Obesogenic and Diabetogenic Effects of High-Calorie Nutrition Require Adipocyte BK Channels

Abstract

Elevated adipose tissue expression of the Ca- and voltage-activated K (BK) channel was identified in morbidly obese men carrying a BK gene variant, supporting the hypothesis that K channels affect the metabolic responses of fat cells to nutrients. To establish the role of endogenous BKs in fat cell maturation, storage of excess dietary fat, and body weight (BW) gain, we studied a gene-targeted mouse model with global ablation of the BK channel (BK) and adipocyte-specific BK-deficient (adipoqBK) mice. Global BK deficiency afforded protection from BW gain and excessive fat accumulation induced by a high-fat diet (HFD). Expansion of white adipose tissue-derived epididymal BK preadipocytes and their differentiation to lipid-filled mature adipocytes in vitro, however, were improved. Moreover, BW gain and total fat masses of usually superobese ob/ob mice were significantly attenuated in the absence of BK, together supporting a central or peripheral role for BKs in the regulatory system that controls adipose tissue and weight. Accordingly, HFD-fed adipoqBK mutant mice presented with a reduced total BW and overall body fat mass, smaller adipocytes, and reduced leptin levels. Protection from pathological weight gain in the absence of adipocyte BKs was beneficial for glucose handling and related to an increase in body core temperature as a result of higher levels of uncoupling protein 1 and a low abundance of the proinflammatory interleukin-6, a common risk factor for diabetes and metabolic abnormalities. This suggests that adipocyte BK activity is at least partially responsible for excessive BW gain under high-calorie conditions, suggesting that BK channels are promising drug targets for pharmacotherapy of metabolic disorders and obesity.

Survival and growth of C57BL/6J mice lacking the BK channel,Kcnma1: lower adult body weight occurs together with higher body fat

“…; Dufer et al 2011), but in the mixed SV129/C57BL6 background, WT fasting blood glucose is higher (~7.5 mmol/L; Dufer et al 2011) than that in the WT C57BL/6J mice from this study (~4.5 mmol/L, Fig. ) and WT mice in a C57BL/6N background (~5.5 mmol/L; Illison et al ). Response to ipGTT for WSU colony C57BL/6J mice supported an enhanced handling of glucose by BK KO mice (Fig.…”

“…Mice with an adipocyte‐specific knockout of BK exhibit identical ipGTT responses compared with WT (Illison et al. ), supporting the lack of involvement of adipocyte BK channels in glucose challenges. Observations of less insulin release during acute BK inhibition (Braun et al.…”

“…) likely contribute to the lower weights attained by these mice (Fig. ; Illison et al ; Sausbier et al ). Other factors also must contribute, because BK KO mice in a FVB/NJ background attain weights similar to wild‐type littermates after 5 weeks of age (Meredith et al.…”

“…Induction of obesity by feeding a high‐fat diet was dramatically blunted in C57BL/6N BK KO male mice, which was partially replicated by silencing BK channel expression only in adipocytes (Illison et al. ). This protective influence of losing BK activity may result in part from suppression of preadipocyte proliferation (Hu et al.…”

“…The 5% shorter tibia length of C57BL/6N BK KO male mice (Illison et al. ) indicates that this lower weight occurred as an overall smaller mouse, both weight and skeletal frame. Presumably this reduced body size resulted as a consequence of lacking BK or from an adaptation to maintain function in the face of this absence.…”