Exercise is well-known to improve metabolic function and reduce the risk of development of cardiometabolic diseases, however, the molecular mechanisms underlying the exercise benefits remain incompletely understood. Fibroblast growth factor-1 (Fgf1) is secreted from brown adipose tissue and skeletal muscle upon acute exercise in rats. We observed increased expression of Fgf1 in skeletal muscle after single bout of exercise in mice. Recent study shows that recombinant FGF1 (rFGF1) injection lowers blood glucose levels in diet-induced obese mice to a healthy range. However, the role the of endogenous FGF1 induced by endurance exercise training in whole-body insulin sensitivity are unknown. To address this question, we have generated loss-of-function Fgf1- knock-in (KI) mice by using CRISPR/Cas9-mediated gene editing. Three-month-old WT and KI (male and female) mice were subjected to voluntary wheel running for 4 weeks with sedentary controls followed by measurements for whole-body metabolism (energy expenditure, locomotor activity and food intake by CLAMS) body composition (Echo MRI), exercise capacity (metabolic treadmill), cardiac function, cognitive function, as well as whole-body and skeletal muscle insulin signaling (GTT, ITT, HOMA-IR and serum insulin levels during GTT). Our data shows that Fgf1KI mice failed to improve glucose tolerance after 4-week training. We therefore, for the first time, demonstrate that Fgf1 plays a critical role in improving insulin sensitivity in response to endurance exercise training in mice. Altogether, our findings support an important role of Fgf1 in promoting insulin sensitivity in response to endurance exercise training, which has improved our understanding of molecular mechanisms underlying exercise-associated health benefits.
Bhonsle et al. (Tue,) studied this question.