Inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-fat diet feeding.

G protein-coupled receptor (GPR) 120 is expressed in enteroendocrine cells secreting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP), and cholecystokinin (CCK). Although GPR120 signaling in adipose tissue and macrophages has been reported to ameliorate obesity and insulin resistance in a high long-chain triglyceride (LCT) diet, intestine-specific roles of GPR120 are unclear. To clarify the metabolic effect of GPR120 in the intestine, we generated intestine-specific GPR120-knockout (GPR120int-/-) mice. In comparison with floxed GPR120 (WT) mice, GPR120int-/- mice exhibited reduced GIP secretion and CCK action without change of insulin, GLP-1, or peptide YY (PYY) secretion after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed a mild reduction of body weight and substantial amelioration of insulin resistance and fatty liver. Moreover, liver and white adipose tissue (WAT) of GPR120int-/-mice exhibited increased Akt phosphorylation and reduced gene expression of suppressor of cytokine signaling (SOCS) 3, which inhibits insulin signaling. In addition, gene expression of inflammatory cytokines in WAT and lipogenic molecules in liver were reduced in GPR120int-/- mice. These findings suggest that inhibition of GPR120 signaling in intestine ameliorates insulin resistance and fatty liver under high-LCT diet feeding.NEW & NOTEWORTHY We generated novel intestine-specific GPR120-knockout (GPR120int-/-) mice and investigated the metabolic effect of GPR120 in the intestine. GPR120int-/- mice exhibited a reduction of GIP secretion and CCK action after a single administration of LCT. Under a high-LCT diet, GPR120int-/- mice showed mild improvement in obesity and marked amelioration of insulin resistance and hepatic steatosis. Our results indicate an important role of intestinal GPR120 on insulin resistance and hepatic steatosis.

Early-life stress and dietary fatty acids impact the brain lipid/oxylipin profile into adulthood, basally and in response to LPS.

Brain lipid dysregulation is a hallmark of depression and Alzheimer's disease, also marked by chronic inflammation. Early-life stress (ELS) and dietary intake of polyunsaturated fatty acids (PUFAs) are risk factors for these pathologies and are known to impact inflammatory processes. However, if these early-life factors alter brain lipid homeostasis on the long-term and thereby contribute to this risk remains to be elucidated. We have recently shown that an early diet enriched in omega(ω)-3 PUFAs protected against the long-term negative effects of ELS on cognition and neuroinflammation. Here, we aim to understand if modulation of brain lipid and oxylipin profiles contributes to the detrimental effects of ELS and the protective ones of the diet. We therefore studied if and how ELS and early dietary PUFAs modulate the brain lipid and oxylipin profile, basally as well as in response to an inflammatory challenge, to unmask possible latent effects. Male mice were exposed to ELS via the limited bedding and nesting paradigm, received an early diet with high or low ω6/ω3 ratio (HRD and LRD) and were injected with saline or lipopolysaccharide (LPS) in adulthood. Twenty-four hours later plasma cytokines (Multiplex) and hypothalamic lipids and oxylipins (liquid chromatography tandem mass spectrometry) were measured. ELS exacerbated the LPS-induced increase in IL-6, CXCL1 and CCL2. Both ELS and diet affected the lipid/oxylipin profile long-term. For example, ELS increased diacylglycerol and LRD reduced triacylglycerol, free fatty acids and ceramides. Importantly, the ELS-induced alterations were strongly influenced by the early diet. For example, the ELS-induced decrease in eicosapentaenoic acid was reversed when fed LRD. Similarly, the majority of the LPS-induced alterations were distinct for control and ELS exposed mice and unique for mice fed with LRD or HRD. LPS decreased ceramides and lysophosphotidylcholine, increased hexosylceramides and prostaglandin E2, reduced triacylglycerol species and ω6-derived oxylipins only in mice fed LRD and ELS reduced the LPS-induced increase in phosphatidylcholine. These data give further insights into the alterations in brain lipids and oxylipins that might contribute to the detrimental effects of ELS, to the protective ones of LRD and the possible early-origin of brain lipid dyshomeostasis characterizing ELS-related psychopathologies.

Medium-chain triglycerides reduce diarrhea with improved immune status and gut microbiomics in tunnel workers in China.

BACKGROUND AND OBJECTIVES: Adverse environmental factors in tunnels increase the occurrence of respiratory and intestinal inflammatory disease, which is seriously harmful to worker health. It is reported that medium-chain triglycerides (MCT) can improve immune status and alter the gut microflora. This study investigates MCT effects on immune status and gut microbiota among tunnel workers. METHODS AND STUDY DESIGN: Forty-five workers were randomly divided into an MCT group (n=30) and control group (n=15), where they ingested MCT-milk or a placebo milk for 12 weeks, respectively. The primary outcome measure was the incidence of respiratory infection and diarrhea. Secondary outcomes were changes in serum immune-related markers and changes in gut microbiota. RESULTS: The incidence of diarrhea in MCT group was significantly decreased after 4 weeks (p<0.01), with no significant differences in the control group. MCT reduced the level of pro-inflammatory cytokines (TNF-α, CRP, and IL-6) and enhanced the anti-inflammatory cytokines (IL-10, C3, C4, IgA, IgG, and IgM), respectively (p<0.01). The Chao index was reduced (p<0.01) and microbiota composition changed significantly after 12 weeks of MCT intervention. MCT reduced the abundance of Bacteroides, Roseburia, Ruminococcus_1, Lachnospira and increased that of Blautia and Fusicatenibacter at the genus level (p<0.01). CONCLUSIONS: The consumption of MCT reduces diarrhea occurrence and improves serum immune profiles together with gut microbiomics in tunnel workers.

Erythrocyte fatty acid membrane composition in children on long-term parenteral nutrition enriched with ω-3 fatty acids.

BACKGROUND: Composite lipid emulsions containing soybean oil (30%), medium-chain triglycerides (30%), olive oil (25%), and fish oil (15%) (SMOF) are now widely used. OBJECTIVES: We aimed to evaluate the tolerance, the efficiency, and the erythrocyte fatty acid (FA) profile for children on long-term home parenteral nutrition (HPN) receiving a composite fish oil-based emulsion (FOLE). METHODS: At baseline, children (n = 46) with severe intestinal failure highly dependent on parenteral nutrition (PN) for ≥1 y were included in the study when they had received the composite FOLE for >6 mo. Out of this baseline group, only 25 children remained highly PN-dependent (SMOF1, n = 25) and could be assessed a second time, 2.4 y later (SMOF2, n = 25). An independent control group ("weaned off PN" group; n = 24) included children who had been weaned off PN for >2 y (median: 4 y). RBC-FA composition was established by GC-MS. Growth parameters, plasma citrulline, conjugated bilirubin, FA profiles, and the Holman ratio (20:3ω-9/20:4ω-6) were compared between groups. RESULTS: No difference for growth parameters, citrulline, and bilirubin was observed between the SMOF groups after 2.4 y (0.2 < P < 0.8). The weaned-off group did not differ from the SMOF groups for growth parameters (0.2 < P < 0.4) but citrulline was higher (P < 0.0001) and conjugated bilirubin lower (P < 0.01). The composite FOLE induced higher proportions of EPA (20:5n-3) (8.4% ± 2.9%) and DHA (22:6n-3) (11.7% ± 2.2%) than what was observed in weaned-off children (0.8% ± 0.4% and 6.6% ± 2.3%, respectively) but lower proportions of arachidonic acid (20:4n-6). However, the Holman ratio did not vary between groups (P = 0.9), whereas the PUFA concentrations varied widely. CONCLUSIONS: Long-term use of the composite FOLE was well tolerated in HPN-dependent children. The RBC-FA profile alterations were consistent with the ω-3 PUFA-enriched composition of this emulsion without evidence of essential FA deficiency.

A Mixed-Lipid Emulsion Containing Fish Oil for the Parenteral Nutrition of Preterm Infants: No Impact on Visual Neuronal Conduction.

Fish oil is rich in omega-3 fatty acids and essential for neuronal myelination and maturation. The aim of this study was to investigate whether the use of a mixed-lipid emulsion composed of soybean oil, medium-chain triglycerides, olive oil, and fish oil (SMOF-LE) compared to a pure soybean oil-based lipid emulsion (S-LE) for parenteral nutrition had an impact on neuronal conduction in preterm infants. This study is a retrospective matched cohort study comparing preterm infants <1000 g who received SMOF-LE in comparison to S-LE for parenteral nutrition. Visual evoked potentials (VEPs) were assessed longitudinally from birth until discharge. The latencies of the evoked peaks N2 and P2 were analyzed. The analysis included 76 infants (SMOF-LE: n = 41 and S-LE: n = 35) with 344 VEP measurements (SMOF-LE: n= 191 and S-LE n = 153). Values of N2 and P2 were not significantly different between the SMOF-LE and S-LE groups. A possible better treatment effect in the SMOF-LE group was seen as a trend toward a shorter latency, indicating faster neural conduction at around term-equivalent age. Prospective trials and follow-up studies are necessary in order to evaluate the potential positive effect of SMOF-LE on neuronal conduction and visual pathway maturation.

Smoflipid Is Better Than Lipofundin for Long-Term Neurodevelopmental Outcomes in Preterm Infants.

Neurodevelopmental morbidities developed more commonly in low-birth-weight premature infants. We sought to determine the effects of different lipid emulsions on the neurodevelopmental outcomes of children born prematurely. This retrospective cross-sectional study had two intervention legs, Lipofundin® MCT/LCT (LIPO) versus Smoflipid® (SMOF), which are mainly differentiated by fish oil. Data of premature neonates born between 2001 and 2015 from the research database of Chang Gung Memorial Hospital with corresponding individual medical records up to July 2020 were analyzed. Long-term neurodevelopmental outcomes were defined by the international classification of disease codes -9 or -10. The prevalence of diseases was compared between LIPO and SMOF groups at five and five years old and further analyzed by stratification of 1500 g birth weight. The LIPO and SMOF groups each included 1120 neonates. Epilepsy, cerebral palsy, developmental disorder and attention-deficit hyperactivity disorder (ADHD) were significantly decreased at age two years in the SMOF group, and epilepsy, language delay (LD), ADHD and autism spectrum disorder (ASD) were significantly decreased in the SMOF group at age five years. In children with birth weight < 1500 g, ADHD was decreased in the SMOF group at ages two and five years, and ASD was decreased in the SMOF group at age five years. In children with birth weight ≥ 1500 g, epilepsy, LD and ADHD were decreased in the SMOF group at age two years. LD was decreased in the SMOF group at age five years. We conclude that lipid emulsions with fish oil improve the neurodevelopmental outcomes of children born prematurely.

Timing of Tributyrin Supplementation Differentially Modulates Gastrointestinal Inflammation and Gut Microbial Recolonization Following Murine Ileocecal Resection.

BACKGROUND: Gastrointestinal surgery imparts dramatic and lasting imbalances, or dysbiosis, to the composition of finely tuned microbial ecosystems. The aim of the present study was to use a mouse ileocecal resection (ICR) model to determine if tributyrin (TBT) supplementation could prevent the onset of microbial dysbiosis or alternatively enhance the recovery of the gut microbiota and reduce gastrointestinal inflammation. METHODS: Male wild-type (129 s1/SvlmJ) mice aged 8-15 weeks were separated into single cages and randomized 1:1:1:1 to each of the four experimental groups: control (CTR), preoperative TBT supplementation (PRE), postoperative TBT supplementation (POS), and combined pre- and postoperative supplementation (TOT). ICR was performed one week from baseline assessment with mice assessed at 1, 2, 3, and 4 weeks postoperatively. Primary outcomes included evaluating changes to gut microbial communities occurring from ICR to 4 weeks. RESULTS: A total of 34 mice that underwent ICR (CTR n = 9; PRE n = 10; POS n = 9; TOT n = 6) and reached the primary endpoint were included in the analysis. Postoperative TBT supplementation was associated with an increased recolonization and abundance of anaerobic taxa including Bacteroides thetaiotomicorn, Bacteroides caecimuris, Parabacteroides distasonis, and Clostridia. The microbial recolonization of PRE mice was characterized by a bloom of aerotolerant organisms including Staphylococcus, Lactobacillus, Enteroccaceae, and Peptostreptococcacea. PRE mice had a trend towards decreased ileal inflammation as evidenced by decreased levels of IL-1ß (p = 0.09), IL-6 (p = 0.03), and TNF-α (p < 0.05) compared with mice receiving TBT postoperatively. In contrast, POS mice had trends towards reduced colonic inflammation demonstrated by decreased levels of IL-6 (p = 0.07) and TNF-α (p = 0.07). These changes occurred in the absence of changes to fecal short-chain fatty acid concentrations or histologic injury scoring. CONCLUSIONS: Taken together, the results of our work demonstrate that the timing of tributyrin supplementation differentially modulates gastrointestinal inflammation and gut microbial recolonization following murine ICR.

An fMRI Investigation into the Effects of Ketogenic Medium-Chain Triglycerides on Cognitive Function in Elderly Adults: A Pilot Study.

Evidence suggests that oral intake of medium-chain triglycerides (MCTs), which promote the production of ketone bodies, may improve cognitive functions in elderly people; however, the underlying brain mechanisms remain elusive. We tested the hypothesis that cognitive improvement accompanies physiological changes in the brain and reflects the use of ketone bodies as an extra energy source. To this end, by using functional magnetic resonance imaging, cerebral blood oxygenation level-dependent (BOLD) signals were measured while 20 healthy elderly subjects (14 females and 6 males; mean age: 65.7 ± 3.9 years) were engaged in executive function tasks (N-back and Go-Nogo) after ingesting a single MCT meal (Ketonformula®) or placebo meal in a randomized, double-blind placebo-controlled design (UMIN000031539). Morphological characteristics of the brain were also examined in relation to the effects of an MCT meal. The MCT meal improved N-back task performance, and this was prominent in subjects who had reduced grey matter volume in the dorsolateral prefrontal cortex (DLPFC), a region known to promote executive functions. When the participants were dichotomized into high/low level groups of global cognitive function at baseline, the high group showed improved N-back task performance, while the low group showed improved Go-Nogo task performance. This was accompanied by decreased BOLD signals in the DLPFC, indicative of the consumption of ketone bodies as an extra energy source.

Home parenteral nutrition patients on mixed oil lipid emulsion have a higher rate of hospitalizations compare to those on soybean oil- a prospective 2-year cohort study.

BACKGROUND & AIMS: Mixed oil intravenous lipid emulsion (MO ILE) that contains 30% soybean oil (SO), 30% medium chain triglycerides, 25% olive oil and 15% fish oil can benefit hospitalized patients receiving parenteral nutrition (PN) but there are very few studies on its long-term use. Our goal was to evaluate the clinical outcomes of adults receiving home PN (HPN) with MO versus those receiving SO ILE over a 2-year period. METHOD: This is a retrospective analysis of data collected prospectively from a cohort of patients recorded in the Canadian HPN Registry over a 2-year period. HPN patients from academic programs across Canada were entered in the Registry according to a validated protocol. For this study, demographic, nutritional, laboratory and clinical data were extracted from January 1st 2015, when MO lipid emulsion became available in Canada, to July 24th 2019. Clinical data for each patient included: number of hospitalizations, number of hospitalizations related to HPN and number of hospitalization days related to HPN, over a year; incidence of line sepsis per 1000 catheter days and mortality. Data are presented as median (1st, 3rd quartile) for continuous variables and frequency (percentage) for categorical variables. Comparisons between groups were performed using two sample t-test or Wilcoxon Rank Sum tests for continuous variables and Chi-square tests or Fisher's exact tests for categorical variables. Univariate and multiple linear regressions were also carried out. Statistical significance is set at a p-value <0.05. RESULTS: A total of 120 patients were included (MO n = 68, SO n = 52). Significant differences at baseline between the two groups were a higher use of Hickman line (62.12% vs 42%, p = 0.038) and more western Canada based hospital care with MO (75% vs 42.31%, p = 0.0002). The MO group had significantly more hospitalizations (p = 0.001), more hospitalizations related to HPN (p = 0.012) and more hospitalization days related to HPN (p = 0.016) per patient per year compared to SO patients. There was no significant difference between groups for line sepsis per 1000 catheter days (MO: 0.05 (0.0, 1.0) vs SO: 0.0 (0.0, 0.22), p = 0.053) or mortality. All other variables, including biochemical variables, were similar between groups. In a multiple regression analysis, the following factors were significantly associated with a greater number of hospitalizations per patient per year: use of MO, high blood glucose from the last recorded value and having died by the end of the study period. CONCLUSION: This 2-year prospective cohort study suggests an increased risk of hospitalization in HPN patients receiving MO lipid emulsion. The long-term effect of using MO lipid emulsion in HPN patients should be further evaluated using a large randomized controlled trial. THE STUDY WAS REGISTERED IN CLINICALTRIALS.GOV: (NCT02299466).

Triglyceride regulate ACE2 level through MTHFD1.

Obesity has been followed with interest as a risk factor for COVID-19, with triglycerides as one of four common criteria used to define obesity, which have been used to study the mechanism of obesity. In this study, we showed that angiotensin-converting enzyme-2 (ACE2) is widely expressed in the mouse body, including the kidney, spleen, brain, heart, lung, liver, and testis, and that ACE2 levels increased after a high-fat diet. The ACE2 levels were recorded at 0 days, 3 days, 7 days, and 14 days after a high-fat diet, and they increased at 14 days after high-fat diet initiation. In addition, triglyceride levels were also significantly increased at 14 days after high-fat diet initiation, but body weight was not changed. Furthermore, we examined the ACE2 levels in Calu3 cells (a lung cancer cell line) after triglyceride treatment, and the results indicated that ACE2 levels were increased at 25 µM and reached their peak at 200 µM. Finally, we found that the mRNA level of mthfd1 was significantly increased in the high-fat diet group. Given these findings, we hypothesize that triglycerides can regulate the expression of ACE2 and Mthfd1.

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency.

We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.

Associations Between Macronutrients From Different Dietary Sources and Serum Lipids in 24 639 UK Biobank Study Participants.

[Figure: see text].

The effect of a 6-month ketogenic medium-chain triglyceride supplement on plasma cardiometabolic and inflammatory markers in mild cognitive impairment.

INTRODUCTION: Mild cognitive impairment (MCI) is often accompanied by metabolic abnormalities and inflammation that might play a role in the development of cognitive impairment. The use of ketogenic medium-chain triglycerides (kMCT) to improve cognition in this population has shown promising results but remains controversial because of the potentially detrimental effect of elevated intake of saturated fatty acids on cardiovascular (CV) health and perhaps inflammatory processes. The primary aim of this secondary data analysis report is to describe changes in cardiometabolic markers and peripheral inflammation during a 6-month kMCT intervention in MCI. METHODS: Thirty-nine participants with MCI completed the intervention of 30 g/day of either a kMCT drink or calorie-matched placebo (high-oleic acid) for 6 months. Plasma concentrations of cardiometabolic and inflammatory markers were collected before (fasting state) and after the intervention (2 h following the last drink). RESULTS: A mixed model ANOVA analysis revealed a time by group interaction for ketones (P < 0.001), plasma 8:0 and 10:0 acids (both P < 0.001) and IL-8 (P = 0.002) with follow up comparison revealing a significant increase in the kMCT group (+48%, P = 0.005), (+3,800 and +4,900%, both P < 0.001) and (+147%, P < 0.001) respectively. A main effect of time was observed for insulin (P = 0.004), triglycerides (P = 0.011) and non-esterified fatty acids (P = 0.036). CONCLUSION: Under these study conditions, 30 g/d of kMCT taken for six months and up to 2-hour before post-intervention testing had minimal effect on an extensive profile of circulating cardiometabolic and inflammatory markers as compared to a placebo calorie-matched drink. Our results support the safety kMCT supplementation in individuals with MCI. The clinical significance of the observed increase in circulating IL-8 levels is presently unknown and awaits future studies.

Octanoic acid a major component of widely consumed medium-chain triglyceride ketogenic diet is detrimental to bone.

Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.

[A case of adult-onset type II citrullinemia triggered by entering a nursing home with a good response to medium-chain triglyceride oil therapy].

A 49-year-old woman with intellectual disability and a food preference for fried chicken entered a nursing home. After nursing home diet, she developed episodic attacks of hyperammonemic encephalopathy. Her characteristic food preference and the negative results for brain and liver imaging studies suggested urea cycle disorder. A high plasma citrulline level on amino acid analysis and a genetic test for citrine gene confirmed a citrine deficiency (adult-onset type II citrullinemia). Although a low-carbohydrate diet was insufficient, a combination therapy of a low-carbohydrate diet and a medium-chain triglyceride (MCT) oil was effective. MCT oil may be a promising treatment option.

Towards an Optimized Fetal DHA Accretion: Differences on Maternal DHA Supplementation Using Phospholipids vs. Triglycerides during Pregnancy in Different Models.

Docosahexaenoic acid (DHA) supplementation during pregnancy has been recommended by several health organizations due to its role in neural, visual, and cognitive development. There are several fat sources available on the market for the manufacture of these dietary supplements with DHA. These fat sources differ in the lipid structure in which DHA is esterified, mainly phospholipids (PL) and triglycerides (TG) molecules. The supplementation of DHA in the form of PL or TG during pregnancy can lead to controversial results depending on the animal model, physiological status and the fat sources utilized. The intestinal digestion, placental uptake, and fetal accretion of DHA may vary depending on the lipid source of DHA ingested by the mother. The form of DHA used in maternal supplementation that would provide an optimal DHA accretion for fetal brain development, based on the available data obtained most of them from different animal models, indicates no consistent differences in fetal accretion when DHA is provided as TG or PL. Other related lipid species are under evaluation, e.g., lyso-phospholipids, with promising results to improve DHA bioavailability although more studies are needed. In this review, the evidence on DHA bioavailability and accumulation in both maternal and fetal tissues after the administration of DHA supplementation during pregnancy in the form of PL or TG in different models is summarized.

Clinical outcomes in a series of 18 patients with long chain fatty acids oxidation disorders treated with triheptanoin for a median duration of 22 months.

INTRODUCTION: Triheptanoin provides long-chain fatty acid oxidation disorder (LC-FAOD) patients with an alternative to medium-even-chain triglycerides therapy. MATERIAL-METHODS: Retrospective analysis of 18 French LC-FAOD patients benefiting from early access to triheptanoin treatment. RESULTS: Eight female and 10 male patients with LC-FAOD (VLCAD, LCHAD, CACT, CPTII and MTP) were treated with triheptanoin for a median duration of 22 months (range: 9-228 months). At last consultation, triheptanoin accounted for 15-35% of their daily caloric intake. In the year following the introduction of triheptanoin, patients reported a reduction of intermittent snacking and nocturnal meals. Three patients, including 1 adult, became free of severe hypoglycaemic events. Ten of 12 paediatric patients and 4 of 6 adult patients reported reduced fatigue with reductions in the number and severity of episodes of myalgia. Of 6 patients, including 1 adult, that had required the use of a wheelchair in the year prior to triheptanoin, all but one no longer required its use. The number of emergency hospitalizations decreased, and none were recorded for paediatric patients during these 12 months. Cumulative annual days of emergency care in the home were reduced from 286 to 51 days in the year before and after initiation, respectively, and 13 patients required no such interventions. Adverse events were limited to digestive issues that dissipated over time. CONCLUSIONS: Our case-series suggests that long-term treatment of LC-FAOD paediatric and adult patients with triheptanoin is safe and leads to marked improvement of symptoms and an improved quality of life.

Assessing the Impact of Factors that Influence the Ketogenic Response to Varying Doses of Medium Chain Triglyceride (MCT) Oil.

Objectives, Design, Setting: The ketogenic effect of medium chain triglyceride (MCT) oil offers potential for Alzheimer's disease prevention and treatment. Limited literature suggests a linear B-hyroxybutyrate (BHB) response to increasing MCT doses. This pharmacokinetic study evaluates factors affecting BHB response in three subject groups. PARTICIPANTS: Healthy subjects without cognitive deficits <65years, similarly healthy subjects >=65years, and those with Alzheimer's Disease were assessed. INTERVENTION: Different doses (0g,14g, 28g, 42g) of MCT oil (99.3% C8:0) were administered, followed by fasting during the study period. MEASUREMENTS: BHB measured by finger prick sampling hourly for 5 hours after ingestion. Each subject attended four different days for each ascending dose. Data was also collected on body composition, BMI, waist/hip ratio, grip strength, gait speed, nutrient content of pre-study breakfast and side effects. RESULTS: Twenty-five participants: eight healthy; average age of 44yr (25-61), nine healthy; 79yr (65-90) and eight with AD; 78.6yr (57-86) respectively. Compiled data showed the expected linear dose response relationship. No group differences, with baseline corrected area under the blood vs. time curve (r2=0.98) and maximum concentrations (r2=0.97). However, there was notable individual variability in maximum BHB response (42g dose: 0.4 -2.1mM), and time to reach maximum BHB response both, within and between individuals. Variability was unrelated to age, sex, sarcopenic or AD status. Visceral fat, BMI, waist/hip ratio and pretest meal CHO and protein content all affected the BHB response (p<0.001). CONCLUSION: There was a large inter-individual variability, with phenotype effects identified. This highlights challenges in interpreting clinical responses to MCT intake.

Exploring the metabolic fate of medium-chain triglycerides in healthy individuals using a stable isotope tracer.

BACKGROUND & AIMS: Medium chain triglyceride (MCT) supplementation is often recommended as treatment for patients with long-chain fatty acid ß-oxidation (lcFAO) disorders, since they can be utilized as an energy source without the use of the defective enzyme. However, studies in mice and preterm infants suggest that not all medium-chain fatty acids (MCFA) are oxidized and may undergo elongation to long-chain fatty acids (LCFA). In this single blinded study, we explored the metabolic fates of MCT in healthy individuals using a 13C-labeled MCT tracer. METHOD: Three healthy males in rest received on two test days a primed continuous infusion of glyceryl tri[1,2,3,4-13C4]-octanoate with either an isocaloric supplementation of 1) exclusively MCT (MCT-only) or 2) a mixture of MCT, proteins and carbohydrates (MCT-mix). Gas chromatography - combustion - isotope ratio mass spectrometry (GC-C-IRMS) was used to determine 13C-enrichment of long-chain fatty acids in plasma and of 13CO2 in exhaled air. RESULTS: When provided as single energy source, an estimated 42% of administered MCT was converted to CO2. In combination with carbohydrates and proteins in the diet, oxidation of MCT was higher (62%). In both diets <1% of 13C-label was incorporated in LCFA in plasma, indicating that administered MCT underwent chain-elongation to LCT. CONCLUSIONS: Although the relative MCT oxidation rate was higher when combined with carbohydrates and protein, quantitatively more MCT was oxidized when given an isocaloric meal with solely MCT. As these results were obtained in the resting state opposed to during exercise, it is too early to give a recommendation concerning the use of MCT in lcFAO disorders. The data show that in resting healthy individuals only a very small part of the MCT is traced back as LCFA in plasma, suggesting that MCT treatment does not result in a large LCFA burden, however further research on storage of MCT in tissues is warranted. REGISTRATION: The study was registered in the Nederlands Trialregister. Protocol ID: Trial NL7417 (NTR7650).