FGF21 improves glucose homeostasis in diabetes-prone NZO mice

Background:

FGF21 is considered a promising therapeutic candidate for the treatment of diabetes, but is elevated in obese and diabetic conditions, suggesting impaired FGF21 action. Therefore, we tested if obese and diabetes-susceptible NZO mice are FGF21 resistant.

Methods:

After weaning, NZO mice were placed on a carbohydrate-free high-fat diet (-CH) for 14 weeks, at which point a random subgroup of animals was transferred to a carbohydrate-containing high-fat diet (+CH) for two weeks. Animals were treated subcutaneously with PBS or FGF21 started three days before and ended seven days after the diet switch. Eight days after the diet switch an OGTT was performed.

Results:

NZO mice on the -CH diet become obese and insulin resistant but are protected from developing diabetes. Changing to the +CH diet induces a rapid hyperglycemia that is associated with elevated insulin and impaired glucose clearance as tested by an OGTT. FGF21 treatment prevented the effects induced by +CH diet, such that FGF21-treated mice exhibited blood glucose and insulin levels that were similar to PBS-treated mice on the -CH diet. FGF21-treated mice on the +CH diet also exhibited improved glucose clearance during the OGTT. FGF21 treatment also elicited a hyperphagic response, did not change the fat mass but decreased the lean mass in mice. The body weight did not differ between all three groups on any day throughout the experiment.

Conclusion:

Without changes in total fat mass, FGF21 prevents hyperglycemia and improves glucose clearance in NZO mice. These data indicate that obesity does not induce FGF21 resistance.

No conflict of interest has been declared by the author(s).