BackgroundStarvation leads to a series of metabolic adaptations that enables continuous production and delivery of nutrients to critical organs, tissues and cells. Under conditions of nutrient withdrawal, ketone bodies provide an alternative source of energy for highly oxidative tissues. Although the AMP‐activated protein kinase (AMPK) is best known as a sensor of cellular energy status, its implication in ketone regulation remains unclear.ObjectiveThe aim of this study was to evaluate the effects of AMPKα2 on ketone body utilization, and to elucidate the underlying mechanisms.MethodsGlobal AMPKα2 knockout mice (AMPKα2−/−), muscle‐specific AMPKα2 knockout mice, and their age‐matched wild type (WT) littermates were subjected to either 3‐day fasting or received an intra‐peritoneal injection of β‐hydroxybutyrate salt (1.5 mg/kg body weight) to assess the β‐hydroxybutyrate consumption.ResultsFasting blood and urine ketone levels were significantly elevated in AMPKα2−/− mice when compared to their littermate WT mice. After an intra‐peritoneal bolus of β‐hydroxybutyrate, the main circulating ketone body, AMPKα2−/− mice presented a lower clearance of β‐hydroxybutyrate compared to their littermate WT mice. Further, fasting induced hyperketosis without any change in body weight or glycaemia in muscle‐specific AMPKα2 knockout mice. Consistently, these mice displayed impaired ketone utilization after β‐hydroxybutyrate injection. Furthermore, AMPKα2 deficiency in muscle significantly decreased locomotor activity, with a quicker switch from utilizing carbohydrate to fat as the predominant energy source compared to their littermate WT mice. Mechanistically, AMPKα2 deficiency in muscle presented a 50% reduced activity of succinyl‐CoA:3‐oxoacid CoA transferase compared to their littermate WT mice.ConclusionTaken together, these findings establish AMPKα2 in muscle as an essential mediator of ketolysis in fasting, through the regulation of the rate‐limiting ketolytic enzyme.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.