 % in male and female control mice, while only an 8 % and 18 % reduction in FI were observed in male and female TRPC6 null mice. At 20 weeks of age, male and female TRPC6 null mice also exhibited impaired glucose tolerance during GTT compared to controls (AUC: 16,138 ± 1,877 vs 8,016 ± 1,476 mg/dL x 120 min in males, and 6,152 ± 1,173 vs 1,975 ± 512 mg/dL x 120 min in females, n=7, p <0.05). BP and HR measured by telemetry for 5 consecutive days at 22 weeks of age were similar between groups. Our results indicate that TRPC6 plays an important role in normal control of food intake, body weight and glucose homeostasis as well as for leptin’s anorexic action. Although TRPC6 deficiency caused obesity and metabolic abnormalities, BP and HR did not increase.