Abstract

Transient Receptor Potential Canonical (TRPC) proteins assemble to form calcium-permeable non-selective cationic channels. We previously showed that TRPC1 and TRPC5 are expressed by adipocytes and that their inhibition increased the concentration of circulating adiponectin, which is an important anti-inflammatory and insulin-sensitising adipokine (Sukumar et al 2012, Circ Res 111, 191). The aim of this study was to investigate if the channels are relevant in hypercholesterolaemia. ApoE-knockout mice with conditional global expression of dominant-negative ion pore mutant TRPC5 (DNT5) were used to suppress ion permeation in the channels in vivo. Mice were fed with western-style diet and male litter-mates were compared with and without DNT5. Mice expressing DNT5 had significantly lower body weight compared to controls after 6 weeks and 12 weeks of treatment. Histological analysis showed significant reduction in adipocyte size. Quantitative RT-PC R analysis of adipose tissue showed that adiponectin mRNA was more abundant in the DNT5 group. By contrast, TNF-alpha and interleukin-6 mRNA were less abundant. No obvious adverse effects of DNT5 were evident. The data suggest that ion flux through heteromeric TRPC1/TRPC5 channels is a driver for weight gain, suppression of adiponectin gene expression and increased inflammation in hypercholesterolaemic mice. Therefore, inhibitors of the ion channels could be a strategy for protecting against obesity, insulin-resistance and inflammation.

Supported by the Medical Research Council