Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints

Cristal M Hill,Hans-Rudolf Berthoud,David H Mcdougal,Diana C Albarado,Christopher D Morrison,Thomas Laeger,Heike Münzberg

doi:10.1038/s41598-017-07498-w

Cristal M Hill, Hans-Rudolf Berthoud + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-07498-w

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Abstract

Dietary protein restriction increases adipose tissue uncoupling protein 1 (UCP1), energy expenditure and food intake, and these effects require the metabolic hormone fibroblast growth factor 21 (FGF21). Here we test whether the induction of energy expenditure during protein restriction requires UCP1, promotes a resistance to cold stress, and is dependent on the concomitant hyperphagia. Wildtype, Ucp1-KO and Fgf21-KO mice were placed on control and low protein (LP) diets to assess changes in energy expenditure, food intake and other metabolic endpoints. Deletion of Ucp1 blocked LP-induced increases in energy expenditure and food intake, and exacerbated LP-induced weight loss. While LP diet increased energy expenditure and Ucp1 expression in an FGF21-dependent manner, neither LP diet nor the deletion of Fgf21 influenced sensitivity to acute cold stress. Finally, LP-induced energy expenditure occurred even in the absence of hyperphagia. Increased energy expenditure is a primary metabolic effect of dietary protein restriction, and requires both UCP1 and FGF21 but is independent of changes in food intake. However, the FGF21-dependent increase in UCP1 and energy expenditure by LP has no effect on the ability to acutely respond to cold stress, suggesting that LP-induced increases in FGF21 impact metabolic but not thermogenic endpoints.

Highlights

Over 40 years ago Rothwell, Stock and colleagues demonstrated that low protein (LP) diets increase energy expenditure (EE)[1, 2]
Wildype and Ucp1-KO mice were placed on control and LP diets for 6 weeks at 28 °C, with energy expenditure measured over the first 7 days (Fig. 1A,B)
We have previously demonstrated that protein restriction increases uncoupling protein 1 (UCP1) and promotes the browning of WAT, and that these effects require FGF214

Summary

Introduction

Over 40 years ago Rothwell, Stock and colleagues demonstrated that low protein (LP) diets increase energy expenditure (EE)[1, 2]. Our lab provided an endocrine mechanism to explain this protein dependent regulation of EE, as we demonstrated that LP diets require the hormone FGF21 to increase EE and Ucp[1] expression and to alter food intake and body weight gain[4, 5]. These data are consistent with evidence that pharmacological FGF21 treatment acts both in the brain and directly on adipose tissue to increase EE, stimulate sympathetic outflow, and upregulate thermogenic markers in BAT and WAT6–10. These data support a model in which LP-induced FGF21 drives UCP1-dependent increases in energy expenditure to influence metabolic but not thermogenic endpoints

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