Project Title: “Identifying Crosstalk Between Ketone and Endocrine Signaling in the Hypothalamus”
Liver-brain crosstalk is now recognized as a fundamental driver of feeding behavior and body weight regulation, which are primary determinants of obesity and type 2 diabetes. Both nutrient fuels and hormones serve as signals from the liver to the brain. A key metabolic fuel that is produced in the liver but serves important roles in the brain is the ketone body. Ketones are produced in the liver, and are by-products of burned fat, serving as an important fuel source for the brain’s neurons. Through unclear mechanisms, ketones also modulate feeding behavior and body weight through actions upon a fundamental energy and metabolism coordinating center in the brain called the hypothalamus. In addition to ketones, the liver also produces the hormone fibroblast growth factor 21 (FGF21) which signals to hypothalamic neurons. However, nothing is known about how hypothalamic function is coordinately regulated by ketones and FGF21 together. This Pilot and Feasibility application proposes the key initial experiments that will address this critical knowledge gap. The proposed experiments forge a new collaboration between an expert in integrated ketone metabolism, metabolomics, and metabolic flux analysis (Crawford) and a co-PI who is an FGF21 signaling expert who is uniquely skilled in targeting, manipulation, and quantifications of hypothalamic neuronal signaling in vivo and ex vivo (Potthoff). The approaches described here will be the first to determine how ketones modulate hypothalamic signaling in response to FGF21, and whether their cooperative effects are dependent on ketone oxidation in neurons.