Liver Derived FGF21 Maintains Core Body Temperature During Acute Cold Exposure

Magdalene Ameka,Sharon O Idiga,Zhiyong Zhu,Lucas D Bondurant,Matthew J Potthoff,Leonid V Zingman,Justin L Grobe,Meghan C Naber,Kathleen R Markan,Kamal Rahmouni,Donald A Morgan

doi:10.1038/s41598-018-37198-y

Magdalene Ameka, Sharon O Idiga + Show 9 more

Open Access

https://doi.org/10.1038/s41598-018-37198-y

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Journal: Scientific Reports	Publication Date: Jan 24, 2019
Citations: 70	License type: open-access

Affiliation: University of Iowa, Fraternal Order of Eagles

Abstract

Fibroblast Growth Factor 21 (FGF21) elicits an array of metabolic effects. However, the physiological role of FGF21 during thermal challenges is not clear. In this study, we assessed the tissue source of FGF21 and its site of action to regulate core body temperature in response to cold. Using mice lacking FGF21 specifically in the liver (FGF21 LivKO) or adipose tissues (FGF21 AdipoKO), we performed a series of cold exposure studies to examine the tissue specific induction of FGF21 in response to cold. We also examined the physiological site of FGF21 action during cold exposure by impairing FGF21 signaling to adipose tissues or the central nervous system (CNS) using genetic ablation of the FGF21 co-receptor β-klotho in adipose tissues (KLB AdipoKO) or pharmacological blockage of FGF21 signaling. We found that only liver-derived FGF21 enters circulation during acute cold exposure and is critical for thermoregulation. While FGF21 signaling directly to adipose tissues during cold is dispensable for thermoregulation, central FGF21 signaling is necessary for maximal sympathetic drive to brown adipose tissue to maintain thermoregulation during cold. These data demonstrate a previously unrecognized role for FGF21 in the maintenance of body temperature in response to cold.

Highlights

Multiple peripheral signals converge upon the fundamental neural circuits controlling energy homeostasis and body temperature
Consistent with the time course experiment, plasma Fibroblast Growth Factor 21 (FGF21) was significantly increased in wild type mice housed in cold for 1 hour and this induction of FGF21 was completely lost in FGF21 LivKO mice (Fig. 1F)
To determine why FGF21 LivKO fail to properly maintain core body temperature, we examined whether FGF21 may regulate core body temperature by physiologically altering blood flow, heat loss, or sympathetic nerve activity (SNA)

Summary

Introduction

Multiple peripheral signals converge upon the fundamental neural circuits controlling energy homeostasis and body temperature. Adipose-derived FGF21 was found to increase beiging of adipocytes through the recruitment of immune cells into subcutaneous white adipose depots thereby regulating body temperature[18]. In contrast to these studies, FGF21 was found to be dispensable for adaptation to prolonged cold exposure[19]. Instead, circulating FGF21 induced by cold acts centrally as a critical signal to fully activate sympathetic nerve activity to BAT in order to maintain body temperature. These data provide new physiological insight into the mechanisms regulating thermoregulation

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