Medium-chain Triglyceride Supplementation Research Articles

Nutritional Management of Patients with Fatty Acid Oxidation Disorders.

Treatment of fatty acid oxidation disorders is based on dietary, pharmacological and metabolic decompensation measures. It is essential to provide the patient with sufficient glucose to prevent lipolysis and to avoid the use of fatty acids as fuel as far as possible. Dietary management consists of preventing periods of fasting and restricting fat intake by increasing carbohydrate intake, while maintaining an adequate and uninterrupted caloric intake. In long-chain deficits, long-chain triglyceride restriction should be 10% of total energy, with linoleic acid and linolenic acid intake of 3-4% and 0.5-1% (5/1-10/1 ratio), with medium-chain triglyceride supplementation at 10-25% of total energy (total MCT+LCT ratio = 20-35%). Trihepatnoin is a new therapeutic option with a good safety and efficacy profile. Patients at risk of rhabdomyolysis should ingest MCT or carbohydrates or a combination of both 20 min before exercise. In medium- and short-chain deficits, dietary modifications are not advised (except during exacerbations), with MCT contraindicated and slow sugars recommended 20 min before any significant physical exertion. Parents should be alerted to the need to increase the amount and frequency of carbohydrate intake in stressful situations. The main measure in emergency hospital treatment is the administration of IV glucose. The use of carnitine remains controversial and new therapeutic options are under investigation.

Impact of MCT Oil and Caffeine on Substrate Metabolism during Submaximal Exercise

Introduction: Recent research has suggested that medium-chain triglyceride (MCT) supplementation may increase fat oxidation (FatOx) during aerobic exercise, sparing muscle glycogen and, perhaps, enhancing performance. As both MCT and caffeine (CAF) are theorized to elicit these effects, this pilot study’s purpose was to compare the physiological responses of their combined supplementation during submaximal cycling exercise. Methods: Eight aerobically trained males (mean±SD; age 23.6±4.4 years; body mass 82.3±15.8 kg; height 180.9±8.7 cm) completed one aerobic capacity (VO2peak) test and three 45-min exercise trials at 60% VO2peak. Blinded and counterbalanced, one-hour prior to each trial, participants consumed: MCT+CAF (20 mL + 100 mg), long-chain triglycerides (LCT)+CAF (40 mL + 100 mg), or CAF (100 mg). Oxygen consumption (VO2), carbon dioxide output (VCO2), and minute ventilation (VE) were measured, subsequently calculating respiratory exchange ratio (RER), energy expenditure (EE), carbohydrate oxidation (CarbOx), and FatOx. Results: No significant differences between conditions were observed for average VO2 (p=0.474; η2=0.101), VE (p=0.323; η2=0.149), (RER (p=0.323; η2=0.149), EE (p=0.474; η2=0.101), CarbOx (p=0.274; η2=0.169), or FatOx (p=0.478; η2=0.100) or for total EE (p=0.474; η2=0.101), CarbOx (p=0.274; η2=0.169), or FatOx (p=0.478; η2=0.100). Conclusions: Co-ingestion of MCT+CAF didn’t produce any significantly different physiological responses compared to co-ingestion of LCT+CAF or the CAF control.

Modified dietary fat intake for treatment of gallstone disease in people of any age.

The prevalence of gallstones varies between less than 1% and 64% in different populations and is thought to be increasing in response to changes in nutritional intake and increasing obesity. Some people with gallstones have no symptoms but approximately 2% to 4% develop them each year, predominantly including severe abdominal pain. People who experience symptoms have a greater risk of developing complications. The main treatment for symptomatic gallstones is cholecystectomy. Traditionally, a low-fat diet has also been advised to manage gallstone symptoms, but there is uncertainty over the evidence to support this. To evaluate the benefits and harms of modified dietary fat intake in the treatment of gallstone disease in people of any age. We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials in the Cochrane Library, MEDLINE ALL Ovid, Embase Ovid, and three other databases to 17 February 2023 to identify randomised clinical trials in people with gallstones. We also searched online trial registries and pharmaceutical company sources, for ongoing or unpublished trials to March 2023. We included randomised clinical trials (irrespective of language, blinding, or status) in people with gallstones diagnosed using ultrasonography or conclusive imaging methods. We excluded participants diagnosed with another condition that may compromise dietary fat tolerance. We excluded trials where data from participants with gallstones were not reported separately from data from participants who did not have gallstones. We included trials that investigated other interventions (e.g. trials of drugs or other dietary (non-fat) components) providing that the trial groups had received the same proportion of drug or other dietary (non-fat) components in the intervention. We intended to undertake meta-analysis and present the findings according to Cochrane recommendations. However, as we identified only five trials, with data unsuitable and insufficient for analyses, we described the data narratively. We included five trials but only one randomised clinical trial (69 adults), published in 1986, reported outcomes of interest to the review. The trial had four dietary intervention groups, three of which were relevant to this review. We assessed the trial at high risk of bias. The dietary fat modifications included a modified cholesterol intake and medium-chain triglyceride supplementation. The control treatment was a standard diet. The trial did not report on any of the primary outcomes in this review (i.e. all-cause mortality, serious adverse events, and health-related quality of life). The trial reported on gallstone dissolution, one of our secondary outcomes. We were unable to apply the GRADE approach to determine certainty of evidence because the included trial did not provide data that could be used to generate an estimate of the effect on this or any other outcome. The trial expressed its finding as "no significant effect of a low-cholesterol diet in the presence of ursodeoxycholic acid on gallstone dissolution." There were no serious adverse events reported. The included trial reported that they received no funding that could bias the trial results through conflicts of interest. We found no ongoing trials. The evidence about the effects of modifying dietary fat on gallstone disease versus standard diet is scant. We lack results from high-quality randomised clinical trials which investigate the effects of modification of dietary fat and other nutrient intakes with adequate follow-up. There is a need for well-designed trials that should include important clinical outcomes such as mortality, quality of life, impact on dissolution of gallstones, hospital admissions, surgical intervention, and adverse events.

Long-term clinical outcomes and management of hypertriglyceridemia in children with Apo-CII deficiency

Background and aimAPO CII, one of several cofactors which regulate lipoprotein lipase enzyme activity, plays an essential role in lipid metabolism. Deficiency of APO CII is an ultra-rare autosomal recessive cause of familial chylomicronemia syndrome. We present the long-term clinical outcomes of 12 children with APO CII deficiency. Methods and resultsThe data of children with genetically confirmed APO CII deficiency were evaluated retrospectively. Twelve children (8 females) with a mean follow-up of 10.1 years (±3.9) were included. At diagnosis, the median age was 60 days (13 days-10 years). Initial clinical findings included lipemic serum (41.6%), abdominal pain (41.6%), and vomiting (16.6%). At presentation, the median triglyceride (TG) value was 4341 mg/dL (range 1277–14,110). All patients were treated with a restricted fat diet, medium-chain triglyceride (MCT), and omega-3-fatty acids. In addition, seven patients (58.3%) received fibrate. Fibrate was discontinued in two patients due to rhabdomyolysis and in one patient because of cholelithiasis. Seven (58.3%) patients experienced pancreatitis during the follow-up period. One female experienced recurrent pancreatitis and was treated with fresh frozen plasma (FFP). ConclusionsApo CII deficiency is an ultra-rare autosomal recessive condition of hypertriglyceridemia associated with significant morbidity and mortality. Low-fat diet and MCT supplementation are the mainstays of therapy, while the benefit of TG-lowering agents are less well-defined.

Pathogenesis and Management of Citrin Deficiency.

Citrin deficiency (CD) is a hereditary disorder caused by SLC25A13 mutations that manifests as neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia caused by CD (FTTDCD), and adult-onset type 2 citrullinemia (CTLN2). Citrin, an aspartate-glutamate carrier primarily expressed in the liver, is a component of the malate-aspartate shuttle, which is essential for glycolysis. Citrin-deficient hepatocytes have primary defects in glycolysis and de novo lipogenesis and exhibit secondarily downregulated PPARα, leading to impaired β-oxidation. They are unable to utilize glucose and free fatty acids as energy sources, resulting in energy deficiencies. Medium-chain triglyceride (MCT) supplements are effective for treating CD by providing energy to hepatocytes, increasing lipogenesis, and activating the malate-citrate shuttle. However, patients with CD often exhibit growth impairment and irreversible brain and/or liver damage. To improve the quality of life and prevent irreversible damage, MCT supplementation with a diet containing minimal carbohydrates is recommended promptly after the diagnosis.

Medium-chain triglycerides (8:0 and 10:0) increase muscle mass and function in frail older adults: a combined data analysis of clinical trials.

Three clinical trials have examined the chronic effects of medium-chain triglycerides (MCTs) on muscle mass and function in frail older adults (mean age 85 years old). However, significant increases in muscle mass and some muscle function relative to long-chain triglycerides (LCTs) have yet to be shown, possibly due to the small number of participants in each trial. We re-analyzed these previous clinical trials to clarify whether MCT supplementation can increase muscle mass and function. After adding post hoc tests to the original report, we compared changes in measurement between the MCT and LCT groups in the first 2 trials and conducted a combined data analysis. In a combined data analysis, changes from baseline in measurements at the 3 months intervention in the MCTs- and LCTs-containing groups were assessed by analysis of covariance adjusted for baseline values of each measurement, age, sex, BMI, allocation to trial, habitual intakes in energy, protein, leucine, octanoic acid, decanoic acid, and vitamin D during the baseline period. The Mann-Whitney U test was used to analyze data on right and left knee extension times. MCT supplementation for 3 months increased muscle function relative to LCT supplementation with and without an L-leucine (1.2 g) and vitamin D (cholecalciferol, 20 μg)-enriched supplement. In a combined data analysis (n = 29 in MCTs, n = 27 in LCTs), relative to supplementation with 6 g LCTs/day, supplementation with 6 g MCTs/day at dinner for 3 months significantly increased body weight (adjusted mean change from baseline: MCTs 1.2 vs. LCTs 0.2 kg, p = 0.023), right arm muscle area (MCTs 1.4 vs. LCTs-0.7 cm2, p = 0.002), left calf circumference (p = 0.015), right-hand grip strength (MCTs 1.6 vs. LCTs 0.3 kg, p = 0.017), right knee extension time (p = 0.021), left knee extension time (p = 0.034), walking speed (p = 0.002), and number of iterations in leg open and close test (p < 0.001) and decreased right triceps skinfold thickness (p = 0.016). In frail older adults, supplementation for 3 months with a low dose (6 g/day) of MCTs (C8:0 and C10:0) increased muscle mass and function. These findings indicate the potential for the practical use of MCTs in daily life in treating sarcopenia.

Ketogenic therapies in Parkinson's disease, Alzheimer's disease, and mild cognitive impairment: An integrative review

BackgroundKetogenic therapies have shown benefit for seizure reduction in epilepsy but their impact on other neurologic conditions is less known. In this literature review, the efficacy of ketogenic therapies were assessed in Parkinson's disease (PD), Alzheimer's disease (AD), and mild cognitive impairment (MCI). MethodsA literature search was conducted using PubMed, Scopus, and Google Scholar focusing on ketogenic therapies in PD, AD, and MCI. ResultsA total of 2565 records were identified with a total of 15 studies (3 for PD and 12 for MCI/AD) meeting criteria for analysis. The ketogenic diet was used in all the PD studies and did show significant improvement in motor function either through vocal quality, gait, freezing, tremor, and/or balance. A variety of ketogenic therapies were utilized in the MCI and AD groups including a ketogenic diet, low-carbohydrate diet, modified Adkins diet, Mediterranean diet with coconut oil supplementation, a ketogenic diet with a ketogenic medium chain triglyceride (kMCT) supplement, as well as ketogenic supplements including a ketogenic drink with kMCT, oral ketogenic compounds (Axona and AC-1202), and MCT oil or emulsion. The ketogenic diet independently showed a non-significant trend towards improvement in cognition. The Mediterranean diet, modified Adkins diet, and low-carbohydrate diet showed statistically significant improvements in some, although not all, of their cognitive measures. Use of ketogenic supplements, drinks, or compounds showed variable results in the AD and MCI groups. The Axona and AC-1202 compounds showed no significant improvement in cognition at the end of their respective 90-day trials. Most MCT supplements did show cognitive improvements, although only after 6 months of adherence. Adherence to the intervention was problematic in most of the diet studies. ConclusionKetogenic therapies have promise in PD, AD, and MCI for symptom improvement although larger studies are needed to support their implementation in clinical practice.

Supplementation of Medium-Chain Triglycerides Combined with Docosahexaenoic Acid Inhibits Amyloid Beta Protein Deposition by Improving Brain Glucose Metabolism in APP/PS1 Mice.

The deterioration of brain glucose metabolism predates the clinical onset of Alzheimer's disease (AD). Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA) positively improve brain glucose metabolism and decrease the expression of AD-related proteins. However, the effects of the combined intervention are unclear. The present study explored the effects of the supplementation of MCTs combined with DHA in improving brain glucose metabolism and decreasing AD-related protein expression levels in APP/PS1 mice. The mice were assigned into four dietary treatment groups: the control group, MCTs group, DHA group, and MCTs + DHA group. The corresponding diet of the respective groups was fed to mice from the age of 3 to 11 months. The results showed that the supplementation of MCTs combined with DHA could increase serum octanoic acid (C8:0), decanoic acid (C10:0), DHA, and β-hydroxybutyrate (β-HB) levels; improve glucose metabolism; and reduce nerve cell apoptosis in the brain. Moreover, it also aided with decreasing the expression levels of amyloid beta protein (Aβ), amyloid precursor protein (APP), β-site APP cleaving enzyme-1 (BACE1), and presenilin-1 (PS1) in the brain. Furthermore, the supplementation of MCTs + DHA was significantly more beneficial than that of MCTs or DHA alone. In conclusion, the supplementation of MCTs combined with DHA could improve energy metabolism in the brain of APP/PS1 mice, thus decreasing nerve cell apoptosis and inhibiting the expression of Aβ.

Medium-chain triglycerides and the impact on fat absorption, growth, nutritional status and clinical outcomes in children with cholestatic liver disease: A scoping review

Medium-chain triglyceride (MCT) supplementation is recommended in cholestatic liver disease, despite unclear evidence and no consensus on the ideal percentage of fat that should be MCT. The aim was to undertake a scoping review to identify the extent and type of evidence regarding how MCT supplementation, and percentage of MCT, affects fat absorption, growth, nutritional status and clinical outcomes (morbidity, mortality, transplant) in children with cholestatic liver disease. Nine databases (MEDLINE, Embase, CINAHL, PubMed, AMED, Cochrane Library, Global Health, Scopus, Proquest) were searched from inception, with hand-searching conference abstracts and forward/backward citation searching. Eligible studies investigated oral/enteral MCT supplementation in children under 18y with cholestatic liver disease. There were no language limits. Two reviewers performed screening and data extraction independently. Data were synthesised narratively. Following title/abstract screening (1202 studies) and full-text review (40 studies), 24 studies were included comprising three small RCTs (n=19 patients), one non-randomised controlled trial (n=2), seven uncontrolled trials (n=83) and thirteen case series/reports (n=211). Seventeen studies were published before 1994. Outcomes included absorption, growth and nutritional status. MCT supplementation was associated with greater fat absorption (9/9 studies) and improved growth in some children (2/4). Higher percentage MCT was associated with greater magnesium and calcium absorption (1/1), essential fatty acid (EFA) deficiency (4/4), but not growth (3/3). The limited, mostly observational evidence from >30 years ago points to greater fat absorption on MCT and EFA deficiency on very high percentage MCT. High quality RCTs are required, particularly examining the impact of MCT at different percentages on growth, nutritional status and clinical outcomes.

Long-Term Treatment of Lipoprotein Lipase Deficiency with Medium-Chain Triglyceride-Enriched Diet: A Case Series.

Background: Lipoprotein lipase (LPL) deficiency is a genetic condition. Affected individuals typically develop symptoms related to severe and persistent hypertriglyceridemia, such as abdominal pain and recurrent pancreatitis, before 10 years of age. No pharmacological treatment sustainably lowering triglycerides (TGs) in LPL deficiency patients has been proven to be effective. This study investigated whether a long-chain triglyceride (LCT)-restricted, medium-chain triglyceride (MCT)-supplemented diet enables a meaningful reduction in TGs and reduces LPL-related symptoms in children with LPL deficiency. Methods: A single-center retrospective case series study of LPL deficiency patients treated at the Hospital of Sick Children between January 2000 and December 2022 was carried out. Data, extracted from hospital charts, included demographics, diagnosis confirmation, clinical and imaging observations, and biochemical profiles. Results: Seven patients with hypertriglyceridemia > 20 mmol/L suspected of an LPL deficiency diagnosis were included. Six patients had a confirmed molecular diagnosis of LPL deficiency, and one had glycogen storage disease type 1a (GSD1a). Clinical presentation was at a median of 30 days of age (range 1-105), and treatment start, excluding one late-treated patient, was at a median of 42 days (range 2-106). The observation and treatment period of the LPL patients was 48.0 patient years (median 7.1, range 4.3-15.5). The LCT-restricted and MCT-supplemented diet led to an immediate drop in TGs in six out of six LPL patients. TGs improved from a median of 40.9 mmol/L (range 11.4-276.5) pre-treatment to a median of 12.0 mmol/L (range 1.1-36.6) during treatment, total cholesterol from 7.6 mmol/L (4.9-27.0) to 3.9 mmol/L (1.7-8.2), and pancreatic lipase from 631 IU/L (30-1200) to 26.5 IU/L (5-289). In 48 patient years, there was only one complication of pancreatitis and no other disease-specific manifestations or complications. Catch-up growth was observed in one late-treated patient. All patients maintained normal growth and development. As expected, the diet failed to treat hypertriglyceridemia in the GSD1a patient. Conclusions: The dietary restriction of LCT in combination with MCT supplementation as long-term management of pediatric patients with LPL deficiency was feasible, well tolerated, and clinically effective in reducing TG levels and in preventing LPL-related complications.

Effect of Simultaneous Intake of Medium-Chain Triglyceride and d-Allulose on Body Fat Accumulation in Rats Fed a High-Fat Diet

Medium-chain triglycerides, lipids containing three 6−12 carbon medium-chain fatty acids, have antiobesity effects because they do not promote lipogenesis. d-Allulose, a low-calorie epimer of fructose commercially used as a low-calorie sweetener, suppresses hepatic lipogenesis and enhances postprandial fat oxidation. Therefore, we have explored whether a simultaneous intake of medium-chain fatty acids and d-allulose may exhibit a greater reduction in de novo lipogenesis and increase their antiobesity effects. To this end, 32 male Wistar rats were divided into four treatment groups of equal sizes: control, 3% d-allulose-treated, 5% medium-chain triglycerides-treated, and 3% d-allulose + 5% medium-chain triglycerides-treated. After 8 weeks of ad libitum exposure to these diets, d-allulose significantly decreased intra-abdominal adipose tissue and total body fat weight, with or without medium-chain triglyceride supplementation. The antiobesity effect of d-allulose was observed with or without dietary medium-chain triglyceride supplementation in high-fat diet-induced obese rats, but no synergistic effect was detected between d-allulose and medium-chain triglycerides.

Medium chain triglycerides with a C8:C10 ratio of 30:70 enhances cognitive performance and mitigates the cognitive decline associated with prolonged exercise in young and healthy adults

IntroductionProlonged exercise has been linked to a decline in cognitive function due to a variety of factors, such as a drop in oxygen in the prefrontal cortex and an increase in stress hormones and neurotransmitters. Medium chain triglycerides (MCTs) may possibly offset this decline as they provide energy for the brain via both direct and indirect pathways, alongside promoting chronic physiological adaptations within the brain. MethodsParticipants were divided into two groups; MCT (n = 9) and Placebo (n = 10). The MCT gels contained 6 g of MCT with a C8:C10 ratio of 30:70, whereas the placebo gels contained carbohydrates of similar calorific value to the MCT gels. Participants visited the laboratory on three occasions (familiarisation/fitness test, pre-supplementation, post-supplementation), during which they performed a battery of cognitive tasks assessing domains such as processing speed, working memory, selective attention, decision making and coordination, before and after a prolonged bout of exercise (60 mins at 90% gas exchange threshold (GET). A 2-week supplementation period between visits 2 and 3 involved the ingestion of 2 gels per day. ResultsExercise resulted in detriments in most cognitive tasks pre-supplementation for both groups, and post-supplementation for the Placebo group (main effect ps< 0.05). Post-supplementation, the effect of exercise was mediated in the MCT group for all cognitive tasks (main effect ps< 0.05), except for the Digit and Spatial Span Backwards test phases (main effect ps> 0.05). Furthermore, MCT supplementation enhanced before-exercise cognitive performance and in some measures, such as working memory, this was maintained after-exercise (interaction effect ps> 0.05). ConclusionsChronic MCT supplementation enhanced before-exercise cognitive performance and offset the cognitive decline caused by a prolonged bout of exercise. In some cases, improvements in before-exercise cognitive performance were maintained after-exercise.

Refueling the post COVID-19 brain: potential role of ketogenic medium chain triglyceride supplementation: an hypothesis.

COVID-19 infection causes cognitive changes in the acute phase, but also after apparent recovery. Over fifty post (long)-COVID symptoms are described, including cognitive dysfunction ("brain fog") precluding return to pre-COVID level of function, with rates twice as high in females. Additionally, the predominant demographic affected by these symptoms is younger and still in the workforce. Lack of ability to work, even for six months, has significant socio-economic consequences. This cognitive dysfunction is associated with impaired cerebral glucose metabolism, assessed using 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), showing brain regions that are abnormal compared to age and sex matched controls. In other cognitive conditions such as Alzheimer's disease (AD), typical patterns of cerebral glucose hypometabolism, frontal hypometabolism and cerebellar hypermetabolism are common. Similar FDG-PET changes have also been observed in post-COVID-19, raising the possibility of a similar etiology. Ketone bodies (B-hydroxybutyrate, acetoacetate and acetone) are produced endogenously with very low carbohydrate intake or fasting. They improve brain energy metabolism in the face of cerebral glucose hypometabolism in other conditions [mild cognitive impairment (MCI) and AD]. Long-term low carbohydrate intake or prolonged fasting is not usually feasible. Medium chain triglyceride (MCT) is an exogenous route to nutritional ketosis. Research has supported their efficacy in managing intractable seizures, and cognitive impairment in MCI and AD. We hypothesize that cerebral glucose hypometabolism associated with post COVID-19 infection can be mitigated with MCT supplementation, with the prediction that cognitive function would also improve. Although there is some suggestion that post COVID-19 cognitive symptoms may diminish over time, in many individuals this may take more than six months. If MCT supplementation is able to speed the cognitive recovery, this will impact importantly on quality of life. MCT is readily available and, compared to pharmaceutical interventions, is cost-effective. Research shows general tolerability with dose titration. MCT is a component of enteral and parenteral nutrition supplements, including in pediatrics, so has a long record of safety in vulnerable populations. It is not associated with weight gain or adverse changes in lipid profiles. This hypothesis serves to encourage the development of clinical trials evaluating the impact of MCT supplementation on the duration and severity of post COVID-19 cognitive symptoms.

Exudative enteropathy in neonates: A case report

The term exudative gastroenteropathy is used to describe an entity characterized by excessive loss of plasma proteins in the gastrointestinal tract. This digestive exudation can be caused either by an obstacle to intestinal lymphatic drainage or by an alteration of the epithelial barrier. The clinical picture is often associated with chronic diarrhea and an edematous syndrome. Lymphedema, infectious complications secondary to lymphopenia or hypogammaglobulinemia, and thromboembolic complications may also be observed. Diagnosis is based on the measurement of fecal alpha-1 antitrypsin clearance. Sometimes primary in the context of Waldmann disease (primary intestinal lymphangiectasis) but more often secondary. It requires an endoscopic and morphological workup to confirm the origin of the protein leak, to evaluate its extent and cause. In addition to etiological treatment, management is based on a hyperprotein and hypolipid diet with medium-chain triglyceride supplementation. We report the case of an exudative enteropathy in a newborn.

Ketogenic Diet as a Promising Non-Drug Intervention for Alzheimer's Disease: Mechanisms and Clinical Implications.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is mainly characterized by cognitive deficits. Although many studies have been devoted to developing disease-modifying therapies, there has been no effective therapy until now. However, dietary interventions may be a potential strategy to treat AD. The ketogenic diet (KD) is a high-fat and low-carbohydrate diet with adequate protein. KD increases the levels of ketone bodies, providing an alternative energy source when there is not sufficient energy supply because of impaired glucose metabolism. Accumulating preclinical and clinical studies have shown that a KD is beneficial to AD. The potential underlying mechanisms include improved mitochondrial function, optimization of gut microbiota composition, and reduced neuroinflammation and oxidative stress. The review provides an update on clinical and preclinical research on the effects of KD or medium-chain triglyceride supplementation on symptoms and pathophysiology in AD. We also detail the potential mechanisms of KD, involving amyloid and tau proteins, neuroinflammation, gut microbiota, oxidative stress, and brain metabolism. We aimed to determine the function of the KD in AD and outline important aspects of the mechanism, providing a reference for the implementation of the KD as a potential therapeutic strategy for AD.

Intestinal Carnitine Status and Fatty Acid Oxidation in Response to Clofibrate and Medium-Chain Triglyceride Supplementation in Newborn Pigs

To investigate the role of peroxisome proliferator-activated receptor alpha (PPARα) in carnitine status and intestinal fatty acid oxidation in neonates, a total of 72 suckled newborn piglets were assigned into 8 dietary treatments following a 2 (±0.35% clofibrate) × 4 (diets with: succinate+glycerol (Succ), tri-valerate (TC5), tri-hexanoate (TC6), or tri-2-methylpentanoate (TMPA)) factorial design. All pigs received experimental milk diets with isocaloric energy for 5 days. Carnitine statuses were evaluated, and fatty acid oxidation was measured in vitro using [1-14C]-palmitic acid (1 mM) as a substrate in absence or presence of L659699 (1.6 µM), iodoacetamide (50 µM), and carnitine (1 mM). Clofibrate increased concentrations of free (41%) and/or acyl-carnitine (44% and 15%) in liver and plasma but had no effects in the intestine. The effects on carnitine status were associated with the expression of genes involved in carnitine biosynthesis, absorption, and transportation. TC5 and TMPA stimulated the increased fatty acid oxidation rate induced by clofibrate, while TC6 had no effect on the increased fatty acid oxidation induced by clofibrate (p > 0.05). These results suggest that dietary clofibrate improved carnitine status and increased fatty acid oxidation. Propionyl-CoA, generated from TC5 and TMPA, could stimulate the increased fatty acid oxidation rate induced by clofibrate as anaplerotic carbon sources.

Ketogenic diets composed of long-chain and medium-chain fatty acids induce cardiac fibrosis in mice

PurposeHeart diseases are the leading cause of death worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome. MethodsThe effects of LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) on cardiac tissue integrity and the plasma metabolome were assessed in adult male C57/BL6NRJ mice after eight weeks on the respective diet. ResultsBoth KDs resulted in increased amount of collagen fibers and cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the observed tissue remodeling is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway. ConclusionWe conclude that regardless of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.

Short- and long-term cognitive and metabolic effects of medium-chain triglyceride supplementation in rats

Medium-chain triglycerides (MCT) possess neuroprotective properties. However, the long-term metabolic consequences of supplementing a regular diet with cognition-enhancing doses of MCT are largely unknown. We studied the effects of chronic (28 days) supplementation of regular diet with different doses of MCT oil (1, 3, or 6 g/kg/day) or water (control) on working memory (Y-maze), behavior in the Open Field, spatial learning (Morris water maze), and weight of internal organs in male Wistar 2.5-m.o. Rats. In a separate experiment, we evaluated acute (single gavage) and chronic (28 days) effects of MCT or lard supplementation (3 g/kg) on blood biochemical parameters. MCT-1 and MCT-3 doses improved working memory in YM. In MWM, MCT-6 treatment improved spatial memory. Chronic MCT-1 or MCT-3 treatment did not affect internal organ weight, while MCT-6 dose increased liver weight and the brown/white adipose tissue ratio. Acutely, MCT administration elevated blood β-hydroxybutyrate and malondialdehyde levels. Chronic MCT administration (3 g/kg) did not affect the blood levels of glucose, lactate, pyruvate, acetoacetate, β-hydroxybutyrate, total and HDL cholesterol, triglycerides, malondialdehyde, and aspartate transaminase and alanine transaminase activities. Therefore, daily supplementation of standard feed with MCT resulted in mild intermittent ketosis. It improved working memory at lower concentrations without significant adverse side effects. At higher concentrations, it improved long-term spatial memory but also resulted in organ weight changes and is likely unsafe. These results highlight the importance of monitoring the metabolic effects of MCT supplementation alongside cognitive assessment in future studies of MCT's neuroprotective properties.

Brain energy rescue with ketones improves cognitive outcomes in MCI

AbstractBackgroundAn emerging strategy to delay the onset of Alzheimer disease (AD) is to use ketones to overcome the progressive brain energy deficit caused by deteriorating brain glucose metabolism in mild cognitive impairment (MCI). Ketones (acetoacetate and beta‐hydroxybutyrate) are the brain’s main alternative fuel to glucose; in contrast to glucose, ketone metabolism by the brain is now known to be unaffected in MCI and AD. Successful brain energy rescue with ketones in MCI was recently reported.MethodsIn the 6‐month, randomized, placebo‐controlled Benefic Trial (NCT02551419), the active arm was a ketogenic medium chain triglyceride (kMCT) supplement in a lactose‐free skim milk emulsion (15 g kMCT twice/day; n = 39 completers). The placebo arm was a non‐ketogenic iso‐energetic vegetable oil (n = 44 completers). Brain ketone and glucose metabolism were assessed by PET.ResultsPerformance on all five cognitive domains improved significantly over 6 months in the kMCT group: (i) Episodic memory (trial 1, Free and Cued Recall Test) increased by 1 word (+0.5 Δ Z‐score); (ii) Executive function (Verbal Fluency Test) correct answers increased by 2 words (+0.3 Δ Z‐score) but decreased by 1 word on placebo (‐0.1 Δ Z‐score), time taken on the Stroop Colour Naming Test decreased by 1 sec (p = 0.09), and errors on the Trail Making Test increased by 0.8 on placebo (p = 0.02); (iii) Language (Boston naming test) correct answers increased by 1.3 words. (iv) Processing speed increased directly with higher brain ketone uptake in several white matter tracts. (v) Improved attention was directly associated with increased ketone uptake and functional connectivity in the dorsal attention network.ConclusionsImproved cognition correlating positively with improved brain energy supply by ketones suggests a direct link to brain energy status. The moderate effect size of this kMCT intervention indicates a clinically meaningful benefit on certain cognitive outcomes, some of which relate directly to risk of MCI progressing to AD. Other potential ketogenic interventions that have been less well studied in MCI or AD include a ketogenic diet and ketone salts or esters. Whether brain energy rescue with ketones can delay the onset or progression of AD should now be assessed.

Medium-chain triglycerides may improve memory in non-demented older adults: a systematic review of randomized controlled trials

BackgroundKetosis has been exploited for its neuroprotective impact and treatment of neurological conditions via ketone production. Exogenous medium-chain triglyceride (MCT) supplementation may induce nutritional ketosis. The aim of this systematic review is to explore the effects of MCTs on memory function in older adults without cognitive impairment.MethodsA systematic literature search of PubMed, Cochrane Library, Scopus, and Web of Science was employed from inception until April 2022 for randomized controlled trials (RCTs) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, investigating the impact of MCT oils on components of memory. Risk of bias (RoB2) tool was utilized for quality assessment.ResultsSix trials were included for qualitative synthesis, in which two studies examined the effect of MCTs through a ketogenic meal. MCT supplementation compared to controls was associated with improved indices of memory function in 4 out of 6 studies, particularly working memory. A meta-analysis was not employed due to the low number of studies, therefore, a true effect measure of MCT supplementation was not explored.ConclusionsMCT supplementation may enhance working memory in non-demented older adults. These effects may be more prominent in individuals with lower baseline scores, from short and long-term supplementation. Further studies are warranted to confirm these findings in terms of optimal dose and MCTs composition, which may protect from memory decline during aging.