Cholesterol sensitivity of a ubiquitous K+ channel, Kir2.1 plays a role in weight gain and healthspan in mice
Authors: Beverley Katie , Granados Sara , Xu Pingwen , Levitan Irena 
Published: May 2023

Background: Inwardly Rectifying Potassium Channel 2.1 (Kir2.1) a ubiquitously expressed K+ channel with the main functions of the maintenance of membrane potential and K+ homeostasis is known to be strongly suppressed by the elevation of membrane cholesterol and diet-induced hypercholesterolemia. To determine the role of cholesterol-induced suppression of Kir2.1 channels in overall health under high fat diet (HFD) conditions, we generated a CRISPR mouse expressing a cholesterol-insensitive Kir 2.1 mutant, Kir2.1L222I. Our recent study showed that this mutation has a strong protective effect against the impairment of flow-induced vasodilation, a hallmark of endothelial function. Objective: In this study, we demonstrate that cholesterol insensitive Kir2.1 has a protective effect against diet induced obesity. Methods: C57/BL6J (WT) male mice with the Kir2.1L222I mutation were fed HFD and weighed weekly for 25 weeks until the mice were 6 months of age. Mouse feeding behavior was assessed under BioDaq monitoring and nuclear magnetic resonance spectroscopy (NMR) was used to determine body composition. Fat mass and serum were analyzed postmortem in these mice. Results: Initially, WT (n=4) and Kir2.1L222I (n=5) male mice weighed the same. After 14 weeks on HFD Kir2.1L222I mice weighed 28±0.60 less than WT mice 36±2.78 grams(p=0.01). After 25 weeks, the protection against weight gain persisted with animals weighing 31±3 compared to 40.5±1.5 grams for WT mice(p=0.053, n=2). Kir2.1L222I mice have decreased fat mass 8.29±1.56 compared to WT mice with 24.75±3.20 percent(p=0.0018, n=4). Kir2.1L222I mice have more lean mass 76.67±1.54 than WT mice with 62.92±2.18 percent(p=0.0011). The lean-to-fat mass ratio for Kir2.1L222I mice was greater 10.47±2.25 than WT 2.77±0.59(p=0.0081). There was no difference in water weight. Kir2.1L222I mice have less brown, visceral white, and subcutaneous adipose than WT mice (n=4). Additionally, Kir2.1L222I mice have a decreased ratio of visceral to subcutaneous adipose 1.39±0.11 compared to WT 2.07±0.21(p=0.015). Kir2.1L222I mice have an increase in brown relative to white adipose 0.71±0.09 compared to WT 0.38±0.06(p=0.011). Total cholesterol, HDL, and LDL were decreased in Kir2.1L222I male mice compared to WT(n=4, p≤0.02). There was also a decrease in serum glucose in Kir2.1L222I 117.50±22.04 compared to WT 230.25±16.42 mg/dL(p=0.003). Liver markers including ALK phosphate, ALT, creatinine, and direct bilirubin(p≤0.03) were decreased. Preliminary data show no difference in mouse feeding behavior. Conclusions: The Kir2.1L222I mutation is protective against weight gain in male mice up to 6 months of age. Kir2.1L222I mice on HFD have reduced fat, increased lean-to-total body mass, and altered fat distribution compared to WT mice. Kir2.1L222I mice had improved lipid profiles and liver markers compared to WT. These findings along with previous cardiovascular protective effects suggest the role of Kir2.1 in improved healthspan. UIC-T32HL144909 to KMB, R01HL073965 to IL This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.