Regulation of metabolic health by dietary histidine in mice

Abstract

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.

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

“…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.…”

Resistance exercise protects mice from protein-induced fat accretion

“…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).…”

“…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).…”

Protein percentage or amino acid profile: which is more important in weight loss diets?

“…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.…”

“…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.…”