Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino ...acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.
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•Reduced isoleucine or valine, but not leucine, promotes metabolic health in mice•Reduced isoleucine is required for the metabolic benefits of a low-protein diet•The benefits of isoleucine restriction are mediated in part by FGF21•Dietary levels of isoleucine are positively associated with BMI in humans
Yu and Richardson et al. find that restriction of dietary isoleucine or valine promotes metabolic health in mice and that restriction of dietary isoleucine is required for the metabolic benefits of a low-protein diet. Furthermore, higher dietary isoleucine levels are associated with increased BMI in humans.
Calorie restriction (CR) extends the healthspan and lifespan of diverse species. In mammals, a broadly conserved metabolic effect of CR is improved insulin sensitivity, which may mediate the ...beneficial effects of a CR diet. This model has been challenged by the identification of interventions that extend lifespan and healthspan yet promote insulin resistance. These include rapamycin, which extends mouse lifespan yet induces insulin resistance by disrupting mTORC2 (mechanistic target of rapamycin complex 2). Here, we induce insulin resistance by genetically disrupting adipose mTORC2 via tissue-specific deletion of the mTORC2 component Rictor (AQ-RKO). Loss of adipose mTORC2 blunts the metabolic adaptation to CR and prevents whole-body sensitization to insulin. Despite this, AQ-RKO mice subject to CR experience the same increase in fitness and lifespan on a CR diet as wild-type mice. We conclude that the CR-induced improvement in insulin sensitivity is dispensable for the effects of CR on fitness and longevity.
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•Calorie restriction (CR) extends lifespan and improves insulin sensitivity•Mice lacking adipose mTORC2 are insulin resistant, even on a CR diet•CR promotes fitness and longevity in mice lacking adipose mTORC2•Improved organismal insulin sensitivity does not mediate the beneficial effects of CR
Calorie restriction (CR) diets improve insulin sensitivity and extend lifespan. Yu et al. find that although mice lacking mTORC2 in adipose remain insulin resistant on a CR diet, their fitness and longevity increases similarly to wild-type mice.
The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved protein kinase that regulates growth and metabolism. mTOR is found in two protein complexes, mTORC1 and mTORC2, that have ...distinct components and substrates and are both inhibited by rapamycin, a macrolide drug that robustly extends lifespan in multiple species including worms and mice. Although the beneficial effect of rapamycin on longevity is generally attributed to reduced mTORC1 signaling, disruption of mTORC2 signaling can also influence the longevity of worms, either positively or negatively depending on the temperature and food source. Here, we show that loss of hypothalamic mTORC2 signaling in mice decreases activity level, increases the set point for adiposity, and renders the animals susceptible to diet‐induced obesity. Hypothalamic mTORC2 signaling normally increases with age, and mice lacking this pathway display higher fat mass and impaired glucose homeostasis throughout life, become more frail with age, and have decreased overall survival. We conclude that hypothalamic mTORC2 is essential for the normal metabolic health, fitness, and lifespan of mice. Our results have implications for the use of mTORC2‐inhibiting pharmaceuticals in the treatment of brain cancer and diseases of aging.
The hypothalamic activity of the protein kinase mTORC2 (mechanistic target of rapamycin complex 2) increases with age. Genetic disruption of hypothalamic mTORC2 leads to a lifelong increase in adiposity, as well as decreased spontaneous activity and increased frailty. Mice lacking hypothalamic mTORC2 have decreased lifespan. These findings demonstrate that hypothalamic mTORC2 is essential for the metabolic health, fitness, and lifespan of mice.
Low‐protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycaemic control in both rodents and humans. While the effects of an LP diet on glycaemic ...control are mediated by reduced levels of the branched‐chain amino acids, 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 an LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet‐induced obesity and hepatic steatosis in diet‐induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction that was started in midlife promoted leanness and glucose tolerance in aged males but not females, 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 male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity.
Key points
Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan.
Restriction of specific individual essential amino acids can recapitulate the benefits of PR.
Reduced histidine promotes leanness and increased energy expenditure in male mice.
Reduced histidine does not extend the lifespan of mice when begun in midlife.
Dietary levels of histidine are positively associated with body mass index in humans.
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A lower dietary level of the essential amino acid histidine reduces adiposity and hepatic steatosis in mice, and is associated with reduced body mass index in humans.
We previously determined the complete primary sequence of a heparin-binding growth-promoting factor, chondromodulin-II (ChM-II), which stimulated the growth of chondrocytes and osteoblasts in ...culture. Bovine ChM-II was a 16-kDa basic protein with 133 amino acid residues and exhibited a significant sequence similarity to the repeats of the chicken mim-1 gene product. Here we report the nucleotide sequences of bovine and mouse ChM-II cDNAs. The cDNAs each contained an open-reading frame corresponding to the ChM-II precursor with 151 amino acid residues. The N-terminus of the precursor included a secretory signal sequence of 18 amino acids prior to the mature ChM-II sequence. Unlike MIM-1, there was no repeat structure in the precursor protein, indicating that ChM-II was encoded as a gene product distinct from MIM-1. We then expressed recombinant bovine ChM-II protein which was purified to homogeneity. The recombinant protein stimulated the growth of rabbit growth plate chondrocytes, mouse MC3T3-E1 cells and rat UMR-106 osteoblastic cells in vitro.
A novel polymer-grafted C(6(0 fullerene having both hydrophilic poly(ethylene oxide) (PEO) and hydrophobic polystyrene (polySt) chains, was successfully synthesized by postpolymerization of St ...initiated by PEO-grafted C(6(0 fullerene, bis-adduct C(6(0-(PEO)(2), having peroxyester (POE) groups. C(6(0-(PEO)(2) was prepared by the reaction of C(6(0 fullerene with PEO-azopolymer. The introduction of POE groups onto C(6(0-(PEO)(2) was achieved by trapping of POE radicals formed by the thermal decomposition of 1,1-bis(t-butyldioxy)cyclohexane (BDOC). The structure of C(6(0-(PEO)(2)(POE) was confirmed by FT-IR, UV-vis, and DSC. The postgraft radical polymerization of St was successfully initiated by the POE groups of C(6(0-(PEO)(2)(POE) to give polySt-grafted C(6(0-(PEO)(2). The structure of polySt-grafted C(6(0-(PEO)(2) was identified by FT-IR, SEC, and thermal decomposition gas chromatograms and mass spectra (GC-MS). The polySt-grafted C(6(0-(PEO)(2) was soluble in good solvents for polySt and PEO, but insoluble in n-hexane which is poor solvent for polySt and PEO, and partially soluble in water which is good solvent for PEO but poor solvent for polySt. The compatibility of polySt-grafted C(6(0-(PEO)(2) in polySt matrix was remarkably improved in comparison with that of C(6(0-(PEO)(2). In addition, thermal stability of polySt-grafted C(6(0-(PEO)(2) increased in comparison with that of polySt and PEO.
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