Ketone esters increase brown fat in mice and overcome insulin resistance in other tissues in the rat.

Brown adipose tissue (BAT) is classically activated by sympathetic nervous stimulation resulting from exposure to cold. Feeding a high-fat diet also induces development of brown fat, but is decreased by caloric restriction. Blood ketone bodies, which function as alternative energy substrates to glucose, are increased during caloric restriction. Here we discuss the unexpected observation that feeding an ester of ketone bodies to the mouse, which increases blood ketone body concentrations, results in an activation of brown fat. The mechanism of this activation of brown fat is similar to that occurring from cold exposure in that cyclic adenosine monophosphate (AMP) levels are increased as are levels of the transcription factor cyclic AMP-responsive element-binding protein, which is also increased by ketone ester feeding. Other effects of feeding ketone esters, in addition to their ability to induce brown fat, are discussed such as their ability to overcome certain aspects of insulin resistance and to ameliorate the accumulation of amyloid and phosphorylated tau protein in brain, and improve cognitive function, in a triple transgenic mouse model of Alzheimer's disease.