Abstract
Background: Inwardly Rectifying Potassium Channel 2.1 (Kir2.1) plays a role in the maintenance of membrane potential and is strongly suppressed by membrane cholesterol and diet-induced hypercholesterolemia. Specifically, Kir2.1 is critical for flow-induced vasodilation in mice. To determine the role of cholesterol-induced suppression of Kir2.1 channels in weight maintenance and energy metabolism under high fat diet (HFD) conditions, we generated a CRISPR mouse expressing a cholesterol-insensitive Kir2.1 mutant, Kir2.1 L222I . Objective: In this study, we demonstrate that Kir2.1 L222I has a protective effect against diet induced obesity, induces changes in mesenteric metabolism, and increased respiratory rate. Methods: C57/BL6J (WT) male mice with the Kir2.1 L222I mutation were fed HFD and weighed after 15 weeks. Mouse feeding was assessed using BioDaq and nuclear magnetic resonance (NMR) determined body composition. Techniplast and iWorx metabolic cages were used for fecal and respiratory analysis. Metabolomic analysis was done on mesentery. Results: Initially, WT (n=6) and Kir2.1 L222I (n=7) male mice weighed the same. After 15 weeks on HFD Kir2.1 L222I mice weighed 16% less than WT mice (p=0.003). Kir2.1 L222I mice also had improved body composition with lean-to-fat ratio a statistically significant 69% greater than WT. Changes in body mass do not depend on feeding behavior as there was no difference between Kir2.1 L222I (n=8) and WT (n=6). The Kir2.1 L222I mice do not excrete more feces than WT (n=5) in terms of weight or caloric content. Kir2.1 L222I mice have increased respiration compared to WT as their exchange rate was a statistically significant 14% higher indicating that Kir2.1 L222I mice burn more calories through respiration. Metabolomic pathway analysis did not identify any changes in carbohydrate or mitochondrial metabolism. However, it identified changes in amino acid and lipid metabolism, specifically, methionine and choline metabolites. Conclusions: The Kir2.1 L222I mutation is protective against weight gain and associated changes in body composition in male mice up to 3 months on diet. Increased respiration may explain this protection. Metabolomics indicated an increase in Akt-dependent amino acid and lipid metabolism.
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