ANTI‐OBESITY EFFECT OF SHK‐186, A K+ CHANNEL BLOCKER

Abstract

We describe the anti‐obesity effects of ShK‐186, a Kv1.3‐selective peptide inhibitor. C57BL/J mice fed a diet containing high fat (21%) diet and fructose solution (60%) were administered ShK‐186 (500 μg/kg) or vehicle on alternate days by subcutaneous injection. ShK‐186‐treatment caused a dose‐dependent reduction in weight gain over the 45‐day trial, the maximal weight difference being 30%. ShK‐186‐treatment reduced plasma levels of free fatty acids without affecting cholesterol, HDL, LDL or glucose. CT scan revealed significant reduction in volume of white adipose tissue in ShK‐186‐treated mice compared to controls. However, histology revealed no difference in cell size and fat content of white fat cells. In metabolic cage experiments, ShK‐186‐treatment increased cumulative intake of food and fluid compared to vehicle‐treated mice, especially during the light‐cycle. Furthermore, their respiratory exchange ratio and energy expenditure were also higher. In PET experiments, ShK‐186 treatment increased uptake of 18‐fluoro‐deoxyglucose (18FDG) by brown adipose tissue (BAT) and skeletal muscle compared to vehicle‐controls; pre‐administration of the beta‐adrenoceptor blocker propranolol (5mg/kg) inhibited 18FDG uptake by BAT but not skeletal muscle. ShK‐186's anti‐obesity effect appears to be mediated by activation of BAT and/or skeletal muscle, two important thermogenic tissues in the body