FGF21 also protects animals from diet-induced obesity when overexpressed in transgenic mice and lowers blood glucose and triglyceride levels when administered to diabetic rodents.

[21] In cows plasma FGF21 was nearly undetectable in late pregnancy (LP), peaked at parturition, and then stabilized at lower, chronically elevated concentrations during early lactation (EL).

Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL.

The liver was the major source of plasma FGF21 in early lactation with little or no contribution by WAT, skeletal muscle, and mammary gland.

Meaningful expression of the FGF21 coreceptor β-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland.

Expression of β-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT.

[11][12][13] Mice lacking FGF21 fail to fully induce PGC-1α expression in response to a prolonged fast and have impaired gluconeogenesis and ketogenesis.

Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α.

FGF21 also blocks somatic growth and sensitizes mice to a hibernation-like state of torpor, playing a key role in eliciting and coordinating the adaptive starvation response.