Abstract
ObjectiveAdministration of FGF21 to mice reduces body weight and increases body temperature. The increase in body temperature is generally interpreted as hyperthermia, i.e. a condition secondary to the increase in energy expenditure (heat production). Here, we examine an alternative hypothesis: that FGF21 has a direct pyrexic effect, i.e. FGF21 increases body temperature independently of any effect on energy expenditure. MethodsWe studied the effects of FGF21 treatment on body temperature and energy expenditure in high-fat-diet-fed and chow-fed mice exposed acutely to various ambient temperatures, in high-fat diet-fed mice housed at 30 °C (i.e. at thermoneutrality), and in mice lacking uncoupling protein 1 (UCP1). ResultsIn every model studied, FGF21 increased body temperature, but energy expenditure was increased only in some models. The effect of FGF21 on body temperature was more (not less, as expected in hyperthermia) pronounced at lower ambient temperatures. Effects on body temperature and energy expenditure were temporally distinct (daytime versus nighttime). FGF21 enhanced UCP1 protein content in brown adipose tissue (BAT); there was no measurable UCP1 protein in inguinal brite/beige adipose tissue. FGF21 increased energy expenditure through adrenergic stimulation of BAT. In mice lacking UCP1, FGF21 did not increase energy expenditure but increased body temperature by reducing heat loss, e.g. a reduced tail surface temperature. ConclusionThe effect of FGF21 on body temperature is independent of UCP1 and can be achieved in the absence of any change in energy expenditure. Since elevated body temperature is a primary effect of FGF21 and can be achieved without increasing energy expenditure, only limited body weight-lowering effects of FGF21 may be expected.
Highlights
Fibroblast growth factor 21 (FGF21) is a hormone secreted in response to several stress stimuli, such as cold, fasting, or a ketogenic diet [1]
To allow for discrimination of the effects of FGF21 on energy expenditure and body temperature control, we have examined here, in several models, the relationship between these parameters and related this to the recruitment, activation, and necessity of uncoupling protein 1 (UCP1) for the observed effects of FGF21
The mechanism of induction of thermogenesis and body temperature by FGF21 is of crucial importance for understanding its body weightlowering effects
Summary
Fibroblast growth factor 21 (FGF21) is a hormone secreted in response to several stress stimuli, such as cold, fasting, or a ketogenic diet [1]. Fisher et al [7] observed that FGF21-deficient mice maintained a lower body temperature than control mice when they were chronically exposed to 5 C The authors interpreted this lower body temperature as an indication that thermogenesis was lower in the FGF21-deficient mice and was insufficient to defend body temperature, i.e. the FGF21-deficient mice were considered to be hypothermic e unable to produce sufficient heat to counteract heat loss. This implied that FGF21 is essential for the development of full thermogenic capacity in the cold.
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