Protein restriction induces FGF21-dependent mechanisms that are distinct from dietary restriction to protect mice from high-fat diet-induced obesity and glucose intolerance

Einleitung:

Dietary protein restriction (PR) reduces body weight gain and increases energy expenditure, and fibroblast growth factor 21 (FGF21) mediates these effects. We tested the efficacy of PR to improve metabolic health in the context of high-fat diet (HFD)-induced obesity and the contribution of FGF21 and the amino acid sensor general control non-derepressible 2 (GCN2) kinase.

Methoden:

Wild-type, Fgf21-KO, and Gcn2-KO mice were placed on isocaloric HFDs (59 kcal%) that provided protein at control (HFCON, 18 kcal%) or low (HFLP, 4 kcal%) levels for 6 weeks. WT HFCON mice were dietarily restricted to match weight loss of the HFLP group. Changes in glucose homeostasis were assessed.

Ergebnisse:

HFLP reduced body weight and adiposity gain in wild-type mice via a mechanism consistent with increased energy expenditure, while also improving glucose tolerance despite increased food intake. These beneficial effects of HFLP were absent in Fgf21-KO mice but not Gcn2-KO mice, where the HFLP diet increased FGF21 levels. Although both protein and dietary restriction improved glucose tolerance, only PR increased FGF21 and browned iWAT, and hepatic gene expression was differentially regulated by the two interventions.

Schlussfolgerung:

These data suggest that PR protects against obesity and improves glucose homeostasis via FGF21-dependent mechanisms that are different from dietary restriction.