Mild Caloric Restriction Research Articles

Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention.

Clocks that measure biological age should predict all-cause mortality and give rise to actionable insights to promote healthy aging. Here we applied dimensionality reduction by principal component analysis to clinical data to generate a clinical aging clock (PCAge) identifying signatures (principal components) separating healthy and unhealthy aging trajectories. We found signatures of metabolic dysregulation, cardiac and renal dysfunction and inflammation that predict unsuccessful aging, and we demonstrate that these processes can be impacted using well-established drug interventions. Furthermore, we generated a streamlined aging clock (LinAge), based directly on PCAge, which maintains equivalent predictive power but relies on substantially fewer features. Finally, we demonstrate that our approach can be tailored to individual datasets, by re-training a custom clinical clock (CALinAge), for use in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study of caloric restriction. Our analysis of CALERIE participants suggests that 2 years of mild caloric restriction significantly reduces biological age. Altogether, we demonstrate that this dimensionality reduction approach, through integrating different biological markers, can provide targets for preventative medicine and the promotion of healthy aging.

Healthy Aging in Times of Extreme Temperatures: Biomedical Approaches.

Climate extremes and rising energy prices present interconnected global health risks. Technical solutions can be supplemented with biomedical approaches to promote healthy longevity in hot and cold conditions. In summer, reducing basal metabolic rate through mild caloric restriction or CR mimetics, such as resveratrol, can potentially be used to lower body temperature. In winter, activating brown adipose tissue (BAT) for non-shivering thermogenesis and improved metabolic health can help adaptation to colder environments. Catechins found in green tea and in other food could be alternatives to drugs for these purposes. This review examines and discusses the biomedical evidence supporting the use of CR mimetics and BAT activators for health benefits amid increasingly extreme temperatures.

Trial of the MIND Diet for Prevention of Cognitive Decline in Older Persons

BackgroundFindings from observational studies suggest that dietary patterns may offer protective benefits against cognitive decline, but data from clinical trials are limited. The Mediterranean–DASH Intervention for Neurodegenerative Delay, known as the MIND diet, is a hybrid of the Mediterranean diet and the DASH (Dietary Approaches to Stop Hypertension) diet, with modifications to include foods that have been putatively associated with a decreased risk of dementia.MethodsWe performed a two-site, randomized, controlled trial involving older adults without cognitive impairment but with a family history of dementia, a body-mass index (the weight in kilograms divided by the square of the height in meters) greater than 25, and a suboptimal diet, as determined by means of a 14-item questionnaire, to test the cognitive effects of the MIND diet with mild caloric restriction as compared with a control diet with mild caloric restriction. We assigned the participants in a 1:1 ratio to follow the intervention or the control diet for 3 years. All the participants received counseling regarding adherence to their assigned diet plus support to promote weight loss. The primary end point was the change from baseline in a global cognition score and four cognitive domain scores, all of which were derived from a 12-test battery. The raw scores from each test were converted to z scores, which were averaged across all tests to create the global cognition score and across component tests to create the four domain scores; higher scores indicate better cognitive performance. The secondary outcome was the change from baseline in magnetic resonance imaging (MRI)–derived measures of brain characteristics in a nonrandom sample of participants.ResultsA total of 1929 persons underwent screening, and 604 were enrolled; 301 were assigned to the MIND-diet group and 303 to the control-diet group. The trial was completed by 93.4% of the participants. From baseline to year 3, improvements in global cognition scores were observed in both groups, with increases of 0.205 standardized units in the MIND-diet group and 0.170 standardized units in the control-diet group (mean difference, 0.035 standardized units; 95% confidence interval, −0.022 to 0.092; P=0.23). Changes in white-matter hyperintensities, hippocampal volumes, and total gray- and white-matter volumes on MRI were similar in the two groups.ConclusionsAmong cognitively unimpaired participants with a family history of dementia, changes in cognition and brain MRI outcomes from baseline to year 3 did not differ significantly between those who followed the MIND diet and those who followed the control diet with mild caloric restriction. (Funded by the National Institute on Aging; ClinicalTrials.gov number, NCT02817074.)

MP-453085-1 CALORIC RESTRICTION ATTENUATES SINOATRIAL NODE AND ATRIAL ARRHYTHMOGENESIS IN AGED AND FRAIL MICE

Atrial fibrillation (AF) and sinoatrial node (SAN) dysfunction are highly prevalent in elderly individuals; however, aging is also highly heterogenous. This heterogeneity has led to the concept of ‘frailty’, a state of increased vulnerability to adverse health outcomes in aging. Mild caloric restriction (CR; reducing caloric intake without malnutrition) can preserve cardiac function and improve frailty (healthspan); however, the effects of late-onset CR on SAN/atrial function in aging mice are unknown. To determine if CR affects frailty and SAN/atrial structure, function and arrhythmogenesis in aging mice. At 56 weeks of age, C57BL/6 mice were placed on either 25% CR or control diet ad libitum. Frailty scores were measured every 4 weeks for 24 weeks, at which point atrial and SAN function was studied using intracardiac electrophysiology, optical mapping, and histology. Young control mice (12 weeks) were used to account for differences in aging. Following 24 weeks of 25% CR, mice exhibited reduced frailty scores compared to the aged control diet (0.207±0.006 vs. 0.273±0.007, n=17-23; P<0.0001). Aged CR mice demonstrated lower AF inducibility (5/16, 31% vs. 12/18, 67%; P<0.05) compared to aged controls, as well as reduced corrected SAN recovery times (27.3±4.5 vs. 42.2±7.1, n=8-15; P<0.05). SAN recovery times in aged CR mice were similar to young mice (27.3±4.5 vs. 24.2.3±6.9, n=13-15; P>0.05). Due to substantial heterogeneity within groups, no difference in P-wave duration (PWD) was observed between groups. However, PWD (R2=0.15, P<0.01) and SAN recovery time (R2=0.19, P<0.0001) were each correlated with FI such that these fell along a continuum regardless of age or diet. Atrial conduction velocities were increased in CR mice compared to aged controls (51.1±2.4 vs. 19.2±2.7, n=5-7; P<0.0001), comparable to young controls (51.1±2.4 vs. 46.3±1.8, n=6-7; P>0.05). Atrial interstitial fibrosis was decreased in aged CR mice compared to aged controls (7.9±0.6 vs. 13.0±2.1, n=3; P<0.05), again comparable to young mice (7.9±0.6 vs. 5.0±0.2, n=3; P>0.05). Both conduction velocity (R2=0.32; P<0.01) and atrial fibrosis (R2=0.81; P<0.0001) showed a strong correlation to frailty score regardless of age or diet. Late-onset CR reduces frailty, improves SAN and atrial structure/function, and attenuates arrhythmogenesis in aging mice. These changes were strongly correlated, and often better predicted, by frailty compared to chronological age.

Overweight Management through Mild Caloric Restriction in Multigenerational Long-Tailed Macaque Breeding Groups.

Caloric restriction (CR) is an effective method to reduce overweight in captive non-human primates (NHPs). CR has been applied to individually- and pair-housed NHPs, but whether applying CR can be effective and safe in group-housed NHPs has not yet been assessed. This study investigates the effect of mild (20%) CR on adult overweight and biochemical parameters, immature growth, veterinary consultations, and reproductive success in multigenerational long-tailed macaque (Macaca fascicularis) breeding groups. Data were derived from anthropometric measurements and blood samples during yearly health checks, complemented with retrospective data on veterinary consultations and reproductive success. Adult body measures decreased after CR, with heavier individuals and females losing more weight compared to leaner individuals and males. CR lowered cholesterol levels in adults but had no overall effect on other biochemical parameters. Yet, biochemical parameters of individuals with high baseline values were reduced more compared to individuals with low baseline values. Immature growth, veterinary consultations and reproductive success were not influenced by CR. Thus, CR targeted the right individuals, i.e., overweight adults, and had no adverse effects on the variables examined in this study. This implies that mild CR can be a valuable overweight management strategy in group-housed NHPs.

Mild calorie restriction, but not 17α-estradiol, extends ovarian reserve and fertility in female mice.

Calorie restriction (CR) (25-40%) is the most commonly studied strategy for curtailing age-related disease and has also been found to extend reproductive lifespan in female mice. However, the effects of mild CR (10%), which is sustainable, on ovarian aging has not yet been addressed. 17α-estradiol (17α-E2) is another intervention shown to positively modulate healthspan and lifespan in mice but its effects on female reproduction remain unclear. We evaluated the effects of mild CR (10%) and 17α-E2 treatment on ovarian reserve and female fertility over a 24-week period, and compared these effects with the more commonly employed 30% CR regimen. Both 10% and 30% CR elicited positive effects on the preservation of ovarian reserve, whereas 17α-E2 did not alter parameters associated with ovarian function. Following refeeding, both 10% and 30% increased fertility as evidenced by greater pregnancy rates. In aligned with the ovarian reserve data, 17α-E2 also failed to improve fertility. Collectively, these data indicate that 10% CR is effective in preserving ovarian function and fertility, while 17α-E2 does not appear to have therapeutic potential for delaying ovarian aging.

Gut Microbiota Predicts Healthy Late-Life Aging in Male Mice.

Calorie restriction (CR) extends lifespan and retards age-related chronic diseases in most species. There is growing evidence that the gut microbiota has a pivotal role in host health and age-related pathological conditions. Yet, it is still unclear how CR and the gut microbiota are related to healthy aging. Here, we report findings from a small longitudinal study of male C57BL/6 mice maintained on either ad libitum or mild (15%) CR diets from 21 months of age and tracked until natural death. We demonstrate that CR results in a significantly reduced rate of increase in the frailty index (FI), a well-established indicator of aging. We observed significant alterations in diversity, as well as compositional patterns of the mouse gut microbiota during the aging process. Interrogating the FI-related microbial features using machine learning techniques, we show that gut microbial signatures from 21-month-old mice can predict the healthy aging of 30-month-old mice with reasonable accuracy. This study deepens our understanding of the links between CR, gut microbiota, and frailty in the aging process of mice.

Myo-Inositol Supplementation in Suckling Rats Protects against Adverse Programming Outcomes on Hypothalamic Structure Caused by Mild Gestational Calorie Restriction, Partially Comparable to Leptin Effects.

We studied whether myo-inositol supplementation throughout lactation, alone and combined with leptin, may reverse detrimental effects on hypothalamic structure and function caused by gestational calorie gestation (CR) in rats. Candidate early transcript-based biomarkers of metabolic health in peripheral blood mononuclear cells (PBMC) were also studied. Offspring of dams exposed to 25% gestational CR and supplemented during lactation with physiological doses of leptin (CR-L), myo-inositol (CR-M), the combination (CR-LM), or the vehicle (CR-V) as well as control rats (CON-V) were followed and sacrificed at postnatal day 25. Myo-inositol and the combination increased the number of neurons in arcuate nucleus (ARC) (only in females) and paraventricular nucleus, and myo-inositol (alone) restored the number of αMSH+ neurons in ARC. Hypothalamic mRNA levels of Lepr in CR-M and Insr in CR-M and CR-LM males were higher than in CR-V and CON-V, respectively. In PBMC, increased expression levels of Lrp11 and Gls in CR-V were partially normalized in all supplemented groups (but only in males for Gls). Therefore, myo-inositol supplementation throughout lactation, alone and combined with leptin, reverts programmed alterations by fetal undernutrition on hypothalamic structure and gene expression of potential early biomarkers of metabolic health in PBMC, which might be attributed, in part, to increased leptin sensitivity.

Protein supplementation during an energy-restricted diet induces visceral fat loss and gut microbiota amino acid metabolism activation: a randomized trial

Interactions between diet and gut microbiota are critical regulators of energy metabolism. The effects of fibre intake have been deeply studied but little is known about the impact of proteins. Here, we investigated the effects of high protein supplementation (Investigational Product, IP) in a double blind, randomised placebo-controled intervention study (NCT01755104) where 107 participants received the IP or an isocaloric normoproteic comparator (CP) alongside a mild caloric restriction. Gut microbiota profiles were explored in a patient subset (n = 53) using shotgun metagenomic sequencing. Visceral fat decreased in both groups (IP group: − 20.8 ± 23.2 cm2; CP group: − 14.5 ± 24.3 cm2) with a greater reduction (p < 0.05) with the IP supplementation in the Per Protocol population. Microbial diversity increased in individuals with a baseline low gene count (p < 0.05). The decrease in weight, fat mass and visceral fat mass significantly correlated with the increase in microbial diversity (p < 0.05). Protein supplementation had little effects on bacteria composition but major differences were seen at functional level. Protein supplementation stimulated bacterial amino acid metabolism (90% amino-acid synthesis functions enriched with IP versus 13% in CP group (p < 0.01)). Protein supplementation alongside a mild energy restriction induces visceral fat mass loss and an activation of gut microbiota amino-acid metabolism.Clinical trial registration: NCT01755104 (24/12/2012). https://clinicaltrials.gov/ct2/show/record/NCT01755104?term=NCT01755104&draw=2&rank=1.

Leptin Supplementation During Lactation Restores Key Liver Metabolite Levels Malprogrammed by Gestational Calorie Restriction.

Perinatal nutritional factors can program offspring metabolic phenotype and risk to obesity. This study investigates the potential role of leptin supplementation (during lactation) in ameliorating the malprogrammed effects caused by mild maternal calorie restriction during gestation, on young rat offspring liver metabolic response. Untargeted and targeted metabolomics studies on liver samples are performed by NMR and GC-MS, respectively. Global DNA methylation and the expression by RT-PCR of key genes involved in different pathways are also determined. By NMR, 15 liver metabolites are observed to be altered in the offspring of gestational calorie-restricted dams (CR group), at days 25-27 of life. Physiological leptin supplementation during lactation partially reverted the effect of CR condition for most of these metabolites. Moreover, targeted fatty acid analysis by GC-MS shows a significant decrease in the hepatic concentration of certain very long-chain fatty acids (VLCFA) in CR offspring, partially or totally reverted by leptin supplementation. No remarkable changes are found in global DNA methylation or mRNA expression. Physiological leptin supplementation during lactation contributes to the reversion of changes caused by maternal mild calorie restriction on the liver metabolome. This agrees with a putative role of leptin supplementation preventing or reversing metabolic disturbances caused by gestational metabolic malprogramming.

Caloric Restriction and Cardiovascular Health: the Good, the Bad, and the Renin-Angiotensin System.

Much excitement exists over the cardioprotective and life-extending effects of caloric restriction (CR). This review integrates population studies with experimental animal research to address the positive and negative impact of mild and severe CR on cardiovascular physiology and pathophysiology, with a particular focus on the renin-angiotensin system (RAS). We also highlight the gaps in knowledge and areas ripe for future physiological research.

Fetal Programming Effects of a Mild Food Restriction During Pregnancy in Mice: How Does It Compare to Intragestational Ghrelin Administration?

To explore in mice if a 15% food restriction protocol during pregnancy programs the offspring postnatal development, with emphasis on reproductive function, and to assess if ghrelin (Ghrl) administration to mouse dams exerts effects that mimic those obtained under mild caloric restriction. Mice were 15% food-restricted, injected with 4 nmol/animal/day of Ghrl, or injected with the vehicle (control) thorough pregnancy. After birth, the pups did not receive further treatment. Pups born from food-restricted dams (FR pups) were lighter than Ghrl pups at birth, but reached normal weight at adulthood. Ghrl pups were heavier at birth and gained more weight than control pups (C pups). This effect was not associated with plasma IGF-1. FR pups showed a delay in pinna detachment and eye opening, while an advance was observed in Ghrl pups. FR pups showed also impairment in the surface-righting reflex. In both female FR and Ghrl pups, there was an advance in vaginal opening and, in adulthood, FR pups showed a significant decrease in their own litter size and plasma progesterone, and an increase in embryo loss. A delay in testicular descent was evident in male Ghrl pups. Changes in puberty onset were not associated with differences in the expression of Kiss1 in hypothalamic nuclei. Finally, in adulthood, FR pups showed a significant decrease in sperm quality. In conclusion, a mild food restriction thorough gestation exerted programming effects on the offspring, affecting also their reproductive function in adulthood. These effects were not similar to those of intragestational Ghrl administration.

Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study: Rationale, design and baseline characteristics of a randomized control trial of the MIND diet on cognitive decline

Alzheimer's dementia (AD) is the sixth leading cause of death in the U.S., with an estimated $305 billion cost of care in 2020. Currently there are no cures or therapies to ameliorate the disease progression and symptoms. Growing evidence links a diet characterized by high antioxidant components with benefits to cognitive function, which is indicative of the preventative potential of dietary inteventions.The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) study is a 3-year, multicenter, randomized controlled trial to test the effects of the MIND diet on cognitive function in 604 individuals at risk for AD.Men and women ages 65 to 84 years were recruited. Eligible participants were randomized to either the MIND diet with mild caloric restriction or their usual diet with mild caloric restriction. Cognitive assessments, medical history, blood pressure, anthropometric measurements, and blood and urine sample collections will be taken at baseline and follow-up visits. MRI scans will be completed on approximately half of the enrolled participants at the start and end of the study.Unique features of the MIND study include: 1) a dietary pattern, rather than single nutrient or food, tested in an at-risk population; 2) foods featured as key components of the MIND diet (i.e. extra-virgin olive oil, blueberries, and nuts) provided for participants; and 3) MRI scans of brain structure and volume that may provide potential mechanistic evidence on the effects of the diet. Results from the study will be crucial to the development of dietary guidelines for the prevention of AD.

Impact of diet and exercise training on physical performance and body composition in male rats: influence of ad libitum feeding and mild caloric restriction

Background: Improvements in body composition have been reported when men and women switch from consuming a Western Diet (WD) to a purified and “clean” diet (PD) known as a "Daniel Fast.” While no laboratory studies have determined physical performance improvements following the Daniel Fast, numerous anecdotal reports of improved physical capacity and well-being have been noted. Methods: In the present study, Long-Evans rats (N=28) were assigned to be exercise trained (+E) by running on a treadmill three days per week or to act as sedentary controls. After baseline physical performance was evaluated by recording run time to exhaustion, half of the animals in each group were fed for 12 months either a PD formulated to mimic the Daniel Fast, or a WD. Food was provided ad libitum during months 1-3 and was restricted to 90% of animals’ daily needs during months 4-12. Physical performance was evaluated again at the end of months 3, 6, 9, and 12, as was body composition and bone mineral density using dual energy x-ray absorptiometry. Results: As expected, exercise resulted in an increase in run time as compared to the non-exercise control animals (p&lt;0.05). Dietary intake did not influence run time. Body composition was largely impacted by diet composition, with the PD resulting in less total mass and fat mass as compared to the WD (p&lt;0.05), with only small differences noted in lean mass between diet groups. Bone mineral density increased in a linear fashion from months 3-12, with no differences noted based on diet or exercise training. Conclusion: A WD, with and without exercise, results in increased total and fat mass in male rats. A PD allows animals to maintain a relatively low body fat, without leading to adverse outcomes pertaining to lean body mass or bone mineral density.

High intensity interval training (HIIT) as a viable alternative to induce the prevention of respiratory diseases: a point of view of exercise immunology during COVID-19 outbreak

The immune system's response against SARS-Cov-2 seems crucial to control viral infection, since this system is homeostatic, dynamic and promotes immunoprotection of the organism through the activation of the innate and adaptive immune system via activation of cellular and chemical complexes that recognize, neutralize, metabolize and eliminate heterologous substances, with or without tissue damage. An obesogenic microenvironment can further increase the risk of disease complications, and cause a more virulent viral strain and a more lethal virus. Moreover, physical inactivity as well as poor eating habits impairs the body's energy metabolism and immune cells due to low-grade chronic inflammation. Studies suggest that light to moderate exercise, as well as mild calorie restriction, as an effective approach to relieve obesity and therefore an interesting strategy to strengthen the immune response during the outbreak of COVID-19, while a vaccine is not developed. Some studies have been shown significant findings in favor of High intensity interval training (HIIT) protocols when compared to moderate intensity exercise, showing how immunological system responds to vigorous to high intensity training. However, HIIT has a lower cost of time, reducing the time/efficiency ratio, that is, a lower cost of time with similar or even better benefits to higher volume exercise programs. Let us not forget: "time is the most precious asset we have".

Metabolic Health Outcomes Following Nine Months Of Mild Caloric Restriction In Male Rats Adhering To A Western Or Vegan Diet

Metabolic Health Outcomes Following Nine Months Of Mild Caloric Restriction In Male Rats Adhering To A Western Or Vegan Diet

Influenza and obesity: its odd relationship and the lessons for COVID-19 pandemic.

AimsAnalyze the relationship between obesity and influenza.MethodsBasal hormone milieu, defective response of both innate and adaptive immune system and sedentariness are major determinants in the severity of influenza viral infection in obese patients. Being overweight not only increases the risk of infection and of complications for the single obese person, but a large prevalence of obese individuals within the population might increase the chance of appearance of more virulent viral strain, prolongs the virus shedding throughout the total population and eventually might increase overall mortality rate of an influenza pandemic.ResultsWaiting for the development of a vaccination against COVID-19, isolation of positive cases and social distancing are the primary interventions. Nonetheless, evidence from previous influenza pandemics suggests the following interventions aimed at improving immune response: (1) lose weight with a mild caloric restriction; (2) include AMPK activators and PPAR gamma activators in the drug treatment for obesity associated with diabetes; and (3) practice mild-to-moderate physical exercise.ConclusionsDue to prolonged viral shedding, quarantine in obese subjects should likely be longer than normal weight individuals.

Cats reorganise their feeding behaviours when moving from ad libitum to restricted feeding.

ObjectivesOne identified solution to prevent obesity in cats is to control and limit their calorie intake. The objective of the present work was to better elucidate the impact of calorie cut-off on the feeding behaviour of cats.MethodsA control (n = 31) and a test group of cats (n = 38) were included in the present study. Both groups received the same food variety during the study. A period of ad libitum feeding was initially set (T0), followed by a 9-month mild calorie restriction period for the test group only (T9; average calorie restriction = 6%), and a final period of ad libitum feeding (T10). The individual cat feeding behaviours were measured via an electronic feeding system, and agonistic interactions between cats during food anticipation via video observations. Generalised linear mixed models were fitted to compare all feeding parameters between periods by group. No statistical analyses could be performed on the agonistic interactions data owing to their structure.ResultsThe feeding behaviour of the control group remained stable during the entire study, while the test group showed fewer but larger meals taken at shorter time intervals and a faster eating rate in response to calorie restriction. The average total number of agonistic interactions per cat increased during the calorie cut-off period in the test group only. One month after returning to ad libitum feeding, all behaviours were largely restored to baseline values.Conclusions and relevanceBehavioural changes expressed by cats under calorie restriction can explain some of the difficulties obtaining cat owners’ compliance with dietary restriction, especially in multi-cat households. Feeding strategies should be utilised to help cats be less impulsive and maintain normal feeding patterns when moving away from ad libitum feeding.

Skeletal muscle thermogenesis induction by exposure to predator odor.

Non-shivering thermogenesis can promote negative energy balance and weight loss. In this study, we identified a contextual stimulus that induces rapid and robust thermogenesis in skeletal muscle. Rats exposed to the odor of a natural predator (ferret) showed elevated skeletal muscle temperatures detectable as quickly as 2 min after exposure, reaching maximum thermogenesis of >1.5°C at 10-15 min. Mice exhibited a similar thermogenic response to the same odor. Ferret odor induced a significantly larger and qualitatively different response from that of novel or aversive odors, fox odor or moderate restraint stress. Exposure to predator odor increased energy expenditure, and both the thermogenic and energetic effects persisted when physical activity levels were controlled. Predator odor-induced muscle thermogenesis is subject to associative learning as exposure to a conditioned stimulus provoked a rise in muscle temperature in the absence of the odor. The ability of predator odor to induce thermogenesis is predominantly controlled by sympathetic nervous system activation of β-adrenergic receptors, as unilateral sympathetic lumbar denervation and a peripherally acting β-adrenergic antagonist significantly inhibited predator odor-induced muscle thermogenesis. The potential survival value of predator odor-induced changes in muscle physiology is reflected in an enhanced resistance to running fatigue. Lastly, predator odor-induced muscle thermogenesis imparts a meaningful impact on energy expenditure as daily predator odor exposure significantly enhanced weight loss with mild calorie restriction. This evidence signifies contextually provoked, centrally mediated muscle thermogenesis that meaningfully impacts energy balance.

Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate.

High-esterified pectin (HEP) is a prebiotic able to modulate gut microbiota, associated with health-promoting metabolic effects in glucose and lipid metabolism and adipostatic hormone sensitivity. Possible effects regulating adaptive thermogenesis and energy waste are poorly known. Therefore, we aimed to study how physiological supplementation with HEP is able to affect microbiota, energy metabolism and adaptive thermogenic capacity, and to contribute to the healthier phenotype promoted by HEP supplementation, as previously shown. We also attempted to decipher some of the mechanisms involved in the HEP effects, including in vitro experiments. We used a model of metabolic malprogramming consisting of the progeny of rats with mild calorie restriction during pregnancy, both under control diet and an obesogenic (high-sucrose) diet, supplemented with HEP, combined with in vitro experiments in primary cultured brown and white adipocytes treated with the postbiotic acetate. Our main findings suggest that chronic HEP supplementation induces markers of brown and white adipose tissue thermogenic capacity, accompanied by a decrease in energy efficiency, and prevention of weight gain under an obesogenic diet. We also show that HEP promotes an increase in beneficial bacteria in the gut and peripheral levels of acetate. Moreover, in vitro acetate can improve adipokine production, and increase thermogenic capacity and browning in brown and white adipocytes, respectively, which could be part of the protection mechanism against excess weight gain observed in vivo. HEP and acetate stand out as prebiotic/postbiotic active compounds able to modulate both brown-adipocyte metabolism and browning and protect against obesity.