Protection against diet-induced weight gain by a single-point mutation in Kir2.1 channels

High-fat diet (HFD)-induced obesity remains a significant global health challenge. In this study, we show that a global knock-in CRISPR mouse with the Kir2.1 L222I single-point mutation exhibits remarkable resistance to HFD-induced weight gain. Specifically, Kir2.1 L222I mutation preserves Kir2.1 currents in endothelial cells isolated from resistance arteries of overweight mice and confers protection against suppression by palmitic acid (PA), a fatty acid prevalent in obesity. Kir2.1 L222I mutation also preserves endothelium-dependent flow-induced vasodilation (FIV) both in mice on HFD and in the presence of PA. Moreover, Kir2.1 L222I confers significant protection against HFD-induced weight gain and adiposity in male mice independent of caloric intake: mutant mice gain significantly less weight on HFD, maintain body composition with higher % lean and lower % fat mass and have significantly smaller fat depots. These protective effects were independent of the food intake (the frequency and the size of the meals) and calories excreted in the feces, as no differences were found between Kir2.1 WT and Kir2.1 L222I mice on HFD. Notably, Kir2.1 L222I mutation resulted in increased Respiratory Exchange Rate (RER), enhanced physical activity during wheel exercise and spontaneous movements in metabolic cages, as well as increased energy expenditure. These findings highlight Kir2.1 channels as potential therapeutic targets for obesity and related metabolic disorders.