Obesity is a major worldwide public health problem and there is a need to find new targets for the development of new treatments. Transient Receptor Potential Canonical (TRPC) channels are a family of cationic ion channels thought to have important roles in calcium signalling. We previously showed that TRPC channels are expressed by adipocytes and that inhibition of these channels increased the concentration of circulating adiponectin, an anti-inflammatory adipokine, without effect on leptin (1). The aim of this study was to investigate if there are implications of TRPC channels when there is metabolic stress. Mice with conditional global expression of dominant-negative ion pore mutant TRPC5 (DNTRPC5) were used to suppress ion permeation in TRPC channels in vivo in adults without deleting TRPC proteins. The study was carried out on ApoE-knockout mice which develop hypercholesterolaemia. Mice were fed with western-style high fat diet for 12 weeks and male litter-mates were compared with and without suppression of TRPC ion permeation. The results are expressed as mean±SEM and compared using Student’s t-test. The difference was considered statistically significant when the probability (P) was less than 0.05. Analysis of adipose tissue showed that adiponectin mRNA was more abundant in the mice expressing DNTRPC5. mRNA of the pro-inflammatory cytokine TNFα was less abundant in adipose tissue of mice expressing DNTRPC5. These results suggest that TRPC channels are regulators of adiponectin and TNFα gene expression in adipocytes and that blocking TRPC channel could have an anti-inflammatory effect. Mice expressing DNTRPC5 showed significantly lower body weight as compared to controls after 6 weeks and 12 weeks of treatment (at 6 weeks: controls=35.8±1.46g, DNTRPC5=31.9±0.65g, P=0.036 ; at 12 weeks: controls=46.7±1.69g, DNTRPC5=40.1±0.99g, P=0.006 ; n=8-7). No obvious adverse effects on health were evident. Overall, this study suggests that ion flux through TRPC channels is a driver for weight gain and that ion pore blockers of TRPC channels could be an approach for protecting against obesity and related inflammation. All procedures were carried out with ethical approval under UK Home Office license.