Sarcolemmal ATP-Sensitive K + Channels Control Energy Expenditure Determining Body Weight

Metabolic processes that regulate muscle energy use are major determinants of bodily energy balance. Here, we find that sarcolemmal ATP-sensitive K + (K ATP) channels, which couple membrane excitability with cellular metabolic pathways, set muscle energy expenditure under physiological stimuli. Disruption of K ATP channel function provoked, under conditions of unaltered locomotor activity and blood substrate availability, an extra energy cost of cardiac and skeletal muscle performance. Inefficient fuel metabolism in K ATP channel-deficient striated muscles reduced glycogen and fat body depots, promoting a lean phenotype. The propensity to lesser body weight imposed by K ATP channel deficit persisted under a high-fat diet, yet obesity restriction was achieved at the cost of compromised physical endurance. Thus, sarcolemmal K ATP channels govern muscle energy economy, and their downregulation in a tissue-specific manner could present an antiobesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise. [Display omitted] ► K ATP channels limit cardiac and skeletal muscle energy use ► Lack of K ATP channels results in inefficient thermogenesis, depleting muscle stores ► K ATP channel knockouts are lean and resistant to diet-induced obesity ► Targeting K ATP channels, making muscle less efficient, could prevent obesity