Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework

Abstract

Fibroblast growth factor 21 (FGF21) is the first known endocrine signal activated by protein restriction. Although FGF21 is robustly elevated in low-protein environments, increased FGF21 is also seen in various other contexts such as fasting, overfeeding, ketogenic diets, and high-carbohydrate diets, leaving its nutritional context and physiological role unresolved and controversial. Here, we use the Geometric Framework, a nutritional modeling platform, to help reconcile these apparently conflicting findings in mice confined to one of 25 diets that varied in protein, carbohydrate, and fat content. We show that FGF21 was elevated under low protein intakes and maximally when low protein was coupled with high carbohydrate intakes. Our results explain how elevation of FGF21 occurs both under starvation and hyperphagia, and show that the metabolic outcomes associated with elevated FGF21 depend on the nutritional context, differing according to whether the animal is in a state of under- or overfeeding.

Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes

“…2a). Confirming earlier studies [3,5], these data indicate that dietary protein restriction is a potent stimulator of hepatic and circulating FGF21.…”

“…LP/HF treatment also increased circulating FGF21 levels by approximately tenfold relative to CON, as a result of increased hepatic Fgf21 mRNA expression. Therefore, these data correspond with the finding of FGF21 as an endocrine signal for a dietary protein restriction independent of energy restriction [3,5]. As recently shown in NZO mice [11], exogenous FGF21 treatment induces thermogenic markers in sWAT, pointing towards a browning capacity in sWAT.…”

“…A large number of studies, however, indicate that high-protein diets show no effects on fasting blood glucose, and that long-term high-protein/low-carbohydrate diets induce insulin resistance, increase the risk of type 2 diabetes, and are associated with increased mortality in humans [35,36]. Paradoxically, low-protein/high-carbohydrate diets improve glucose tolerance and have the most beneficial effect on longevity in rodents without a reduction in total caloric intake [5,37,38]. Effects of low-protein diets on populations at high risk of diabetes remain unknown.…”

“…However, dietary protein restriction is an emerging alternative for treating obesity and glucose intolerance induced by a high-fat diet [1,2]. Mediated by FGF21, dietary protein restriction reduces body weight gain, increases energy expenditure, changes food intake and metabolism, and improves glucose homeostasis in obese models [3][4][5][6].…”

“…Low-protein diets reduce body weight by decreasing body fat gain, improving glucose tolerance and increasing energy expenditure. These effects are mediated by fibroblast growth factor 21 (FGF21) [3][4][5][6].…”