The central nervous system is acknowledged as a major regulator of both energy and glucose homeostasis. Our data demonstrates that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that this effect is largely mediated by the metabolic hormone FGF21. Indeed, our data suggest that FGF21 is the only known endocrine hormone that specifically coordinates adaptive responses to protein restriction. Therefore, this project uses the model of dietary protein restriction to probe the physiological mechanisms through which FGF21 influences energy expenditure and glucose homeostasis, specifically testing whether FGF21 signaling within the CNS is required for the metabolic effects of protein restriction. This model will be tested by deleting the required FGF co-receptor beta-Klotho (Klb) from neurons, and determining if mice lacking CNS FGF21 signaling fail to exhibit increased energy expenditure or improved glucose homeostasis when placed on a low protein diet. Considering our current lack of certainty regarding the mechanisms through which FGF21 acts, this work will both define the contribution of the CNS to FGF21 signaling while also delineating the first known neuroendocrine model to explain the coordinated metabolic changes induced by dietary protein restriction.
The central nervous system is well documented to contribute to whole body energy and glucose metabolism. Furthermore, diet interventions such as protein restriction are reported to increase hormones, including FGF21, to maintain whole body homeostasis. This project will focus the specific role of CNS FGF21 signaling in the detection of protein restriction and resulting changes in energy expenditure and glucose metabolism.
| Hill, Cristal M; Berthoud, Hans-Rudolf; Münzberg, Heike et al. (2018) Homeostatic sensing of dietary protein restriction: A case for FGF21. Front Neuroendocrinol 51:125-131 |
| Hill, Cristal M; Morrison, Christopher D (2018) Dietary branched chain amino acids and metabolic health: when less is more. J Physiol 596:555-556 |
