Sex differences in the hormonal and metabolic response to dietary protein dilution
Abstract
Consumption of a low-protein, high-carbohydrate diet induces a striking increase in circulating fibroblast growth factor-21 (FGF21), which is associated with improved cardiometabolic health and increased longevity. Increased lifespan during this dietary protein "dilution" has been explained by resource-mediated trade-offs between reproduction and survival, such that fecundity is optimized at a greater relative intake of proteins/carbohydrates. The magnitude of this trade-off is thought to be sex-dependent. In this study, we tested the hypothesis that metabolic responses to dietary protein dilution are likewise dependent on sex. We maintained age-matched adult male and female C57BL/6J mice on isocaloric diets containing 22% fat and differing in the ratio of protein/carbohydrate. The normal protein (NP) control diet contained 18% protein and 60% carbohydrate by kcal. The protein diluted (PD) diet contained 4% protein and 74% carbohydrate. Consistent with previous reports, PD males gained less weight and less fat than did normal protein controls and exhibited both improved glucose tolerance and decreased plasma lipids. In contrast, these metabolic benefits were absent among age-matched females maintained on the same diets. Likewise, whereas circulating FGF21 was increased up to 66-fold among PD male mice, this was substantially blunted among female counterparts. Sex differences in energy balance, glucose control, and plasma FGF21 were reversed upon ovariectomy. Collectively, our findings support that female mice are relatively less sensitive to the metabolic improvements observed following dietary protein dilution. This is accompanied by blunted circulating levels of FGF21 and requires an intact female reproductive system.
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Liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans.
“liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [152]
Reductions in dietary protein intake-or the intake of specific amino acids-increase liver FGF21 mRNA expression and circulating FGF21 protein levels.
“reductions in dietary protein intake—or the intake of specific amino acids—increase liver FGF21 mRNA expression and circulating FGF21 protein levels”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [152]
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- Authors
- Larson, K. R., Russo, K. A., Fang, Y., Mohajerani, N., Goodson, M. L., & Ryan, K. K.
- Affiliations
- University of California, Davis (US)
- Corresponding author
- Ryan, Karen K
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2017-08-09
- Volume
- 158
- Issue
- 10
- Pages
- 3477-3487
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2742831577
- Cited by
- 66
- References
- 31
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 9 · 2023: 5 · 2022: 13 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 3 · 2017: 3
- FWCI
- 2.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- University of California, Davis
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- sex differences, low-protein high-carbohydrate diet, FGF21, glucose tolerance, plasma lipids, energy balance, ovariectomy, reproductive system, longevity, cardiometabolic health, fat mass, C57BL/6J mice
- MeSH terms
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Uncoupling Protein 1, Animals, Blood Glucose, Body Composition, Energy Intake, Dietary Carbohydrates, Dietary Proteins, Energy Metabolism, Female, Fibroblast Growth Factors, Glucose Tolerance Test, Male, Mice, Inbred C57BL, Ovariectomy, RNA, Messenger, Sex Factors, Weight Gain, Diet, Protein-Restricted, Lipid Metabolism, Mice, Receptor, Fibroblast Growth Factor, Type 1, Transcriptome
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