Introduction and Objective: The brain is a primary target for the beneficial metabolic effects of members of the fibroblast growth factor (FGF) family. For example, our group and others have shown that a single intracerebroventricular (icv) injection of fibroblast growth factor-1 (FGF1) induces both transient anorexia and weight loss and sustained remission of diabetic hyperglycemia in rodent models of type 2 diabetes (T2D) via actions involving the mediobasal hypothalamus (MBH). While FGF1 is endogenously expressed in the MBH, its physiological role in the regulation of energy homeostasis is unknown. The goal of the current studies was to determine the role of endogenous FGF1 signaling in MBH in the regulation of energy balance. Methods: To test whether MBH FGF1 plays a physiological role in energy and/or glucose homeostasis, we selectively deleted FGF1 from the MBH neurons of adult male FGF1-floxed (FGF1fl/fl) mice by microinjecting either control AAV1-CAG-GFP or AAV1-hSyn-Cre-WPRE.hGH into the MBH bilaterally. We then conducted a comprehensive physiological assessment in indirect calorimetry metabolic chambers. The mice were initially chow-fed, then switched to high fat diet (HFD). Results: FGF1 deletion specifically from MBH neurons caused increased bodyweight, body adiposity, and glucose intolerance (*p0.05). This phenotype was characterized by pronounced disruption of circadian patterns of feeding and locomotion, in which animals consumed a greater proportion of food intake during the light cycle complemented by reduced dark cycle locomotion. Interestingly, these effects were robustly exacerbated once the mice were switched to HFD, in which FGF1-deleted mice showed an exaggerated obesogenic phenotype, characterized by hyperphagia, reduced energy expenditure and locomotion. Conclusion: Based on these findings, we conclude that endogenous FGF1 signaling by MBH neurons is required both for normal energy and glucose homeostasis and for protection against diet induced obesity. Disclosure P. Choi: None. K.H. Kadlec: None. C. Bryan: None. B.N. Phan: None. G. Morton: None. M.W. Schwartz: Consultant; Current; Eli Lilly and Company. J. Scarlett: None.
CHOI et al. (Fri,) studied this question.