FGF21-Mediated Improvements in Glucose Clearance Require Uncoupling Protein 1

Abstract

Fibroblast growth factor 21 (FGF21)-mediated weight loss and improvements in glucose metabolism correlate with increased uncoupling protein 1 (Ucp1) levels in adipose tissues, suggesting that UCP1-dependent thermogenesis may drive FGF21 action. It was reported that FGF21 is equally effective at reducing body weight and improving glucose homeostasis without UCP1. We find while FGF21 can lower body weight in both wild-type and Ucp1 knockout mice, rapid clearance of glucose by FGF21 is defective in the absence of UCP1. Furthermore, in obese wild-type mice there is a fall in brown adipose tissue (BAT) temperature during glucose excursion, and FGF21 improves glucose clearance while preventing the fall in BAT temperature. In Ucp1 knockout mice, the fall in BAT temperature during glucose excursion and FGF21-mediated changes in BAT temperature are lost. We conclude FGF21-mediated improvements in clearance of a glucose challenge require UCP1 and evoke UCP1-dependent thermogenesis as a method to increase glucose disposal.

Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood

“…The discovery of thermogenic adipose tissue in adult humans, once thought to be absent after infancy, has fueled interest to promote thermogenesis in multiple metabolic disorders 20, 48, 49 . Evidence that thermogenically active brown fat promotes glucose disposal 50 and, arguably, consumption of lipids 51 are among the points of logic behind the concept. Indeed, it has evolved that cold exposure is now often viewed as a natural approach to improved metabolism.…”

Single ingestion of soy β-conglycinin induces increased postprandial circulating FGF21 levels exerting beneficial health effects

“…Although an increase in Ucp-1 expression is believed to assist browning of WAT, recent papers demonstrated that the effects of FGF21 on body weight reduction and glucose homeostasis can occur in Ucp-1 knockout mice3334. In contrast, some authors claim that FGF21 requires UCP1 to improve glucose clearance, likely involving increased UCP1-dependent thermogenesis35. Further experiments will be required to elucidate the link between FGF21 and Ucp-1 involved in beneficial effects caused by β-conglycinin.…”

Emerging Complexities in Adipocyte Origins and Identity

“…However, these results may depend on the conditions used (e.g. lean versus obese mice) [97]. Importantly, the influences of temperature are also beginning to be recognized in other fields [98–100] suggesting that housing mice at current standard laboratory conditions may actually compromise the ability to model certain human diseases.…”