Ketone bodies and inflammation modulation:A mini-review on ketogenic diet’s potential mechanisms in mood disorders

Mental disorders such as depression and anxiety inflict significant burdens on individuals and society.Commonly prescribed treatments often involve cognitive therapy and medications.However,for patients resistant to these conventional methods,alternative therapies like the Ketogenic Diet(KD)offer a promising avenue.KD and its key metabolite,β-hydroxybutyrate(BHB),have been hypothesized to alleviate mental disorders through antiinflammatory actions,a crucial pathway in the pathophysiology of depression.This mini-review examines 15 clinical trials exploring the influence of KD and BHB on inflammation and their potential roles in managing mental disorders.Both human and animal studies were scrutinized to elucidate possible cellular and molecular mechanisms.Out of the 15 trials,10 reported reduced levels of at least one inflammatory mediator or mRNA post KD or BHB treatment,while two observed an elevation in anti-inflammatory agents.These findings suggest that KD and BHB could modulate cellular inflammatory pathways,highlighting their potential for therapeutic application in mental disorders.

Effects of ketogenic diet and ketone bodies on the cardiovascular system:Concentration matters

Ketone bodies have emerged as central mediators of metabolic health,and multiple beneficial effects of a ketogenic diet,impacting metabolism,neuronal pathologies and,to a certain extent,tumorigenesis,have been reported both in animal models and clinical research.Ketone bodies,endogenously produced by the liver,act pleiotropically as metabolic intermediates,signaling molecules,and epigenetic modifiers.The endothelium and the vascular system are central regulators of the organism’s metabolic state and become dysfunctional in cardiovascular disease,atherosclerosis,and diabetic micro-and macrovascular complications.As physiological circulating ketone bodies can attain millimolar concentrations,the endothelium is the first-line cell lineage exposed to them.While in diabetic ketoacidosis high ketone body concentrations are detrimental to the vasculature,recent research revealed that ketone bodies in the low millimolar range may exert beneficial effects on endothelial cell(EC)functioning by modulating the EC inflammatory status,senescence,and metabolism.Here,we review the long-held evidence of detrimental cardiovascular effects of ketoacidosis as well as the more recent evidence for a positive impact of ketone bodies—at lower concentrations—on the ECs metabolism and vascular physiology and the subjacent cellular and molecular mechanisms.We also explore arising controversies in the field and discuss the importance of ketone body concentrations in relation to their effects.At low concentration,endogenously produced ketone bodies upon uptake of a ketogenic diet or supplemented ketone bodies(or their precursors)may prove beneficial to ameliorate endothelial function and,consequently,pathologies in which endothelial damage occurs.

Influence of biological sex and exercise on murine cardiac metabolism

Although the structural and functional effects of exercise on the heart are well established,the metabolic changes that occur in the heart during and after exercise remain unclear.In this study,we used metabolomics to assess time-dependent changes in the murine cardiac metabolome following 1 session of treadmill exercise.After the exercise bout,we also recorded blood lactate,glucose,and ketone body levels and measured cardiac mitochondrial respiration.In both male and female mice,moderate-and high-intensity exercise acutely increased blood lactate levels.In both sexes,low-and moderate-intensity exercise augmented circulating 3-hydroxybutryrate levels immediately after the exercise bout;however,only in female mice did high-intensity exercise increase 3-hydroxybutyrate levels,with significant increases occurring 1 h after the exercise session.Untargeted metabolomics analyses of sedentary female and male hearts suggest considerable sex-dependent differences in basal cardiac metabolite levels,with female hearts characterized by higher levels of pantothenate,pyridoxamine,homoarginine,tryptophan,and several glycerophospholipid and sphingomyelin species and lower levels of numerous metabolites,including acetyl coenzyme A,glucuronate,gulonate,hydroxyproline,prolyl-hydroxyproline,carnosine,anserine,and carnitinylated and glycinated species,as compared with male hearts.Immediately after a bout of treadmill exercise,both male and female hearts had higher levels of corticosterone;however,female mice showed more extensive exercise-induced changes in the cardiac metabolome,characterized by significant,time-dependent changes in amino acids(e.g.,serine,alanine,tyrosine,tryptophan,branched-chain amino acids)and the ketone body 3-hydroxybutyrate.Results from experiments using isolated cardiac mitochondria suggest that high-intensity treadmill exercise does not acutely affect respiration or mitochondrial coupling;however,female cardiac mitochondria demonstrate generally higher adenosine diphosphate sensitivity compared with male cardiac mitochondria.Collectively,these findings in mice reveal key sex-dependent differences in cardiac metabolism and suggest that the metabolic network in the female heart is more responsive to physiological stress caused by exercise.

Role of nutritional ketosis in the improvement of metabolic parameters following bariatric surgery

BACKGROUND Ketone bodies(KB)might act as potential metabolic modulators besides serving as energy substrates.Bariatric metabolic surgery(BMS)offers a unique opportunity to study nutritional ketosis,as acute postoperative caloric restriction leads to increased lipolysis and circulating free fatty acids.AIM To characterize the relationship between KB production,weight loss(WL)and metabolic changes following BMS.METHODS For this retrospective study we enrolled male and female subjects aged 18-65 years who underwent BMS at a single Institution.Data on demographics,anthropometrics,body composition,laboratory values and urinary KB were collected.RESULTS Thirty-nine patients had data available for analyses[74.4%women,mean age 46.5±9.0 years,median body mass index 41.0(38.5;45.4)kg/m^(2),fat mass 45.2%±6.2%,23.1%had diabetes,43.6%arterial hypertension and 74.4%liver steatosis].At 46.0±13.6 d post-surgery,subjects had lost 12.0%±3.6%of pre-operative weight.Sixty-nine percent developed ketonuria.Those with nutritional ketosis were significantly younger[42.9(37.6;50.7)years vs 51.9(48.3;59.9)years,P=0.018],and had significantly lower fasting glucose[89.5(82.5;96.3)mg/dL vs 96.0(91.0;105.3)mg/dL,P=0.025]and triglyceride levels[108.0(84.5;152.5)mg/dL vs 152.0(124.0;186.0)mg/dL,P=0.045]vs those with ketosis.At 6 mo,percent WL was greater in those with postoperative ketosis(-27.5%±5.1%vs 23.8%±4.3%,P=0.035).Urinary KBs correlated with percent WL at 6 and 12 mo.Other metabolic changes were similar.CONCLUSION Our data support the hypothesis that subjects with worse metabolic status have reduced ketogenic capacity and,thereby,exhibit a lower WL following BMS.

Ketogenic diets and Alzheimer’s disease

Alzheimer’s disease(AD)is a progressive neurodegenerative disorder characterized by decline in cognitive functions and associated with the neuropathological hallmarks of amyloid-peptide plaques and neurofibrillary tangles.Cerebral glucose uptake and metabolism deteriorate in AD and this hypometabolism precedes the onset of clinical signs in AD.The early decline in brain glucose metabolism in AD has become a potential target for therapeutic intervention.This has led to investigations assessing the supplementation of the normal glucose supply with ketone bodies which are produced by the body during glucose deprivation and can be metabolized by the brain when glucose utilization is impaired.The present review provides a synopsis of preclinical studies and clinical trials assessing the efficacy of ketogenic diets in the treatment of AD.Both the direct administration of ketone bodies and the use of high-fat,low-carbohydrate ketogenic diets have been shown to be efficacious in animal models of AD and clinical trials with AD patients.The mechanism underlying the efficacy of ketogenic diets remains unclear,but some evidence points to the normalization of aberrant energy metabolism.At present there is only limited evidence of the usefulness of ketogenic diets in AD.However,this dietary approach seems to be promising and deserves further clinical investigations.

The effects of nutritional ketosis induced by Bigu-herbs regimen and ketogenic diet on diseases and aging

The Bigu-herbs regimen,a Taoism(Taoism is an ancient Chinese Taoist philosophy system)special health-preserving technique to achieve longevity through strict abstinence from food,limits the intake of grains and uses herbs to replace normal diet to gain energy.Practicing Bigu-herbs regimen for several weeks to several years can make one lose weight,prevent diseases,and prolong life.The modern ketogenic diet(KD)mainly limits carbohydrate intake and increase fat intake.The low-carbohydrate,high-fat,and adequate protein diet is well known for its antiepileptic and neurotrophic effects.Limiting the intake of carbohydrate results in energy metabolism reprogramming to mobilize the steatolysis,energize and promote ketone bodies(KBs)production,achieving a state of nutritional ketosis(NK).The researchers summarized how ketone bodies or NK affects diseases and the aging process,as well as the side effects of KD.NK has a favorable effect on caloric intake,lipid parameters,glycemic index,and insulin sensitivity;moreover,it can be used as a treatment option for diabetes,obesity,and other metabolic disorders.NK is recognized as being neuroprotective and is good for epilepsy,Alzheimer’s disease,and emotional disturbance.Targeting the metabolic differences between tumor and normal cells,NK limits the use of glucose and impairs energy metabolism in cancer cells,inhibiting their growth and rendering them susceptible to clinical treatments.NK also affects inflammation and the release of cytokines,regulate gut flora,extend longevity and health span,and preserve physiologic functions.The side effects of KDs are controllable under the guidance of a specially trained dietitian and medical team.

The neonatal ketone body is important for primordial follicle pool formation and regulates ovarian ageing in mice

Adverse nutritional conditions during the perinatal stage are related to early menopause in adulthood;however,the underlying mechanism is still unclear.Herein,we revealed that colostrum-activated ketone body elevation during the postnatal stage regulated primordial follicle reservoir size and then affected ovarian ageing.We found that the expression of the ketogenesis rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA synthase 2(Hmgcs2)was largely enhanced during primordial follicle pool formation after birth and might be activated in the ovaries by colostrum.Reactive oxygen species(ROS)elevation in the ovaries leads to follicle apoptosis to deplete damaged follicles,while Hmgcs2 deficiency enhances follicle apoptosis and thus decreases the size of the primordial follicle pool and leads to premature ovarian ageing(POA),which might be related to the activation of cellular endogenous antioxidant system.All these defects could be rescued by ketone body administration,which suppressed ROS-activated follicle apoptosis.Our results suggest that the internal metabolic homeostasis of newborn mice is critical for the primordial reservoir and that any intrauterine and perinatal undernutrition could result in POA.

Circulating metabolic signatures of heart failure in precision cardiology

Precision cardiology aims to implement personalized health care and precise medical decisions based on the specific characteristics of individuals.Metabolic remodeling plays a causal role in the pathogenesis of heart failure(HF).Changes in metabolic pathways such as substrate preference,high-energy phosphate metabolism and amino acid metabolism,are involved in pathological structural remodeling and functional impairment.These metabolic alterations are usually not restricted in the cardiac tissue,but also manifest in circulation.In clinical practice,blood sample is routinely used for HF screening.Metabolomics is an emerging omics technology that provides an efficient way to acquire dynamic metabolic profiles in circulation.An increasing number of metabolic biomarkers have been implicated in disease progression,making it possible to fight HF in a more effective and precise way.This review summarizes the modern analytical techniques in metabolomics as well as emerging circulating metabolites during the pathogenesis of HF,aiming to provide new insights into the prevention,diagnosis and treatment of HF in the era of precision medicine.

Coconut oil as a therapeutic treatment for Alzheimer’s disease:a review

The coconut tree(Cocos nucifera)which is also known as the“Tree of life”has its own values in each part of the tree and coconut oil is more prestigious among them.At present,the consumption of coconut oil is booming all around the world owing to its tremendous health benefits.The unique chemical composition of coconut oil enriched with medium chain fatty acids(MCFAs)has led to the exploration of these nutritional and therapeutic influences.Unlike the long chain fatty acids(LCFAs),the MCFAs generated from the digestion of medium chain triglycerides(MCTs)has a specific pathway for the metabolism,as it bypasses the lymphatic system and enter the liver directly through the portal vein.Due to such distinct attributes in absorption and metabolism,MCTs are readily capable of forming ketone bodies than other triglycerides.These ketone bodies are a competent energy source for the brains,especially those having cognitive impairments like Alzheimer's disease(AD).AD is a neurodegenerative disease characterized clinically by accelerating shortfalls in memory and behavioral changes.The principal biochemical hallmarks behind the pathogenesis of AD are the development of extracellular amyloidβplaques and the accumulation of intracellular neurofibrillary tangles.Occurrence of Cardiovascular diseases(CVD)with elevated LDL levels,hypertension,Type 2 diabetes,obesity,and insulin resistance are some key risk factors that are responsible for the increasing prevalence and incidence of AD.There is sufficient evidence to prove that MCTs in coconut oil are metabolized and absorbed in such a way that retards the severity of these physiological risk factors.Besides,coconut oil is endowed with many polyphenolic compounds that are serving as antioxidants by combating oxidative stress and inflammation,which in turn downregulates the etiology of AD.But depending on the different processing conditions applied in extraction techniques of coconut oil,variations in antioxidant capacity can take place.Even though there are inadequacies in peer-reviewed large cohort clinical data for the long run,this article reviews that coconut oil,its constituents,and metabolism have positive findings on the potentiality to treat AD as a nutritional supplement.

Metabolic modulation of acetaminophen-induced hepatotoxicity by osteopontin

Induction of osteopontin(OPN),a well-known pro-inflammatory molecule,has been observed in acetaminophen(APAP)-induced hepatotoxicity.However,the precise cell source for OPN induction and its role during APAP-induced hepatotoxicity has not been fully explored.By employing a hepatotoxic mouse model induced by APAP overdose,we demonstrate that both serum and hepatic OPN levels were significantly elevated in response to APAP treatment.Our in vivo and in vitro studies clearly indicated that the induced expression of hepatic OPN was mainly located in necrosis areas and produced by dying or dead hepatocytes.Functional experiments showed that OPN deficiency protected against the APAP-induced liver injury by inhibiting the toxic APAP metabolism via reducing the expression of the cytochrome P450 family 2 subfamily E member 1(CYP2E1).Interestingly,this inhibition of CYP2E1 expression did not occur in unfasted Opn−/−mice,but was significant in fasted Opn−/−mice and maintained for 2hours after APAP challenge in fasted Opn−/−mice.In addition,despite the early protective role of OPN deficiency on APAP-induced hepatotoxicity,OPN deficiency retarded injury resolution by sensitizing hepatocytes to apoptosis and impairing liver regeneration.Finally,we demonstrated that a siRNA-mediated transient hepatic Opn knockdown could sufficiently and significantly protect animals from APAP-induced hepatotoxicity and death.In conclusion,this study clearly defines the cell source of OPN induction in response to APAP treatment,provides a novel insight into the metabolic role of OPN to APAP overdose,and suggests an Opn-targeted therapeutic strategy for the treatment or prevention of APAP-induced hepatotoxicity.