Methionine Restriction Affects Metabolic Parameters in a Fibroblast Growth Factor 21- and Sex-Dependent Manner

OBJECTIVES: In rodents, dietary restriction of the amino acid methionine produces profound protection against obesity and obesity-related comorbidities. Fibroblast growth factor 21 (FGF21) is now recognized as an important mediator of methionine restriction's (MR) metabolic benefits. Most preclinical work investigating the impact of diet on weight gain and metabolism has been conducted in males, leaving a gap in our understanding of female responses to dietary changes. This study aimed to examine the impact of high-fat diet (HFD) feeding and MR on body weight and adiposity in male and female mice. Furthermore, we sought to determine the sex-dependent role of endogenous FGF21 in mediating metabolic responses to HFD and MR. METHODS: Male and female wild-type (WT) and Fgf21 knockout (Fgf21(−)(/)(−)) mice were fed low-fat diet (LFD) or HFD versions of control (0.86% methionine) or MR (0.17% methionine) diets for 5 weeks. Average body weight (BW) and food intake were recorded weekly. Insulin tolerance tests were performed at week 4. After 5 weeks, mice were euthanized, and adipose depots were collected. RESULTS: Neither HFD nor MR significantly altered BW of female mice regardless of genotype. However, while HFD did not significantly affect BW, MR significantly reduced BW of both WT and Fgf21(−)(/)(−) males (p < 0.0001). Neither HFD nor MR significantly altered adiposity (gonadal adipose tissue weight/body weight) in female mice regardless of genotype. However, HFD significantly increased adiposity in male WT and Fgf21(−)(/)(−) mice, and MR prevented this increase in both genotypes. MR increased energy intake in LFD- and HFD-fed WT mice. The ability of MR to increase energy intake was abolished in LFD- and HFD-fed Fgf21(−)(/)(−) mice. CONCLUSIONS: The effects of MR on BW and adiposity are sex-dependent, but FGF21-independent. Short-term HFD feeding affects adiposity differently in males and females. The effects of MR on energy intake are dependent upon FGF21. As the field progresses towards developing FGF21 as a therapeutic agent, it will be essential to understand its impact on both sexes. FUNDING SOURCES: Sources Center for Neuroinflammation and Cardiometabolic Diseases Seed Grant.