Moderate Dietary Restriction Research Articles

Dietary restriction reveals sex-specific expression of the mTOR pathway genes in Japanese quails

Limited resources affect an organism’s physiology through the conserved metabolic pathway, the mechanistic target of rapamycin (mTOR). Males and females often react differently to nutritional limitation, but whether it leads to differential mTOR pathway expression remains unknown. Recently, we found that dietary restriction (DR) induced significant changes in the expression of mTOR pathway genes in female Japanese quails (Coturnix japonica). We simultaneously exposed 32 male and female Japanese quails to either 20%, 30%, 40% restriction or ad libitum feeding for 14 days and determined the expression of six key genes of the mTOR pathway in the liver to investigate sex differences in the expression patterns. We found that DR significantly reduced body mass, albeit the effect was milder in males compared to females. We observed sex-specific liver gene expression. DR downregulated mTOR expression more in females than in males. Under moderate DR, ATG9A and RPS6K1 expressions were increased more in males than in females. Like females, body mass in males was correlated positively with mTOR and IGF1, but negatively with ATG9A and RS6K1 expressions. Our findings highlight that sexes may cope with nutritional deficits differently and emphasise the importance of considering sexual differences in studies of dietary restriction.

Moderate dietary restriction delays the onset of age-associated sarcopenia in Caenorhabditis elegans due to reduced myosin UNC-54 degradation

Sarcopenia, a gradual decrease in skeletal muscle mass and strength, is a major component of frailty in the elderly, with age, (lack of) exercise and diet found to be the major risk factors. The nematode Caenorhabditis elegans is an important model of sarcopenia. Although many studies describe loss of muscle function in ageing C. elegans, surprisingly few report on the loss of muscle mass. Here, in order to quantify loss of muscle mass under various dietary restriction (DR) conditions, we used an internal GFP standard to determine levels of the major body wall muscle myosin (UNC-54) in transgenic unc-54::gfp worms over their lifespan. Myosin density linearly increased during the first week of adulthood and there was no significant effect of DR. In contrast, an exponential decrease in myosin density was seen during the second week of adulthood, with reduced rates of myosin loss for mild and medium DR compared to control. UNC-54 turnover rates, previously determined using pulse-labelling methods, correspond well with the t1/2 value found here for UNC-54-GFP using fluorescence (control t1/2 = 12.0 days), independently validating our approach. These data indicate that sarcopenia is delayed in worms under mild and medium DR due to a reduced rate of myosin UNC-54 degradation, thereby maintaining protein homeostasis.

Moderate dietary salt restriction improves blood pressure and mental well-being in patients with primary aldosteronism: The salt CONNtrol trial.

Primary aldosteronism (PA) is a frequent cause of hypertension. Aldosterone excess together with high dietary salt intake aggravates cardiovascular damage, despite guideline-recommended mineralocorticoid receptor antagonist (MRA) treatment. To investigate the antihypertensive impact of a moderate dietary salt restriction and associated physiological changes, including mental well-being. A total of 41 patients with PA on a stable antihypertensive regimen-including MRA-followed a dietary salt restriction for 12 weeks with structured nutritional training and consolidation by a mobile health app. Salt intake and adherence were monitored every 4 weeks using 24-h urinary sodium excretion and nutrition protocols. Body composition was assessed by bioimpedance analysis and mental well-being by validated questionnaires. Dietary salt intake significantly decreased from 9.1 to 5.2g/d at the end of the study. In parallel, systolic (130 vs. 121mmHg) and diastolic blood pressure (BP) (84 vs. 81mmHg) improved significantly. Patients' aptitude of estimating dietary salt content was refined significantly (underestimation by 2.4 vs. 1.4g/d). Salt restriction entailed a significant weight loss of 1.4kg, improvement in pulse pressure (46 vs. 40mmHg) and normalization of depressive symptoms (PHQD scale, p<0.05). Salt restriction, cortisol after dexamethasone suppression test and dosage of renin-angiotensin-aldosterone-system (RAAS) blockers were independently associated with BP reduction. A moderate restriction of dietary salt intake in patients with PA substantially reduces BP and depressive symptoms. Moreover, the findings underline that a sufficient RAAS blockade seems to augment the effects of salt restriction on BP and cardiovascular risk.

Impact of moderate dietary protein restriction on glucose homeostasis in a model of estrogen deficiency

The need to consume adequate dietary protein to preserve physical function during ageing is well recognized. However, the effect of protein intakes on glucose metabolism is still intensively debated. During age-related estrogen withdrawal at the time of the menopause, it is known that glucose homeostasis may be impaired but the influence of dietary protein levels in this context is unknown. The aim of the present study is to elucidate the individual and interactive effects of estrogen deficiency and suboptimal protein intake on glucose homeostasis in a preclinical model involving ovariectomy (OVX) and a 13 week period of a moderately reduced protein intake in 7 month-old ageing rats. To investigate mechanisms of action acting via the pancreas-liver-muscle axis, fasting circulating levels of insulin, glucagon, IGF-1, FGF21 and glycemia were measured. The hepatic lipid infiltration and the protein expression of GLUT4 in the gastrocnemius were analyzed. The gene expression of some hepatokines, myokines and lipid storage/oxidation related transcription factors were quantified in the liver and the gastrocnemius. We show that, regardless of the estrogen status, moderate dietary protein restriction increases fasting glycemia without modifying insulinemia, body weight gain and composition. This fasting hyperglycemia is associated with estrogen status-specific metabolic alterations in the muscle and liver. In estrogen-replete (SHAM) rats, GLUT4 was down-regulated in skeletal muscle while in estrogen-deficient (OVX) rats, hepatic stress-associated hyperglucagonemia and high serum FGF21 were observed. These findings highlight the importance of meeting dietary protein needs to avoid disturbances in glucose homeostasis in ageing female rats with or without estrogen withdrawal.

The Role of Life Style Modifications in Comprehensive Non-Alcoholic Fatty Liver Disease Treatment.

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Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3β in 3xTg-AD mice.

Moderate dietary restriction can ameliorate age-related chronic diseases such as Alzheimer's disease (AD) by increasing the expression of neurotrophic factors and promoting neurogenesis in the brain. Glycogen synthase kinase-3β (GSK-3β) signaling is essential for the coordination of progenitor cell proliferation and differentiation during brain development. The mechanisms by which GSK-3β is involved in dietary restriction-induced neurogenesis and cognitive improvement remain unclear. Six-month-old male 3xTg-AD and wild-type mice were fed on alternate days (intermittent fasting, IF) or ad libitum (AL) for 3months. GSK-3β activity was regulated by bilaterally infusing lentiviral vectors carrying siRNA targeting GSK-3β into the dentate gyrus region of the hippocampus. Intermittent fasting promoted neuronal differentiation and maturation in the dentate gyrus and ameliorated recognized dysfunction in 3xTg-AD mice. These effects were reversed by siRNA targeting GSK-3β. After intermittent fasting, the insulin and protein kinase A signaling pathways were inhibited, while the adenosine monophosphate-activated protein kinase and brain-derived neurotrophic factor pathways were activated. These findings suggest that intermittent fasting can promote neuronal differentiation and maturation in the hippocampus by activating GSK-3β, thus improving learning and memory.

Effect of a Combined Exercise and Dietary Intervention on Self-Control in Obese Adolescents.

ObjectiveThe aim of this study was to determine whether a combined exercise and dietary intervention improved cognitive and physical self-control and whether pre-to-post interventional changes in self-control were mediated by changes in body mass index (BMI) and maximal grip strength (MGS), in a sample of obese adolescents.MethodsForty-four obese adolescents were randomly assigned to a combined exercise and dietary program or to a waitlist control group; the data from 36 participants (n = 18 for each group) were analyzed. The combined exercise and dietary program was performed over 6 weeks and was supervised by qualified trainers in a closed boot camp. The exercise consisted primarily of typical aerobic training, sports, outdoor training, yoga, and resistance training. Participants were placed on moderate dietary restriction according to individual target body weight (30 kcal/kg × target weight). The primary outcomes of this study were metrics based on cognitive and physical self-control, assessed by the Stroop task and a handgrip task, respectively. Secondary outcomes included BMI and MGS.ResultsThe combined exercise and dietary intervention significantly improved both cognitive and physical self-control. Similar positive effects were also found for reduced BMI and enhanced MGS. Correlation analyses showed that the reduced BMI and enhanced MGS were significantly closely associated with improved cognitive and physical self-control. The mediation analyses revealed that the pre-to-post intervention changes in BMI and MGS significantly mediated physical self-control, but did not mediate cognitive self-control.ConclusionOur combined exercise and dietary intervention is an effective approach to improve multiple aspects of self-control, reduce BMI, and strengthen MGS among obese adolescents. These findings also suggest that reduced BMI and enhanced MGS mediate specific aspects of self-control.

Ovarian follicular development, hormonal and metabolic profile in prepubertal ewe lambs with moderate dietary restriction and lipid supplementation

To evaluate the effects of moderate dietary restriction and lipid supplementation on ovarian follicular development, hormonal and metabolic profile, thirty-five prepuberal ewe lambs were blocked by body weight and randomly assigned to treatments: ALUS (control) - unsupplemented-diet ad libitum (3.5% ether extract, n = 9); R-US - intake restricted to 85% of the ALUS diet (n = 9); AL-LS - lipid-supplemented-diet ad libitum (9.8% ether extract, n = 8); R-LS - intake restricted to 85% of the ALLS diet (n = 9), from 95 ± 8 days of age until estrus or 7 months of age. Lipid supplementation did not reduce dry matter intake. Daily weight gain was greater in lambs fed ad libitum. Plasma glucose was greater in the RLS treatment group, while serum insulin was less with lipid supplementation. There was a treatment by age interaction on total cholesterol, HDL cholesterol and triglyceride serum concentrations. Estrus was detected in 43% of the animals and the overall ovulation rate was 60%. The number of follicles, diameter of the largest follicle, body weight, age and serum progesterone at puberty did not differ among treatment groups. The mean diameter of the largest follicle was greater in lambs having than in those not having ovulations and increased with age in both groups. There was an interaction between the effects of occurrence of ovulation and age on the number of follicles between 3 and 5 mm and > 5 mm. Lipid supplementation and dietary restriction altered the metabolic profile in ewe lambs with no concomitant changes in values for reproductive variables.

Effects of Bacillus subtilis DSM32315 supplementation and dietary crude protein level on performance, gut barrier function and microbiota profile in weaned piglets1

Seventy-two piglets aged at 25 d were chosen to investigate the effects of Bacillus subtilis DSM32315 supplementation in diets with different protein levels on growth performance, intestinal barrier function, and gut microbiota profile in a 42-d trial. The animals were allotted to four treatment groups in a randomized complete block design involving a 2 (protein levels) × 2 (probiotic levels) factorial arrangement of treatments. Two protein levels included the high CP (HP) diets (0 to 14 d, 20.5%; 15 to 42 d, 19.5%) and the low CP (LP) diets (0 to 14 d, 18%; 15 to 42 d, 17%), and added probiotic (PRO) levels included at 0 and 500 mg/kg diet. Two interactions between CP and PRO for ADG (P < 0.01) and F/G (P < 0.05) were observed in phase 1. Within the piglets given the LP diet, probiotic supplementation increased ADG and decreased F/G ratio. Likewise, there were interactions between CP and PRO on the digestibility of CP (P < 0.01) and EE (P < 0.05), and probiotic supplementation increased the digestibility of CP and ether extract (EE) of piglets fed with LP diet, but that was not the case for piglets fed with HP diet. Furthermore, there were interactions between CP and PRO on villus height (P < 0.01) and villus height:crypt depth ratio (P < 0.05) in ileum. Piglets fed with LP diet containing probiotic had the greatest villus height and villus height:crypt depth ratio in ileum among treatments. There were also main effects of PRO on the propionic acid (P < 0.05) and butyric acid (P < 0.05), and the concentrations of propionic acid and butyric acid in colonic digesta were increased with the inclusion of probiotic in diet. Piglets fed with LP diet containing probiotic had the greatest population of Bacillus and Bifidobacterium (P < 0.05) in colon. In addition, there were interactions between CP and PRO on the mRNA expressions of occludin-1 (P < 0.05), epidermal growth factor (EGF) (P < 0.05), and insulin-like growth factor 1 receptor (IGF-1R) (P < 0.05). The LP fed piglets plus probiotic exhibited the greatest mRNA expressions of occludin-1, EGF, and IGF-1R in ileum compared with other treatments. In conclusion, moderate dietary protein restriction combining with the addition of B. subtilis DSM32315 synergistically increased growth performance, altered hindgut bacterial composition and metabolites, maintained intestinal barrier function in ileum of piglets.

Tryptophan restriction partially recapitulates the age-dependent effects of total amino acid restriction on energy balance in diet-induced obese rats

Moderate dietary protein restriction promotes hyperphagia and thermogenesis; however, little is known of whether these responses are due to restriction of the essential amino acids tryptophan and histidine. Here, we determined whether restriction of tryptophan and histidine alone recapitulate the effects of total amino acid restriction on energy balance, and whether the metabolic responses are age-dependent. We fed young (12 weeks old) and older (29 weeks old) diet-induced obese rats with one of four high-fat diets: control (CON, 100% amino acid requirement), total amino acid restriction (TAA, 67% amino acid restriction), tryptophan restriction (TRP, 67% tryptophan restriction) or histidine restriction (HIS, 67% histidine restriction) for 21 days. Energy balance, hormones, and key markers of hepatic nutrient sensing and brown adipose thermogenesis were measured. We found that TAA increased food intake in both young and older rats, with TRP, but not HIS, transiently simulating the hyperphagia. TAA promoted sympathetically mediated increase in energy expenditure in young rats partly through increased β2-adrenergic and FGF21 signaling in brown fat; TRP partially emulated these responses. TRP and HIS transiently increased fat mass in young rats, and TAA promoted adiposity in older rats. TAA, TRP and HIS increased postprandial FGF21 concentrations in older rats. TAA induced age-dependent differential changes in markers of hepatic amino acid sensing; TRP and HIS partially mimicked these responses. Collectively, restriction of tryptophan, but not histidine, partially recapitulated the age-dependent metabolic effects of total amino acid restriction, in concert with distinct changes in hepatic amino acid sensing and signaling mechanisms.

Moderate Dietary Protein Restriction Optimized Gut Microbiota and Mucosal Barrier in Growing Pig Model.

Appropriate protein concentration is essential for animal at certain stage. This study evaluated the effects of different percentages of dietary protein restriction on intestinal health of growing pigs. Eighteen barrows were randomly assigned to a normal (18%), low (15%), and extremely low (12%) dietary protein concentration group for 30 days. Intestinal morphology and permeability, bacterial communities, expressions, and distributions of intestinal tight junction proteins, expressions of biomarkers of intestinal stem cells (ISCs) and chymous bacterial metabolites in ileum and colon were detected. The richness and diversity of bacterial community analysis with Chao and Shannon index were highest in the ileum of the 15% crude protein (CP) group. Ileal abundances of Streptococcaceae and Enterobacteriaceae decreased respectively, while beneficial Lactobacillaceae, Clostridiaceae_1, Actinomycetaceae, and Micrococcaceae increased their proportions with a protein reduction of 3 percentage points. Colonic abundances of Ruminococcaceae, Christensenellaceae, Clostridiaceae_1, Spirochaetaceae, and Bacterodales_S24-7_group declined respectively, while proportions of Lachnospiraceae, Prevotellaceae, and Veillonellaceae increased with dietary protein reduction. Concentrations of most bacterial metabolites decreased with decreasing dietary protein concentration. Ileal barrier function reflected by expressions of tight junction proteins (occludin, zo-3, claudin-3, and claudin-7) did not show significant decrease in the 15% CP group while sharply reduced in the 12% CP group compared to that in the 18% CP group. And in the 15% CP group, ileal distribution of claudin-3 mainly located in the cell membrane with complete morphological structure. In low-protein treatments, developments of intestinal villi and crypts were insufficient. The intestinal permeability reflected by serous lipopolysaccharide (LPS) kept stable in the 15% CP group while increased significantly in the 12% CP group. The expression of ISCs marked by Lgr5 slightly increased in ileum of the 15% CP group. Colonic expressions of tight junction proteins declined in extremely low protein levels. In conclusion, moderate protein restriction (15% CP) can optimize the ileal microbiota structure via strengthening beneficial microbial populations and suppressing harmful bacterial growth and altering the function of ileal tight junction proteins as well as epithelial cell proliferation.

Invited Commentary: A Matter of Survival-The Detrimental Consequences of Adverse Early-Life Conditions.

Studies across different species have shown that moderate dietary restriction is associated with a longer life span. Surprisingly, however, when diet is restricted in prenatal life, the effect is completely the opposite. Animal studies and human epidemiologic data have shown that undernutrition in utero negatively affects health in later life and reduces life span considerably. In this issue of the Journal, Schoeps et al. (Am J Epidemiol. 2018;187(10):2085-2092) provide new evidence that variations in nutritional conditions during pregnancy relate to the future health of the unborn child. In a detailed analysis of data from Muslim and non-Muslim pregnant women in Burkina Faso, they showed that the occurrence of Ramadan in early life was strongly associated with mortality rates among children under 5 years of age. Mortality rates were highest when Ramadan had occurred in the preconception period or during the first trimester. That nutritional conditions in early life can have such profound consequences for child mortality is both astonishing and extremely relevant from a public health perspective.

Determination of the Intervention Strategies for the Prevention of Fetal Macrosomia Dependent Cesarean Sections in Nigeria

Background: Subsequent to the rising cesarean section rates worldwide over the past three decades, this study was done to determine the risk factors that predispose to fetal macrosomia with the aim of determining the intervention strategies for preventing fetal macrosomia dependent cesarean sections in Nigeria. Subjects and Methods: A record review of the birth weights of 2410 babies delivered in St Philomena’s Hospital, a survey of the nutritional habits of 75 mothers of macrosomic babies attending postnatal clinic within the study period, and an assessment of the level of awareness’ of the fasting blood glucose status of 75 mothers of macrosomic babies and 330 pregnant women with interviewer administered questionnaire were done. Results: The prevalence rate for fetal macrosomia in St Philomena’s Hospital was 8.4% during the study period. Cesarean section rate among women with fetal macrosomia was 39.2% compared to a rate of 18% in women who gave birth to babies with normal birth weight. It was also found that most pregnant women and mothers of macrosomic babies were not aware of their fasting blood glucose status. Majority of mothers of macrosomic babies preferred high glycemic index diets and also consumed sugary beverages on daily basis. Conclusion: Fetal macrosomia is a preventable outcome of pregnancy in the presence of moderate dietary restriction, low glycemic index diets as well as the inclusion of dietary fiber in the diet of pregnant women. Furthermore, a lower incidence of fetal macrosomia is capable of reducing cesarean section rates in Nigeria.

A moderate diet restriction during pregnancy alters the levels of endocannabinoids and endocannabinoid-related lipids in the hypothalamus, hippocampus and olfactory bulb of rat offspring in a sex-specific manner.

Undernutrition during pregnancy has been associated to increased vulnerability to develop metabolic and behavior alterations later in life. The endocannabinoid system might play an important role in these processes. Therefore, we investigated the effects of a moderate maternal calorie-restricted diet on the levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG), arachidonic acid (AA) and the N-acylethanolamines (NAEs) anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) in the brain of newborn rat offspring. We focused on brain structures involved in metabolism, feeding behavior, as well as emotional and cognitive responses. Female Wistar rats were assigned during the entire pregnancy to either control diet (C) or restriction diet (R), consisting of a 20% calorie-restricted diet. Weight gain and caloric intake of rat dams were monitored and birth outcomes were assessed. 2-AG, AA and NAE levels were measured in hypothalamus, hippocampus and olfactory bulb of the offspring. R dams displayed lower gain weight from the middle pregnancy and consumed less calories during the entire pregnancy. Offspring from R dams were underweight at birth, but litter size was unaffected. In hypothalamus, R male offspring displayed decreased levels of AA and OEA, with no change in the levels of the endocannabinoids 2-AG and AEA. R female exhibited decreased 2-AG and PEA levels. The opposite was found in the hippocampus, where R male displayed increased 2-AG and AA levels, and R female exhibited elevated levels of AEA, AA and PEA. In the olfactory bulb, only R female presented decreased levels of AEA, AA and PEA. Therefore, a moderate diet restriction during the entire pregnancy alters differentially the endocannabinoids and/or endocannabinoid-related lipids in hypothalamus and hippocampus of the underweight offspring, similarly in both sexes, whereas sex-specific alterations occur in the olfactory bulb. Consequently, endocannabinoid and endocannabinoid-related lipid signaling alterations might be involved in the long-term and sexual dimorphism effects commonly observed after undernutrition and low birth weight.

Moderate dietary protein restriction alters the composition of gut microbiota and improves ileal barrier function in adult pig model

This study was conducted to investigate impacts of dietary protein levels on gut bacterial community and gut barrier. The intestinal microbiota of finishing pigs, fed with 16%, 13% and 10% crude protein (CP) in diets, respectively, were investigated using Illumina MiSeq sequencing. The ileal bacterial richness tended to decrease when the dietary protein concentration reduced from 16% to 10%. The proportion of Clostridium_sensu_stricto_1 in ileum significantly decreased, whereas Escherichia-Shigella increased with reduction of protein concentration. In colon, the proportion of Clostridium_sensu_stricto_1 and Turicibacter increased, while the proportion of RC9_gut_group significantly decreased with the dietary protein reduction. Notably, the proportion of Peptostreptococcaceae was higher in both ileum and colon of 13% CP group. As for metabolites, the intestinal concentrations of SCFAs and biogenic amines decreased with the dietary protein reduction. The 10% CP dietary treatment damaged ileal mucosal morphology, and decreased the expression of biomarks of intestinal cells (Lgr5 and Bmi1), whereas the expression of tight junction proteins (occludin and claudin) in 13% CP group were higher than the other two groups. In conclusion, moderate dietary protein restriction (13% CP) could alter the bacterial community and metabolites, promote colonization of beneficial bacteria in both ileum and colon, and improve gut barrier function.

Effects of Vitamin D Receptor Activation and Dietary Sodium Restriction on Residual Albuminuria in CKD: The ViRTUE-CKD Trial.

Reduction of residual albuminuria during single-agent renin-angiotensin-aldosterone blockade is accompanied by improved cardiorenal outcomes in CKD. We studied the individual and combined effects of the vitamin D receptor activator paricalcitol (PARI) and dietary sodium restriction on residual albuminuria in CKD. In a multicenter, randomized, placebo (PLAC)-controlled, crossover trial, 45 patients with nondiabetic CKD stages 1-3 and albuminuria >300 mg/24 h despite ramipril at 10 mg/d and BP<140/90 mmHg were treated for four 8-week periods with PARI (2 μg/d) or PLAC, each combined with a low-sodium (LS) or regular sodium (RS) diet. We analyzed the treatment effect by linear mixed effect models for repeated measurements. In the intention-to-treat analysis, albuminuria (geometric mean) was 1060 (95% confidence interval, 778 to 1443) mg/24 h during RS + PLAC and 990 (95% confidence interval, 755 to 1299) mg/24 h during RS + PARI (P=0.20 versus RS + PLAC). LS + PLAC reduced albuminuria to 717 (95% confidence interval, 512 to 1005) mg/24 h (P<0.001 versus RS + PLAC), and LS + PARI reduced albuminuria to 683 (95% confidence interval, 502 to 929) mg/24 h (P<0.001 versus RS + PLAC). The reduction by PARI beyond the effect of LS was nonsignificant (P=0.60). In the per-protocol analysis restricted to participants with ≥95% compliance with study medication, PARI did provide further albuminuria reduction (P=0.04 LS + PARI versus LS + PLAC). Dietary adherence was good as reflected by urinary excretion of 174±64 mmol Na+ per day in the combined RS groups and 108±61 mmol Na+ per day in the LS groups (P<0.001). In conclusion, moderate dietary sodium restriction substantially reduced residual albuminuria during fixed dose angiotensin-converting enzyme inhibition. The additional effect of PARI was small and nonsignificant.

The Effect of Moderate Dietary Protein and Phosphate Restriction on Calcium-Phosphate Homeostasis in Healthy Older Cats.

BackgroundDietary phosphate and protein restriction decreases plasma PTH and FGF‐23 concentrations and improves survival time in azotemic cats, but has not been examined in cats that are not azotemic.HypothesisFeeding a moderately protein‐ and phosphate‐restricted diet decreases PTH and FGF‐23 in healthy older cats and thereby slows progression to azotemic CKD.AnimalsA total of 54 healthy, client‐owned cats (≥ 9 years).MethodsProspective double‐blinded randomized placebo‐controlled trial. Cats were assigned to test diet (protein 76 g/Mcal and phosphate 1.6 g/Mcal) or control diet (protein 86 g/Mcal and phosphate 2.6 g/Mcal) and monitored for 18 months. Changes in variables over time and effect of diet were assessed by linear mixed models.ResultsA total of 26 cats ate test diet and 28 cats ate control diet. There was a significant effect of diet on urinary fractional excretion of phosphate (P = 0.045), plasma PTH (P = 0.005), and ionized calcium concentrations (P = 0.018), but not plasma phosphate, FGF‐23, or creatinine concentrations. Plasma PTH concentrations did not significantly change in cats fed the test diet (P = 0.62) but increased over time in cats fed the control diet (P = 0.001). There was no significant treatment effect of the test diet on development of azotemic CKD (3 of 26 (12%) test versus 3 of 28 (11%) control, odds ratio 1.09 (95% CI 0.13–8.94), P = 0.92).Conclusions and Clinical ImportanceFeeding a moderately protein‐ and phosphate‐restricted diet has effects on calcium‐phosphate homeostasis in healthy older cats and is well tolerated. This might have an impact on renal function and could be useful in early chronic kidney disease.

Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice

We aimed to determine whether moderate diet restriction could restore cardiac, oxidative and metabolic alterations induced by postnatal overfeeding (PNOF). Litters of C57BL/6 male mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce PNOF. At 6 months, half of the NL and SL mice were subjected to 20% calorie-restriction (CR: NLCR, SLCR) for one month, while the other half continued to eat ad libitum (AL: NLAL, SLAL). Six-month old SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance, increased cardiac ROS production and decreased left ventricular ejection fraction (LVEF). After CR, SL mice body weight was normalized; however, their fat mass and leptinemia were not decreased, glucose metabolism was improved and LVEF was increased. In SL mice, CR increased the cardiac mitochondrial respiratory rate and decreased cardiac ROS production. Hearts from SLCR mice showed better recovery and smaller postischemic infarct size. Intriguingly, no difference was observed between NLAL and NLCR mice for most of the parameters investigated. Short-term moderate CR not only normalized body weight in SL mice but also improved metabolic programming and reversed oxidative and cardiac dysfunction induced by PNOF.

0132 : Oxidative stress and cardio-metabolic alterations induced by postnatal programming can be reversed in adulthood by a short-term moderate caloric restriction

Postnatal overfeeding (PNOF) in rodents induces early programming of cardio-metabolic risk. Our aim was to determine if a moderate diet restriction could restore cardio-metabolic alterations induced by PNOF. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) to induce PNOF. At weaning, all mice received a standard diet ad libitum (AL). At 6 month of age, half of the NL and SL mice were assigned to a moderate 20% calorie restriction (CR: NLCR, SLCR) for one month, while the other mice continued to eat AL (AL: NLAL, SLAL). Glucose and insulin tolerance tests, cardiac function (echocardiography), body composition (Echo-MRI), cardiac sensitivity to ischemia-reperfusion injury, mitochondrial function, reactive oxygen species (ROS) generation (EPR spectroscopy) and insulin signaling were assessed before and/or after one month of CR. Adult SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance and decreased left ventricular ejection fraction (LVEF). After one month of moderate CR, body weight of SLCR was normalized to this of NLAL however their fat mass and leptinemia were not decreased. Glucose metabolism was improved and LVEF was increased In SLCR. After 30 min of global ischemia, hearts isolated from SLCR mice showed better recovery and smaller infarct size than this of others groups. CR increased the cardiac mitochondrial respiratory rate in SLCR mice whereas cardiac ROS production was significantly decreased in SLCR mice. Insulin signaling in heart was affected neither by PNOF nor by CR. Intriguingly, no difference was observed in NLCR mice for most of the parameters investigated. Our results confirmed the programming of early overfeeding on metabolic and cardiac function. A short-term moderate CR in not only normalized body weight in SL mice but also ameliorate the metabolic programming and reverse the cardiac dysfunction induced by PNOF. The author hereby declares no conflict of interest

Hepatic autophagy contributes to the metabolic response to dietary protein restriction

Autophagy is an essential cellular response which acts to release stored cellular substrates during nutrient restriction, and particularly plays a key role in the cellular response to amino acid restriction. However, there has been limited work testing whether the induction of autophagy is required for adaptive metabolic responses to dietary protein restriction in the whole animal. Here, we found that moderate dietary protein restriction led to a series of metabolic changes in rats, including increases in food intake and energy expenditure, the downregulation of hepatic fatty acid synthesis gene expression and reduced markers of hepatic mitochondrial number. Importantly, these effects were also associated with an induction of hepatic autophagy. To determine if the induction of autophagy contributes to these metabolic effects, we tested the metabolic response to dietary protein restriction in BCL2-AAA mice, which bear a genetic mutation that impairs autophagy induction. Interestingly, BCL2-AAA mice exhibit exaggerated responses in terms of both food intake and energy expenditure, whereas the effects of protein restriction on hepatic metabolism were significantly blunted. These data demonstrate that restriction of dietary protein is sufficient to trigger hepatic autophagy, and that disruption of autophagy significantly alters both hepatic and whole animal metabolic response to dietary protein restriction.