Project description:Adequate calorie restriction (CR) as a healthy lifestyle is recommended not only for people with metabolic disorders but also for healthy adults. Previous studies have mainly focused on the beneficial metabolic effects of CR on obese subjects, while its effects on non-obese subjects are still scarce. Here, we conducted a three-week non-controlled CR intervention in 41 subjects, with approximately 40% fewer calories than the recommended daily energy intake. We measured BMI, and applied targeted metabolic profiling on fasting blood samples and shotgun metagenomic sequencing on fecal samples, before and after intervention. Subjects were stratified into two enterotypes according to their baseline microbial composition, including 28 enterotype Bacteroides (ETB) subjects and 13 enterotype Prevotella (ETP) subjects. CR decreased BMI in most subjects, and ETP subjects exhibited a significantly higher BMI loss ratio than the ETB subjects. Additionally, CR induced limited changes in gut microbial composition but substantial microbial-independent changes in blood AAs, including a significant increase in 3-methylhistidine, a biomarker of the skeletal muscle protein turnover. Finally, baseline abundances of seven microbial species, rather than baseline AA levels, could well predict CR-induced BMI loss. This non-controlled intervention study revealed associations between baseline gut microbiota and CR-induced BMI loss and provided evidence to accelerate the application of microbiome stratification in future personalized nutrition intervention.
Project description:Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR's mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR-associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA-based homeostatic mechanisms to coordinate a program of delayed aging.
Project description:Caloric restriction (CR) improves insulin sensitivity and reduces the incidence of diabetes in obese individuals. The underlying mechanisms whereby CR improves insulin sensitivity are not clear. We evaluated the effect of 16 weeks of CR on whole-body insulin sensitivity by pancreatic clamp before and after CR in 11 obese participants (BMI = 35 kg/m(2)) compared with 9 matched control subjects (BMI = 34 kg/m(2)). Compared with the control subjects, CR increased the glucose infusion rate needed to maintain euglycemia during hyperinsulinemia, indicating enhancement of peripheral insulin sensitivity. This improvement in insulin sensitivity was not accompanied by changes in skeletal muscle mitochondrial oxidative capacity or oxidant emissions, nor were there changes in skeletal muscle ceramide, diacylglycerol, or amino acid metabolite levels. However, CR lowered insulin-stimulated thioredoxin-interacting protein (TXNIP) levels and enhanced nonoxidative glucose disposal. These results support a role for TXNIP in mediating the improvement in peripheral insulin sensitivity after CR.
Project description:Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR’s mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approxi- mately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR- associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regula- tion of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA- based homeostatic mechanisms to coordinate a program of delayed aging.
Project description:We recruited ten normal-weight healthy men using inclusion criteria as previously described (Collet et al 2017). All males were healthy and not obese or overweight (average age: 23.8 years, average BMI (kg/m2): 23.3). Participants at baseline consumed a balanced diet (50% carbohydrate, 30% fat, and 20% protein). During caloric restriction, volunteers consumed 10% of normal energy requirement (226 kcal/d) for two days, again balanced (50% carbohydrate, 30% fat, and 20% protein), with the same macronutrient composition. After caloric restriction, volunteers were offered three substantial ad libitum buffet meals per day (20 MJ = 4,777 kcal) and additional snacks (16 MJ = 3,821 kcal) between meals for 2 days. They were invited to eat freely until comfortably full; food consumption was covertly measured. We collected fasting plasma samples at 0800 AM at baseline, after CR and refeeding (RF).
Project description:In women, obesity is associated with decrements in reproductive health that are improved with weight loss. Due to the difficulty of maintaining weight loss through lifestyle interventions, surgical interventions have become popular treatments for obesity. We examined how weight loss induced by Roux-en Y gastric bypass surgery (RYGB) or calorie restriction impacted expression of hypothalamic genes related to energy intake and reproduction. RYGB and calorie restriction induced equivalent weight loss; however, expression of the anorexigenic melanocortin pathway decreased only in calorie restricted mice. Serum estradiol concentrations were lower in calorie restricted mice relative to RYGB during proestrous, suggesting that RYGB maintained normal estrous cycling. Thus, the effects of RYGB for female mice, and possibly humans, extend beyond weight loss to include enhanced reproductive health.
Project description:In this study, we examined the 24-hour plasma melatonin patterns of young adult (∼11 years of age) and old (∼24 years of age) rhesus macaques, and determined how they would be influenced by 30% caloric restriction (CR). Well-defined 24-hour plasma melatonin rhythms were observed in all the males but only the old animals showed significant attenuation of night-time melatonin levels. Moreover, 4.5 years of CR failed to prevent the age-associated decline in plasma melatonin levels in the old males and caused a significant decrease in the young adult males. Similar plasma melatonin rhythms were also observed in all the females but no age-related decline was detected, and 2 years of CR had no obvious effect on plasma melatonin levels. If anything, there was a trend for the CR to decrease melatonin levels in the young adult females. Taken together, the results fail to show any clear benefit of CR on plasma melatonin levels in old rhesus macaques and may even be detrimental to plasma melatonin levels in young adults.