Severe protein deficiency induces hepatic expression and systemic level of FGF21 but inhibits its hypothalamic expression in growing rats

Abstract

To study, in young growing rats, the consequences of different levels of dietary protein deficiency on food intake, body weight, body composition, and energy balance and to assess the role of FGF21 in the adaptation to a low protein diet. Thirty-six weanling rats were fed diets containing 3%, 5%, 8%, 12%, 15% and 20% protein for three weeks. Body weight, food intake, energy expenditure and metabolic parameters were followed throughout this period. The very low-protein diets (3% and 5%) induced a large decrease in body weight gain and an increase in energy intake relative to body mass. No gain in fat mass was observed because energy expenditure increased in proportion to energy intake. As expected, Fgf21 expression in the liver and plasma FGF21 increased with low-protein diets, but Fgf21 expression in the hypothalamus decreased. Under low protein diets (3% and 5%), the increase in liver Fgf21 and the decrease of Fgf21 in the hypothalamus induced an increase in energy expenditure and the decrease in the satiety signal responsible for hyperphagia. Our results highlight that when dietary protein decreases below 8%, the liver detects the low protein diet and responds by activating synthesis and secretion of FGF21 in order to activate an endocrine signal that induces metabolic adaptation. The hypothalamus, in comparison, responds to protein deficiency when dietary protein decreases below 5%.

Figure 1

Effect of protein deficiency on body weight and energy intake. (a) Evolution of body weight; (b) Final body weight; (c) Daily energy intake; (d) Energy intake adjusted to 100 g MAM. Values are means ± SEM (n = 6 per group). ^a,b,c,d,eData that do not share the same letter are different at the P < 0.05 level.

Figure 2

Component of energy expenditure in ad libitum-fed rats: resting energy expenditure (a: REE), energy expenditure of motor activity (b: EE—Act), total energy expenditure (c: TEE), activity level (d) and cost of activity (e). Values are means ± SEM (n = 6 per group). ^a,b,c,dData that do not share the same letter are different at the P < 0.05 level.

Figure 3

Expression of Fgf21 mRNA in the liver (a) and the hypothalamus (b), and FGF21 plasma concentrations (c) two hours after ingestion of a 4 g test-meal. Correlations between mean group values of Fgf21 mRNA hypothalamus values vs energy intake (EI) and protein intake (PI) (d), and correlation between Fgf21 mRNA liver vs energy intake and protein intake (e). Values are means ± SEM (n = 6 per group). ^a,b,c,dData that do not share the same letter are different at the P < 0.05 level.