Pharmacological but Not Physiological Levels of GDF15 and FGF21 Regulate Body Weight and Glycemic Control in Obese Mice

GDF15 and FGF21 are stress-induced hormone-like factors with putative roles in the regulation of energy homeostasis. Since their plasma levels increase with obesity, it has been proposed that GDF15 and FGF21 jointly impose a cap on weight gain during diet-induced obesity. To test this hypothesis, we generated single Gdf15 knockout (KO) and Fgf21 KO, and double Gdf15/Fgf21 KO mice. Depletion of both GDF15 and FGF21 had minimal effects on the gain of body weight, fat, and fat-free mass in male or female mice fed either chow diet or high-fat, high-sucrose diet. Similarly, glucose tolerance, fasting glucose, and plasma insulin levels were largely unaffected by the combined absence of GDF15 and FGF21. Thus, combined deletion of endogenous Gdf15 and Fgf21 exerted a limited influence on body weight gain or glycaemic control. By contrast, pharmacological dosing of obese male mice with long-acting recombinant GDF15 or FGF21 produced meaningful weight loss on their own (8%-10%), and GDF15 + FGF21 co-administration yielded an impressive, additive weight reduction of 25%. Combinatorial treatment also improved glucose tolerance, lowered fasting insulin levels, and reduced hepatic fat content. In conclusion, while endogenous GDF15 and FGF21 appear largely nonessential for the regulation of weight gain and glycemia, pharmacological co-treatment with GDF15 and FGF21 elicits robust weight-loss benefits.