Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction

Green, Cara L; Pak, Heidi H.; Richardson, Nicole; Flores, Victoria; Yu, Deyang; Tomasiewicz, Jay L.; Dumas, Sabrina N; Kredell, Katherine; Fan, Jesse W; Kirsh, Charlie; Chaiyakul, Krittisak; Murphy, Michaela E; Babygirija, Reji; Barrett-Wilt, Gregory A.; Rabinowitz, Joshua D.; Ong, Irene M.; Jang, Cholsoon; Simcox, Judith; Lamming, Dudley W.

doi:10.1016/j.cmet.2021.12.018

Cited by 46 publications

(40 citation statements)

References 111 publications

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“…A recent publication tested how different levels of dietary protein impacted the metabolic health and molecular profile of multiple strains of male and female mice. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, there was large variability in adiposity, insulin sensitivity, and circulating hormones with sex, strain, and age of onset (Green et al, 2022 ). This study also demonstrated that short‐term PR was effective at improving metabolic health when started much later in life, and the pattern of sexual dimorphism was altered at old age.…”

Section: Sexual Dimorphism In Response To Protein and Bcaa Restrictionmentioning

confidence: 99%

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Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

2022

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Around the globe, human life expectancy increased by almost 20 years between 1950 (Collaborators, 2018. Despite the effect of the global COVID-19 pandemic, which has caused life expectancy in the United States to slightly decline (Arias et al., 2021), advances in medicine have shifted population demographics, and humans older than 65 now represent the fastest growing age group worldwide (United Nations, 2019). As a result, the portion of deaths attributed to noncommunicable diseases, such as age-related diseases, has risen and will continue to rise (Foreman et al., 2018).Though human life expectancy has largely increased, the prevalence of obesity and related disorders has grown rapidly, threatening the quality and duration of healthy years for an ever-expanding aged population. Obesity is more than tripled in men and doubled in women from 1975 to 2014, and 43% of American adults aged 40-59 are now obese (Collaboration, 2016). Obesity is increasingly impacting younger individuals, with about 40% of children now overweight

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Section: Sexual Dimorphism In Response To Protein and Bcaa Restrictionmentioning

confidence: 99%

“…Interestingly, our laboratory recently discovered that the metabolic and molecular response to PR has sex‐ and strain‐dependent effects (Green et al, 2022 ). Though many benefits of PR diets are attributed to FGF21, these studies have primarily been conducted in C57BL/6J males.…”

Section: Future Directions In Bcaa Research Metabolism and Agingmentioning

confidence: 99%

Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

2022

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“…Similarly, it has been reported that diet-mediated functions exhibit sexual disparity in diverse organisms including humans. 365 , 366 Therefore, gender necessitates consideration in nutrient-based therapies. Because demographic factors such as age and sex and genotypes are currently not taken into consideration in diet-based trials, successive studies need to elucidate their pivotal roles based on multi-omics data analysis and systems biology.…”

Section: Discussionmentioning

confidence: 99%

Dietary regulation in health and disease

Gao

et al. 2022

Sig Transduct Target Ther

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Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.

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“…The decreased weight and adiposity of histidine-restricted animals was not associated not with decreased caloric intake, but instead with increased calorie intake and increased energy expenditure. In this respect histidine restriction is similar to the effects of protein restriction, methionine restriction, BCAA and isoleucine restriction, as well as threonine and tryptophan restriction, in C57BL/6J male mice (Laeger et al ., 2014; Hill et al ., 2017; Wanders et al ., 2017; Cummings et al ., 2018; Yap et al ., 2020; Richardson et al ., 2021; Green et al ., 2022; Hill et al ., 2022). However, restriction of protein, BCAAs/isoleucine, and methionine in C57BL/6J male mice activate the FGF21-UCP1 axis, and these effect of these restriction on food intake and energy expenditure require Fgf21 (Laeger et al ., 2014; Hill et al ., 2017; Wanders et al ., 2017; Yu et al ., 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Limitations of our study include that our analysis of the effects of histidine restriction on young and diet-induced obese mice were conducted exclusively in male mice of a single inbred strain. Over the last few years, it has become apparent that both sex and genetic background play an important role in the response to dietary interventions (Mitchell et al ., 2016; Green & Lamming, 2021; Roy et al ., 2021; Green et al ., 2022); our own previous work has shown that protein or BCAA restriction has distinct metabolic and molecular effects when examined in both sexes and different strains of mice (Richardson et al ., 2021; Green et al ., 2022). In our analysis of histidine restriction as a midlife intervention, we observed distinct effects of a Low His diet on body composition and glucose tolerance in males and females.…”

Section: Discussionmentioning

confidence: 99%

Regulation of metabolic health by dietary histidine in mice

Flores

Spicer

Sonsalla

et al. 2022

Preprint

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The increasing prevalence of obesity is a serious threat to global health. Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and a low protein diet promotes leanness and glycemic control in both rodents and humans. The effects of a LP diet on glycemic control are mediated by reduced dietary levels of the branched-chain amino acids (BCAAs). However, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet. Specifically reducing dietary levels of histidine by 67% reduces weight gain of young, lean C57BL/6J mice, reducing both adipose and lean mass gain, without altering glucose metabolism. Specifically reducing dietary histidine rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese mice, increasing insulin sensitivity; this normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure that surprisingly did not require Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in both mice and humans, and suggest that reducing dietary levels of histidine may be a highly translatable option for the treatment of obesity.

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Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction

Cited by 46 publications

References 111 publications

Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

Protein restriction and branched‐chain amino acid restriction promote geroprotective shifts in metabolism

Dietary regulation in health and disease

Regulation of metabolic health by dietary histidine in mice

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