1529-P: Hypothalamic FGF1 Regulates Systemic Glucose and Energy Homeostasis

Systemic glucose and energy homeostasis is maintained by interorgan communication networks and the hypothalamus plays a key part in this process. Many research are being conducted to investigate the hypothalamus as a therapeutic target for metabolic diseases such as diabetes and obesity. Recent studies demonstrate that a single intracerebroventricular (icv) injection of FGF1 causes sustained glucose remission in diabetic rodent models (Scarlett et al.), and further study is being conducted. However, there are limited findings about how metabolic status affects endogenous brain FGF1 expression and how brain FGF1 plays in energy homeostasis. A study published in 2012 (Jonker et al.) found severe insulin resistance and a defect in adipose tissue remodeling in HFD-fed FGF1 null-mice. However, these investigations have a limitation in that it is not obvious which tissue/organ mediates insulin resistance due to FGF1 depletion. We found that CNS-deletion of FGF1 (BKO) shows impaired glucose sensing and decreased ERK/STAT3 signaling in ventromedial hypothalamus (VMH) and arcuate nucleus (ARC). This decreased leptin sensitivity leads to decreased muscle glucose uptake following glucose intolerance. We evaluated FGF1 expression in hypothalamus in several metabolic states such as fasting-feeding or other postprandial stimuli to discover which hypothalamic area mediates endogenous FGF1 activity. Interestingly, FGF1 expression in the VMH, but not other brain regions, are increased upon feeding or glucose administration and this induction of FGF1 does not require leptin or insulin. Acute FGF1 deletion in adult VMH causes glucose intolerance as well as increased body weight gain due to reduced leptin sensitivity and brown fat dysfunction, which leads to decreased energy expenditure. In keeping with this finding, germ-line ablation of FGF1 in VMH neurons results in increased adiposity. We propose that endogenous brain FGF1 regulates glucose and energy homeostasis through modulating VMH leptin sensitivity. Disclosure H.Shin: None. J.Suh: None.