The role of metabolic hormone Fibroblast Growth Factor 21 (FGF21) in mammalian hibernation using transgenic ground squirrels

Abstract

Hibernation is a natural adaptation that allows certain mammals to survive physiological extremes that are lethal to humans. Near freezing body temperatures, heart rates of 4 to 6 beats per minute and depressed metabolism are characteristic of hibernation torpor bouts that are periodically interrupted by brief interbout arousals (IBAs). The molecular basis of torpor induction is unknown, however studies of fibroblast growth factor 21 (FGF21) in starved mice have shown the involvement of this hormone in promoting fat utilization and reducing body temperature and physical activity--all hallmarks of mammalian hibernation. We hypothesized that increased FGF21 sensitizes the natural hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus) to enter torpor and changes the metabolic profile to indicate increased lipolysis. In this study we isolated the FGF21 cDNA from the ground squirrel and found that levels of FGF21 mRNA in liver and FGF21 protein in serum are elevated during IBAs compared to summer active animals. The effects of elevating circulating FGF21 concentrations 50 to 100-fold via adenoviral-mediated overexpression were examined at key times in the annual hibernation cycle. FGF21 overexpression decreased blood insulin and free fatty acid concentrations sampled 7 days after injection in fed squirrels kept at 23 °C with a 12:12 l:d cycle in April, effects similar to those observed in obese mice. However, elevated FGF21 concentrations did not cause torpor in thirteen-lined ground squirrels. We conclude that FGF21 is strongly regulated during torpor and IBA in hibernating thirteen-lined ground squirrels but that its overexpression is not sufficient to cause torpor.