DESCRIPTION (provided by applicant): Ketone bodies are energy-rich molecules which circulate in the blood. They are essential during the response to fasting when their levels in the blood rise. During this time they provide an alternative energy source which is used by many tissues and ensures that the nervous system, which preferentially uses glucose, can remain adequately supplied. Normally the plasma level of ketone bodies is tightly regulated. However under some circumstances, such as poorly managed type I diabetes, their levels rise and this can lead to ketoacidosis, a potentially life-threatening condition. The long-term objective of the proposed study is to determine the mechanisms that control ketogenesis. The primary hormone that stimulates ketone body production is epinephrine which is released from chromaffin cells in the adrenal medulla, a branch of the sympathetic nervous system. During fasting the secretion of epinephrine is increased and this leads to elevated lipolysis and consequent ketogenesis. A major puzzle is the mechanism that restrains ketogenesis once it is initiated. What normally prevents a pathological rise in ketone bodies in these circumstances? Our hypothesis is that a recently identified G protein-coupled receptor termed GPR109A is a key component of a negative feedback loop that regulates ketogenesis by inhibiting epinephrine release. The endogenous agonist of GPR109A is Beta-OHB, the most abundant ketone body. To test this idea we have two specific aims. In the first set of experiments we will test the idea that GPR109A receptors are expressed by chromaffin cells and that during fasting these receptors are activated by the increased levels of Beta OHB in the blood. As a result, the secretion of epinephrine is acutely inhibited and the ketogenic drive is reduced. Our second specific aim is to test the hypothesis that the activation of GPR109A receptors during ketogenesis leads to a long-lasting suppression of epinephrine synthesis and that this effect is mediated by a local adrenal signaling loop that inhibits the expression of tyrosine hydroxylase, the rate limiting step for catecholamine synthesis. Using in situ and in vivo approaches to monitor epinephrine release and the levels of ketone bodies, we aim to determine how ketogenesis is regulated under physiological conditions and ultimately whether this control system is altered in metabolic disease.

PUBLIC HEALTH RELEVANCE: Ketone bodies are energy-rich molecules that circulate in the blood. They are essential during the response to fasting but high levels, such as occur in type I diabetes, can be life-threatening. Identification of the factors that control ketogenesis is needed for the development of treatments that could limit their synthesis.