Search

Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions.

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. [ABSTRACT FROM AUTHOR]

Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. Although central oxytocin has antistress effects, the role of central oxytocin in stress-induced gastric dysmotility remains unknown. Solid gastric emptying was measured in rats receiving acute restraint stress, 5 consecutive days of repeated restraint stress (chronic homotypic stress), and 7 consecutive days of varying types of stress (chronic heterotypic stress). Oxytocin and oxytocin receptor antagonist were administered intracerebroventricularly (icv). Expression of corticotropin-releasing factor (CRF) mRNA and oxytocin mRNA in the paraventricular nucleus (PVN) of the hypothalamus was evaluated by real-time RT-PCR. The changes of oxytocinergic neurons in the PVN were evaluated by immunohistochemistry. Acute stress delayed gastric emptying, and the delayed gastric emptying was completely restored after 5 consecutive days of chronic homotypic stress. In contrast, delayed gastric emptying persisted following chronic heterotypic stress. The restored gastric emptying following chronic homotypic stress was antagonized by icv injection of an oxytocin antagonist. Icv injection of oxytocin restored delayed gastric emptying induced by chronic heterotypic stress. CRF mRNA expression, which was significantly increased in response to acute stress and chronic heterotypic stress, returned to the basal levels following chronic homotypic stress. In contrast, oxytocin mRNA expression was significantly increased following chronic homotypic stress. The number of oxytocin-immunoreactive cells was increased following chronic homotypic stress at the magnocellular part of the PVN. Icy injection of oxytocin reduced CRF mRNA expression induced by acute stress and chronic heterotypic stress. It is suggested that the adaptation mechanism to chronic stress may involve the upregulation of oxytocin expression in the hypothalamus, which in turn attenuates CRF expression. chronic homotypic stress; chronic heterotypic stress; corticotropin-releasing factor; hypothalamus-pituitary-adrenal axis; paraventricular nucleus doi: 10.1152/ajpgi.00483.2009.

Am J Physiol Regul Integr Comp Physiol 298: R157-R165, 2010. First published November 4, 2009; doi: 10.1152/ajpregu.00328.2009.--Accumulation of continuous life stress (chronic stress) often causes gastric symptoms. The development of gastric symptoms may depend on how humans adapt to the stressful events in their daily lives. Although acute stress delays gastric emptying and alters upper gastrointestinal motility in rodents, the effects of chronic stress on gastric motility and its adaptation mechanism remains unclear. Central oxytocin has been shown to have antistress effects. We studied whether central oxytocin is involved in mediating the adaptation mechanism following chronic repeated stress. Mice were loaded with acute and chronic stress (repeated stress for five consecutive days), and solid gastric emptying and postprandial gastric motility were compared between acute and chronic repeated stress. Expression of oxytocin and CRF mRNA in the hypothalamus was studied following acute and chronic repeated stress. Delayed gastric emptying during acute stress (43.1 [+ or -] 7.8%; n = 6, P < 0.05) was completely restored to normal levels (72.1 [+ or -] 2.4%; n = 6) following chronic repeated stress. Impaired gastric motility induced by acute stress was also restored following chronic repeated stress. Intracerebroventricular injection of oxytocin (0.1 and 0.5 [micro]g) restored the impaired gastric emptying and motility induced by acute stress. The restored gastric emptying and motility following chronic repeated stress were antagonized by intracerehroventricular injection of oxytocin antagonists. Oxytocin mRNA expression in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus was significantly increased following chronic repeated stress. In contrast, increased CRF mRNA expression in the SON and PVN in response to acute stress was significantly reduced following chronic repeated stress. Our study suggests the novel finding that the upregulation of central oxytocin expression is involved in mediating the adaptation mechanism following chronic repeated stress in mice. key words; acute stress; chronic stress; corticotropin-releasing factor; hypothalamus-pituitary-adrenal axis

In our daily life, individuals encounter with various types of stress. Accumulation of daily life stress (chronic stress) often causes gastrointestinal symptoms and functional gastrointestinal diseases. Although some can adapt toward chronic stress, the adaptation mechanism against chronic stress remains unknown. Although acute stress delays gastric emptying and alters upper gastrointestinal motility, effects of chronic stress on gastric motility still remain unclear. We investigated the effects of acute (single stress) and chronic (repeated stress for 5 consecutive days) stress on solid gastric emptying and interdigestive gastroduodenal contractions in rats. It is well established that acute restraint stress inhibits solid gastric emptying via central corticotropin-releasing factor (CRF). To investigate whether the sensitivity to CRF is altered following chronic stress, CRF was administered intracisternally. Ghrelin is involved in regulating gastric emptying and upper gastrointestinal motility in rodents. The changes in plasma active ghrelin levels and mRNA expression in the stomach were studied following chronic stress. To evaluate the effects of chronic stress on the hypothalamus-pituitary-adrenal (HPA) axis, plasma corticosterone levels were also measured. Delayed gastric emptying observed in acute stress was completely restored following chronic stress. Acute stress abolished gastric phase III-like contractions, without affecting duodenal phase III-like contractions in the interdigestive state. Impaired gastric phase III-like contractions were also restored following chronic stress. Plasma ghrelin levels and ghrelin mRNA expression were increased significantly after chronic stress. Intracisternal injection of CRF delayed gastric emptying and impaired gastric motility in rats who received chronic stress. Plasma corticosterone concentrations were no more elevated following chronic stress. The restored gastric emptying following chronic stress was antagonized by the administration of ghrelin receptor antagonists. The adaptation mechanism may involve upregulation of ghrelin expression and attenuation of the HPA axis. In contrast, the sensitivity to central CRF remained unaltered following chronic stress in rats. adaptation; corticotropin releasing factor; growth hormone secretagogue receptor; hypothalamus-pituitary-adrenal axis; migrating motor complex

Stress can increase the release of corticotropin-releasing factor (CRF) in the hypothalamus, resulting in attenuation of gastric motor functions. In contrast, central neuropeptide Y (NPY) can reduce the biological actions of CRF, and in turn weaken stress responses. Although electroacupuncture (EA) at stomach 36 (ST-36) has been shown to have anti-stress effects, its mechanism has not yet been investigated. The effect of EA at ST-36 on the hypothalamus-pituitary-adrenal (HPA) axis and gastrointestinal motility in chronic complicated stress (CCS) conditions have not been studied and the inhibitory mechanism of NPY on CRF through the gamma-aminobutyric acid (GABA) A receptor need to be further investigated. A CCS rat model was set up, EA at ST-36 was applied to the bilateral hind limbs every day prior to the stress loading. Further, a GABA A receptor antagonist was intracerebroventricularly (ICV) injected daily. Central CRF and NPY expression levels were studied, serum corticosterone and NPY concentrations were analyzed, and gastric motor functions were assessed. CCS rats showed significantly elevated CRF expression and corticosterone levels, which resulted in inhibited gastric motor functions. EA at ST-36 significantly increased central NPY mRNA expression and reduced central CRF mRNA expression as well as the plasma corticosterone level, helping to restore gastric motor function. However, ICV administration of the GABA A receptor antagonist significantly abolished these effects. EA at ST-36 upregulates the hypothalamic NPY system. NPY may, through the GABA A receptor, significantly antagonize the overexpressed central CRF and attenuate the HPA axis activities in CCS conditions, exerting influences and helping to restore gastric motor function. [ABSTRACT FROM AUTHOR]

Background: Age is the greatest risk factor in developing Alzheimer's Disease (AD); hence, there is great interest in the possibility of targeting AD through interventions that slow or delay aging. Dietary protein restriction (PR) has been shown to be beneficial in improving overall healthspan in both humans and mice. However, the effect of PR in delaying the symptom progression of AD is largely unknown. In this study, we sought to determine the effects of PR in improving metabolic dysfunction, cognitive deficits and AD pathology along with examining the role of mTORC1 and its downstream targets in the 3xTg mouse model of AD. Method: Six month old male and female 3xTg‐AD mice were placed on either 21% protein (control) or 7% protein (PR) diets starting from 6 months and continued until 15 months to determine their effects on cognition, metabolic health and AD neuropathology. Cognitive functioning was assessed via Novel Object Recognition (NOR) test and Barnes maze test. Result: Female 3xTg‐AD mice on PR diet showed improved long‐term memory (LTM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Based on latency measurements in Barnes maze, we found that a PR diet substantially improved spatial memory in both male and female 3xTg mice. Female and male mice on low protein diets exhibited improvement in glucose tolerance, however females showed a stronger effect in glycemic control than males following a glucose tolerance test (GTT). Histopathological analysis of the hallmarks of AD showed that mice on PR had decreased tau phosphorylation and Aß plaques. Phosphorylation of the mTORC1 substrate S6K1 was decreased in PR fed 3xTg mice which suggest that reduced mTORC1 signaling may be mediating the beneficial effects of PR on AD pathology. We also found that levels of p62 protein, the major autophagy cargo receptor, is increased in 3xTg AD mice and following PR, decreased p62 expression was observed, suggesting that PR activates autophagy. Conclusion: These results suggests the molecular interplay between mTORC1 and autophagy in PR mediated beneficial effects in diminishing AD pathology. [ABSTRACT FROM AUTHOR]