Regulation of metabolic health by dietary histidine in mice

Flores, Victoria; Spicer, A.; Sonsalla, Michelle; Richardson, Nicole; Yu, Deyang; Sheridan, Grace E; Murphy, Michaela E; Babygirija, Reji; Cheng, Eunhae P.; Rojas, Juan; Yang, Shany E.; Wakai, Matthew H.; Hubbell, Ryan; Kasza, Ildikó; Tomasiewicz, Jay L.; Green, Cara L; Dantoin, Claudia; Alexander, Caroline M.; Baur, Joseph A.; Malecki, Kristen; Lamming, Dudley W.

doi:10.1113/jp283261

Cited by 23 publications

(18 citation statements)

References 68 publications

(149 reference statements)

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“…Notably, restriction of many individual amino acids, including methionine, leucine, isoleucine, histidine, threonine, tryptophan, and valine as well as simultaneous restriction of the three BCAAs, have been associated with increased energy expenditure, at least in C57BL/6J males, but not all of these restrictions induce the FGF21-UCP1 thermogenic axis in iWAT (Cummings et al, 2018; Flores et al, 2022; Fontana et al ., 2016; Forney et al, 2020; Lees et al, 2017; Yap et al, 2020; Yu et al ., 2021). Similarly, in HET3 mice fed either the Low AA or Low Ile diets, there is not a clear upregulation of iWAT Ucp1 in males and no change in females.…”

Section: Discussionmentioning

confidence: 99%

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Green

Murphy

Babygirija

et al. 2022

Preprint

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Low protein (LP) diets promote health and longevity in diverse species. Although the precise components of an LP diet that mediate its beneficial effects have not been defined, reducing dietary levels of the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine promotes metabolic health in both sexes, and increases lifespan while reducing frailty in male, but not female, C57BL/6J mice. Each BCAA has unique metabolic effects, and we recently showed that restriction of isoleucine is both sufficient to promote metabolic health and required for the metabolic benefits of an LP diet in male C57BL/6J mice. Here, we tested the hypothesis that specifically restricting isoleucine could promote healthy aging in genetically heterogenous UM-HET3 mice. We find that a reduced isoleucine diet improves the metabolic health of both young and old HET3 mice, promoting leanness and glycemic control. Restriction of isoleucine starting in adult, 6 month old HET3 mice reprograms hepatic metabolism in a way distinct from an LP diet. Finally, we find that a reduced isoleucine diet reduces frailty and extends the lifespan of both male and female HET3 mice, but to a much greater degree in males. Our results demonstrate that restricting dietary isoleucine can increase health span and longevity in a genetically diverse population of mice, and suggests that reducing dietary levels of isoleucine may have great potential as a geroprotective intervention.

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Section: Discussionmentioning

confidence: 99%

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice

Green

Murphy

Babygirija

et al. 2022

Preprint

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“…In model organisms and humans, dietary protein is a critical regulator of a wide variety of biological processes that determine metabolic health and lifespan (Trautman et al, 2022). Low protein diets promote healthspan and lifespan in flies and rodents (Fontana et al, 2016;Hill et al, 2022a;Solon-Biet et al, 2014), and emerging data suggests the same may be true for humans (Ferraz-Bannitz et al, 2022;Fontana et al, 2016;Laeger et al, 2014;Levine et al, 2014;Mair et al, 2005;Yu et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Dietary protein in particular has been shown to have a critical role in the regulation of metabolic health and longevity; low protein diets are associated with reduced rates of diabetes and other age related diseases in human longitudinal studies, and promote leanness and insulin sensitivity in human randomized clinical trials (Ferraz-Bannitz et al, 2022; Fontana et al, 2016; Levine et al, 2014; Sluijs et al, 2010). In mice, low protein, high carbohydrate diets promote leanness, glucose tolerance, and extend lifespan (Hill et al, 2022b; Richardson et al, 2021; Solon-Biet et al, 2014; Solon-Biet et al, 2015); many of the benefits of a low protein diet are mediated by reduced consumption of the branched-chain amino acids (BCAAs), particularly isoleucine and valine, and we have recently shown dietary histidine is also associated with increased adiposity and body mass index (BMI) (Flores et al, 2022; Green et al, 2022b; Jang et al, 2016; Yu et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Resistance exercise protects mice from protein-induced fat accretion

Murphy

Braucher

Elliehausen

et al. 2022

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Lower intake of dietary protein is associated with improved metabolic health and reduced rates of age-associated diseases in humans, while low protein (LP) diets improve fitness and extend the lifespan of diverse animal species. Paradoxically, many athletes and bodybuilders consume high protein (HP) diets and protein or branched-chain amino acid supplements, yet remain fit and metabolically healthy. Here, we examine the effect of weight pulling, a validated progressive resistance exercise training regimen in mice fed either a LP diet or an isocaloric HP diet. We find that sedentary HP-fed male C57BL/6J mice gain significantly more fat mass than sedentary mice fed a LP diet, despite not consuming more calories. Resistance exercise was protective against this effect, blocking excess fat gain overall and in specific fat depots in HP-fed mice, but did not alter fat mass gain or distribution in LP-fed mice. In accordance with the widespread belief that high protein diets help promote muscle mass gain, the HP diet augmented the hypertrophy of the soleus, flexor digitorum longus (FDL) and the forearm flexor complex that occurred in response to exercise. While strength increased more rapidly in HP-fed mice, the maximum strength pulled by LP and HP-fed mice after 12 weeks was indistinguishable. Our results confirm the widespread belief that HP diets can augment muscle hypertrophy and strength gain induced by resistance exercise without negative metabolic consequences, while demonstrating that LP diets may be relatively advantageous in the sedentary. The results here highlight the need to consider both dietary composition and activity levels, not simply calories, when taking a precision nutrition approach to health.

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“…Although the experiments were performed initially in both sexes, the experiment by Flores et al. (2022) was focused on the effects in male mice, because the effects of the low‐histidine diet were observed to be specific for that sex. Therefore, more studies with females can help to elucidate the sex‐specific molecular pathways involved in the metabolism of histidine in mice.…”

Section: Figure Interventions and Benefits Of Weight Lossmentioning

confidence: 99%

“…In this context, the brilliant research of Flores et al (2022) provides a new perspective on the topic. These researchers demonstrate that reducing dietary levels of histidine by 67% reduces weight gain in young, lean male mice and reduces both the fat mass and the lean mass, without altering glucose metabolism.…”

mentioning

confidence: 99%