Dietary Medium-chain Fatty Acids Research Articles

Pharmacological inhibition of ENT1 enhances the impact of specific dietary fats on energy metabolism gene expression

Medium chain fatty acids are commonly consumed as part of diets for endurance sports and as medical treatment in ketogenic diets where these diets regulate energy metabolism and increase adenosine levels. However, the role of the equilibrative nucleoside transporter 1 (ENT1), which is responsible for adenosine transport across membranes in this process, is not well understood. Here, we investigate ENT1 activity in controlling the effects of two dietary medium chain fatty acids (decanoic and octanoic acid), employing the tractable model system Dictyostelium. We show that genetic ablation of three ENT1 orthologues unexpectedly improves cell proliferation specifically following decanoic acid treatment. This effect is not caused by increased adenosine levels triggered by both fatty acids in the presence of ENT1 activity. Instead, we show that decanoic acid increases expression of energy-related genes relevant for fatty acid β-oxidation, and that pharmacological inhibition of ENT1 activity leads to an enhanced effect of decanoic acid to increase expression of tricarboxylicacid cycle and oxidative phosphorylation components. Importantly, similar transcriptional changes have been shown in the rat hippocampus during ketogenic diet treatment. We validated these changes by showing enhanced mitochondria load and reduced lipid droplets. Thus, our data show that ENT1 regulates the medium chain fatty acid-induced increase in cellular adenosine levels and the decanoic acid-induced expression of important metabolic enzymes in energy provision, identifying a key role for ENT1 proteins in metabolic effects of medium chain fatty acids.

Serum Medium-Chain Fatty Acids and the Risk of Incident Diabetes: Findings from the 4C Study.

Emerging studies have revealed associations between dietary medium-chain fatty acids (MCFAs) and glucose homeostasis. However, the relationship between serum MCFAs and the incidence of diabetes, and potential interactions with genetic predisposition, remains unclear in prospective cohort studies. To investigate associations and genetic susceptibility between serum MCFAs and diabetes risk. We investigated baseline serum MCFAs (n=5) in a nested case-control study comprising incident diabetes cases (n=1,707) and matched normoglycemic control subjects (n=1,707) from the China Cardiometabolic Disease and Cancer Cohort Study. Associations between MCFAs and type 2 diabetes mellitus (T2DM) were examined, both overall and stratified by diabetes genetic susceptibility. Genetic risk scores (GRS) were calculated based on 86 T2DM-associated genetic variants. In the fully adjusted conditional logistic regression model, serum octanoic acid and nonanoic acid exhibited inverse dose-response relationships with diabetes risk, showing odds ratios (95% confidence intervals) of 0.90 (0.82-0.98) and 0.84 (0.74-0.95), respectively. Subgroup analysis demonstrated that inverse associations between MCFAs and incident diabetes were more pronounced among individuals with physical inactivity (Pinteraction = 0.042, 0.034, and 0.037, for octanoic, nonanoic and decanoic acid, respectively). Moreover, inverse associations of octanoic acid with diabetes risk were notably enhanced among individuals with high genetic risk compared to those with low genetic risk. Significant interactions were observed between octanoic acid and GRS on T2DM risk (Pinteraction = 0.003). These findings provide evidence supporting inverse associations between serum MCFAs and T2DM risk, and reveal potential interplay between genetic susceptibility and circulating octanoic acid in modulating diabetes risk.

Dietary medium-chain fatty acids reduce hepatic fat accumulation via activation of a CREBH-FGF21 axis

ObjectiveDietary medium-chain fatty acids (MCFAs), characterized by chain lengths of 8–12 carbon atoms, have been proposed to have beneficial effects on glucose and lipid metabolism, yet the underlying mechanisms remain elusive. We hypothesized that MCFA intake benefits metabolic health by inducing the release of hormone-like factors. MethodsThe effects of chow diet, high-fat diet rich in long-chain fatty acids (LCFA HFD) fed ad libitum or pair-fed to a high-fat diet rich in MCFA (MCFA HFD) on glycemia, hepatic gene expression, circulating fibroblast growth factor 21 (FGF21), and liver fat content in both wildtype and Fgf21 knockout mice were investigated. The impact of a single oral dose of an MCFA-rich oil on circulating FGF21 and hepatic Fgf21 mRNA expression was assessed. In flag-tagged Crebh knockin mice and liver-specific Crebh knockout mice, fed LCFA HFD or MCFA HFD, active hepatic CREBH and hepatic Fgf21 mRNA abundance were determined, respectively. ResultsMCFA HFD improves glucose tolerance, enhances glucose clearance into brown adipose tissue, and prevents high-fat diet-induced hepatic steatosis in wildtype mice. These benefits are associated with increased liver expression of CREBH target genes (Apoa4 and Apoc2), including Fgf21. Both acute and chronic intake of dietary MCFAs elevate circulating FGF21. Augmented hepatic Fgf21 mRNA following MCFA HFD intake is accompanied by higher levels of active hepatic CREBH; and MCFA-induced hepatic Fgf21 expression is blocked in mice lacking Crebh. Notably, while feeding male and female Fgf21 wildtype mice MCFA HFD results in reduced liver triacylglycerol (TG) levels, this liver TG-lowering effect is blunted in Fgf21 knockout mice fed MCFA HFD. The reduction in liver TG levels observed with MCFA HFD was independent of weight loss. ConclusionsDietary MCFAs reduce liver fat accumulation via activation of a CREBH-FGF21 signaling axis.

Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study

BackgroundNo prospective observational study has specifically examined the associations between dietary intakes of medium-chain fatty acids and risk of colorectal cancer. ObjectivesThis study examined the association between dietary intakes of medium-chain fatty acids and colorectal cancer risk overall and by racial subgroups in a predominantly low-income United States population. MethodsThis prospective study included 71,599 eligible participants aged 40 to 79 who were enrolled in the Southern Community Cohort Study between 2002 and 2009 in 12 southeastern United States states. Incident colorectal cancer cases were ascertained via linkage to state cancer registries, which was completed through 31 December, 2016. The dietary intakes of medium-chain fatty acids were assessed using a validated 89-item food frequency questionnaire. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between intakes of medium-chain fatty acids and risk for incident colorectal cancer. ResultsAmong 71,599 participants, 48,008 (67.3%) were Black individuals and 42,260 (59.0%) were female. A total of 868 incident colorectal cancer cases occurred during a median follow-up of 13.7 y. Comparing the highest to the lowest quartile, high intake of dodecanoic acid/lauric acid (C12:0) was associated with reduced risk of colorectal cancer among White participants (HR: 0.52; 95% CI: 0.30, 0.91; P-trend = 0.05), but not in Black individuals (HR: 0.92; 95% CI, 0.68, 1.24; P-trend = 0.80) in multivariable-adjusted models. No associations were found between intakes of hexanoic acid/caproic acid (C6:0), octanoic acid/caprylic acid (C8:0), or decanoic acid/capric acid (C10:0) and risk of incident colorectal cancer overall or within racial subgroups. ConclusionsIn a predominantly low-income United States population, an increased dietary C12:0 intake was associated with a substantially reduced risk of colorectal cancer only among White individuals, but not in Black individuals.

Medium-chain fatty acid oxidation is independent of l-carnitine in liver and kidney but not in heart and skeletal muscle.

Medium-chain fatty acid (MCFA) consumption confers a wide range of health benefits that are highly distinct from long-chain fatty acids (LCFAs). A major difference between the metabolism of LCFAs compared with MCFAs is that mitochondrial LCFA oxidation depends on the carnitine shuttle, whereas MCFA mitochondrial oxidation is not. Although MCFAs are said to range from 6 to 14 carbons long based on physicochemical properties in vitro, the biological cut-off length of acyl chains that can bypass the carnitine shuttle in different mammalian tissues is unknown. To define the range of acyl chain length that can be oxidized in the mitochondria independent of carnitine, we determined the oxidative metabolism of free fatty acids (FFAs) from 6 to 18 carbons long in the liver, kidney, heart, and skeletal muscle. The liver oxidized FFAs 6 to 14 carbons long, whereas the kidney oxidized FFAs from 6 to 10 carbons in length. Heart and skeletal muscle were unable to oxidize FFAs of any chain length. These data show that while the liver and kidney can oxidize MCFAs in the free form, the heart and skeletal muscle require carnitine for the oxidative metabolism of MCFAs. Together these data demonstrate that MCFA oxidation independent of carnitine is tissue-specific.NEW & NOTEWORTHY This work demonstrates that the traditional concept of mitochondrial medium-chain fatty acid oxidation as unregulated and independent of carnitine applies only to liver metabolism, and to kidney to a lesser extent, but not the heart or skeletal muscle. Thus, the benefits of dietary medium-chain fatty acids are set by liver metabolic activity and peripheral tissues are unlikely to receive direct benefits from medium-chain fatty acid metabolism, but rather metabolic byproducts of liver's medium-chain oxidative metabolism.

Dietary medium-chain fatty acids reduce food intake via the GDF15-GFRAL axis in mice

ObjectiveMedium chain fatty acids (MCFAs), which are fatty acids with chain lengths of 8–12 carbon atoms, have been shown to reduce food intake in rodents and humans, but the underlying mechanisms are unknown. Unlike most other fatty acids, MCFAs are absorbed from the intestine into the portal vein and enter first the liver. We thus hypothesized that MCFAs trigger the release of hepatic factors that reduce appetite. MethodsThe liver transcriptome in mice that were orally administered MCFAs as C8:0 triacylglycerol (TG) was analyzed. Circulating growth/differentiation factor 15 (GDF15), tissue Gdf15 mRNA and food intake were investigated after acute oral gavage of MCFAs as C8:0 or C10:0 TG in mice. Effects of acute and subchronic administration of MCFAs as C8:0 TG on food intake and body weight were determined in mice lacking either the receptor for GDF15, GDNF Family Receptor Alpha Like (GFRAL), or GDF15. ResultsHepatic and small intestinal expression of Gdf15 and circulating GDF15 increased after ingestion of MCFAs, while intake of typical dietary long-chain fatty acids (LCFAs) had no effect. Plasma GDF15 levels also increased in the portal vein with MCFA intake, indicating that in addition to the liver, the small intestine contributes to the rise in circulating GDF15. Acute oral provision of MCFAs decreased food intake over 24 h compared with a LCFA-containing bolus, and this anorectic effect required the GDF15 receptor, GFRAL. Moreover, subchronic oral administration of MCFAs reduced body weight over 7 days, an effect that was blunted in mice lacking either GDF15 or GFRAL. ConclusionsWe have identified ingestion of MCFAs as a novel nutritional approach that increases circulating GDF15 in mice and have revealed that the GDF15-GFRAL axis is required for the full anorectic effect of MCFAs.

Abstract 6451: Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study (SCCS)

Abstract Purpose: Previous studies have investigated medium-chain fatty acids (MCFAs) as a part of saturated fat intake and risk of colorectal cancer (CRC). However, unlike long-chain saturated fatty acids, MCFAs possess many unique properties, including inhibition of pro-carcinogenic bacteria, biofilm formation, and induction of apoptosis. Further, C12:0 has been consistently shown in vitro to exhibit the most potent anti-microbial properties in a dose-dependent manner compared to other MCFAs. Black Americans have the highest CRC incidence and mortality across all racial subgroups in the US. In a predominantly low-income population, we aimed to examine whether dietary intake of MCFAs is associated with a reduced risk of CRC overall and among racial subgroups. Methods: The daily intake of total energy and individual nutrients, including MCFAs, was derived from a food frequency questionnaire. Multivariable-adjusted Cox regression was used to assess the associations between dietary intake of MCFAs and the risk of incident CRC during the 13.75-year follow up after adjustment for confounders. Results: Among 71,599 eligible participants, 868 incident CRC cases were identified (622 Blacks, 220 Whites and 26 other racial groups). High intake of C12:0 was significantly associated with a reduced risk of CRC only in White participants in a dose-response manner (for highest VS lowest quartile: HR, 0.37; 95% CI, 0.17 to 0.80; P for trend =0.0068). This protective association primarily appeared in White participants at high risk of CRC, such as those aged 50 years or older, overweight or obese, ever smokers, or living in a neighborhood with greater deprivation. On the other hand, we did not find a significant association in Black participants (HR, 0.87; 95% CI, 0.59 to 1.27); P for trend =0.72). However, there was a marginal linear association in Black participants with the lowest deprivation index while the association disappeared among Black participants with higher deprivation index. Finally, we found from the NHANES 2005-2016, a representative sample of the US general population, that Black Americans had the lowest intake of MCFAs across all racial subgroups and, overall, intakes of MCFAs decreased with reducing poverty-income ratio. No associations were found between intakes of C6:0, C8:0, or C10:0 and the risk of incident CRC overall or within the racial group. Conclusion: In this predominantly low-income population, increasing dietary C12:0 intake was associated with a substantially reduced risk of CRC only among White participants, but not in Black participants. This racial difference in associations may be because Black Americans consumed the lowest levels of MCFAs in all racial groups while a much higher proportion of Black participants had lactose intolerance and a lower proportion of them consumed lactose-free fermented foods. Citation Format: Lei Fan, Xiangzhu Zhu, Qingxia Chen, Xiang Huang, Mark D. Steinwandel, Martha Shrubsole, Qi Dai. Dietary medium-chain fatty acids and risk of incident colorectal cancer in a predominantly low-income population: a report from the Southern Community Cohort Study (SCCS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6451.

Dietary Medium-Chain Fatty Acids Raise and (n-3) Polyunsaturated Fatty Acids Lower Hepatic Triacylglycerol Synthesis in Rats

The hypothesis tested was that dietary medium-chain or (n-3) polyunsaturated fatty acids, when compared with (n-6) polyunsaturated fatty acids, alter plasma triacylglycerol levels by affecting hepatic triacylglycerol synthesis as reflected by the activities of acetyl-CoA carboxylase, fatty acid synthase and diacylglycerol acyltransferase in liver. In two separate experiments rats were fed purified diets containing (n-6) polyunsaturated fatty acids in the form of corn oil and either (n-3) polyunsaturated fatty acids in the form of fish oil or medium-chain triacylglycerols (MCT). Consumption of MCT significantly raised plasma triacylglycerol concentrations, whereas fish oil feeding had a lowering effect compared with the corn oil-fed group. In individual rats, the hepatic triacylglycerol concentration was directly correlated with the plasma triacylglycerol concentration (r = 0.60, P < 0.001). The MCT oil diet vs. the corn oil diet markedly raised the activities of hepatic acetyl-CoA carboxylase, fatty acid synthase and diacylglycerol acyltransferase. In the rats fed fish oil, the activities of fatty acid synthase and diacylglycerol acyltransferase were significantly reduced, whereas the activity of acetyl-CoA carboxylase was not affected relative to activities in rats fed corn oil. The activities of the three enzymes were directly correlated with plasma triacylglycerol concentrations in individual rats (r = 0.60–0.75, P < 0.001). The type of fat in the diet probably affects the rate of hepatic triacylglycerol synthesis which is an important determinant of plasma triacylglycerol concentrations.

Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84.

Medium-chain triglycerides (MCTs), which consist of medium-chain fatty acids (MCFAs), are unique forms of dietary fat with various health benefits. G protein-coupled 84 (GPR84) acts as a receptor for MCFAs (especially C10:0 and C12:0); however, GPR84 is still considered an orphan receptor, and the nutritional signaling of endogenous and dietary MCFAs via GPR84 remains unclear. Here, we showed that endogenous MCFA-mediated GPR84 signaling protected hepatic functions from diet-induced lipotoxicity. Under high-fat diet (HFD) conditions, GPR84-deficient mice exhibited nonalcoholic steatohepatitis (NASH) and the progression of hepatic fibrosis but not steatosis. With markedly increased hepatic MCFA levels under HFD, GPR84 suppressed lipotoxicity-induced macrophage overactivation. Thus, GPR84 is an immunomodulating receptor that suppresses excessive dietary fat intake-induced toxicity by sensing increases in MCFAs. Additionally, administering MCTs, MCFAs (C10:0 or C12:0, but not C8:0), or GPR84 agonists effectively improved NASH in mouse models. Therefore, exogenous GPR84 stimulation is a potential strategy for treating NASH.

Medium-chain fatty acids for the prevention or treatment of Alzheimer's disease: a systematic review and meta-analysis.

In preclinicalAlzheimer's disease (AD), the brain gradually becomes insulin resistant. As a result, brain glucose utilization is compromised, causing a cellular energy deficit that leads to the accumulation of free radicals, which increases inflammation and damages neurons. When glucose utilization is impaired, ketone bodies offer an alternative energy source. Ketone bodies are synthesized from fats, obtained from either the diet or adipose tissue. Dietary medium-chain fatty acids (MCFAs), which are preferentially metabolized into ketone bodies, have the potential to supply the insulin-resistant brain with energy. This systematic review and meta-analysis aims to review the effect of MCFA supplements on circulating ketone bodies and cognition in individuals with subjective cognitive decline, mild cognitive impairment, and AD. A comprehensive search of electronic databases was performed on August 12, 2019, to retrieve all publications meeting the inclusion criteria. Alerts were then set to identify any publications after the search date up until January 31, 2021. Data were extracted by 2 authors and assessed by a third. In total, 410 publications were identified, of which 16 (n = 17 studies) met the inclusion criteria. All studies assessing change in levels of blood ketone bodies due to MCFA supplementation (n = 12) reported a significant increase. Cognition outcomes (measured in 13 studies), however, varied, ranging from no improvement (n = 4 studies) to improvement (n = 8 studies) or improvement only in apolipoprotein E allele 4 (APOE ε4) noncarriers (n = 2 studies). One study reported an increase in regional cerebral blood flow in APOE ε4 noncarriers and another reported an increase in energy metabolism in the brain. MCFA supplementation increases circulating ketone body levels, resulting in increased brain energy metabolism. Further research is required to determine whether this MCFA-mediated increase in brain energy metabolism improves cognition. PROSPERO registration number CRD42019146967.

Dietary medium-chain fatty acid and Bacillus in combination alleviate weaning stress of piglets by regulating intestinal microbiota and barrier function.

The present study evaluated the effects of dietary medium-chain fatty acid (MCFA) and Bacillus on growth performance, nutrient digestibility, antioxidant capacity, colonic fermentation, and microbiota of weaning piglets. A total of 400 weaned piglets were randomly divided into 4 treatments, with 10 replicates per treatment and 10 pigs per replicate. The treatment included: basal diet (control, CON), basal diet with 0.588 g/kg MCFA (MCF), basal diet with 1.3 × 109 CFU/kg Bacillus (BAC), and basal diet with 0.588 g/kg MCFA and 1.3 × 109 CFU/kg Bacillus (SYN). Compared with CON group, the average daily gain of MCF and SYN in the early (1 to 9 d) and whole stage (1 to 36 d) of trail were improved (P < 0.05), the feed to gain ratio of MCF in later (10 to 36 d) and whole stage of trial were decreased (P < 0.05), and the diarrhea rate of SYN in the early stage (1 to 9 d) of trial decreased (P < 0.05). The digestibility of dry matter, ether extract, acid detergent fiber digestibility of MCF were decreased (P < 0.05) compared with CON. The serum d-lactic acid in MCF, BAC, and SYN were lower (P < 0.05) compared with CON group. Compared with CON group, the contents of total antioxidant capacity, superoxide dismutase, and glutathione peroxidase were greater (P < 0.05), whereas the content of malondialdehyde and the contents of colonic isobutyrate and isovalerate were lower (P < 0.05) in MCF. The microbial Shannon and Simpson diversity was lower in MCF (P < 0.05) than that in BAC and SYN. The relative abundance of Prevotella was greater (P < 0.05), whereas the Treponema and Oscillibacter were lower (P < 0.05) in MCF than that in BAC and SYN. In addition, the metabolic pathways of bacteria such as pentose phosphate pathway, adenosine nucleotides degradation II were enhanced (P < 0.05), whereas the pathways such as incomplete reductive TCA cycle, and TCA cycle IV (2-oxoglutarate decarboxylase) were decreased (P < 0.05) in MCF compared with BAC. The results indicated that dietary MCFA and Bacillus in combination improved the intestinal barrier function of piglets by changing the intestinal microbiota and its metabolic function, and finally alleviated the diarrhea rate in early weaning stage and improved growth performance in whole trial period. In addition, MCFA was effective in improving feed efficiency and antioxidant capacity of piglets.

The ghrelin system follows a precise post-natal development in mini-pigs that is not impacted by dietary medium chain fatty-acids.

The ghrelin-ghrelin receptor (GHSR1) system is one of the most important mechanisms regulating food intake and energy balance. To be fully active, ghrelin is acylated with medium-chain fatty acids (MCFA) through the ghrelin-O-acetyl transferase (GOAT). Several studies reported an impact of dietary MCFA on ghrelin acylation in adults. Our study aimed at describing early post-natal development of the ghrelin system in mini-pigs as a model of human neonates and evaluating the impact of dietary MCFA. Suckled mini-pigs were sacrificed at post-natal day (PND) 0, 2, 5, and 10 or at adult stage. In parallel, other mini-pigs were fed from birth to PND10 a standard or a dairy lipid-enriched formula with increased MCFA concentration (DL-IF). Plasma ghrelin transiently peaked at PND2, with no variation of the acylated fraction except in adults where it was greater than during the neonatal period. Levels of mRNA coding pre-proghrelin (GHRL) and GOAT in the antrum did not vary during the post-natal period but dropped in adults. Levels of antral pcsk1/3 (cleaving GHRL into ghrelin) mRNA decreased significantly with age and was negatively correlated with plasma acylated, but not total, ghrelin. Hypothalamic ghsr1 mRNA did not vary in neonates but increased in adults. The DL-IF formula enriched antral tissue with MCFA but did not impact the ghrelin system. In conclusion, the ghrelin maturation enzyme PCSK1/3 gene expression exhibited post-natal modifications parallel to transient variations in circulating plasma ghrelin level in suckling piglets but dietary MCFA did not impact this post-natal development.

The Impact of Medium Chain and Polyunsaturated ω-3-Fatty Acids on Amyloid-β Deposition, Oxidative Stress and Metabolic Dysfunction Associated with Alzheimer's Disease.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly population, is closely linked to a dysregulated cerebral lipid homeostasis and particular changes in brain fatty acid (FA) composition. The abnormal extracellular accumulation and deposition of the peptide amyloid-β (Aβ) is considered as an early toxic event in AD pathogenesis, which initiates a series of events leading to neuronal dysfunction and death. These include the induction of neuroinflammation and oxidative stress, the disruption of calcium homeostasis and membrane integrity, an impairment of cerebral energy metabolism, as well as synaptic and mitochondrial dysfunction. Dietary medium chain fatty acids (MCFAs) and polyunsaturated ω-3-fatty acids (ω-3-PUFAs) seem to be valuable for disease modification. Both classes of FAs have neuronal health-promoting and cognition-enhancing properties and might be of benefit for patients suffering from mild cognitive impairment (MCI) and AD. This review summarizes the current knowledge about the molecular mechanisms by which MCFAs and ω-3-PUFAs reduce the cerebral Aβ deposition, improve brain energy metabolism, and lessen oxidative stress levels.

Effect of medium chain fatty acid in human health and disease

• Dietary supplementation with MCFAs can improve metabolic features as well as cognition in humans. • Studies have shown that MCFA-induce changes to the gut microbiota on host physiology and immunity. • At a constant energy intake, increased dietary MCFA can be an effective tool in addressing obesity. • MCFA, a preventative strategy against diabetes risk by β-cell function preservation. Medium chain fatty acids (MCFAs) has unique transport system and is rapidly metabolized in the body. It mainly occurs in coconut oil, palm kernel oil and milk products. Dietary supplementation with MCFAs can improve metabolic features as well as cognition in humans. Some of the effects of MCFAs may be through direct receptor-mediated intracellular pathways, but MCFAs are also metabolic regulators that can alter circulating levels of hormones and metabolites, and hence may indirectly mediate body metabolism. Here we describe how dietary medium chain fatty acid, previously found to improve immune response and insulin secretion via G-protein coupled receptors, can increase apoptosis in cancer cells through the activation of the EGFR/ERK/AP1 transduction pathway. MCFA-enriched diets could therefore be used to manage metabolic diseases through the modification of gut microbiota, activation of GPR 40 and GPR 84.

Small Amounts of Dietary Medium-Chain Fatty Acids Protect Against Insulin Resistance During Caloric Excess in Humans.

Medium-chain fatty acids (MCFAs) have in rodents been shown to have protective effects on glucose homeostasis during high-fat overfeeding. In this study, we investigated whether dietary MCFAs protect against insulin resistance induced by a hypercaloric high-fat diet in humans. Healthy, lean men ingested a eucaloric control diet and a 3-day hypercaloric high-fat diet (increase of 75% in energy, 81-83% energy [E%] from fat) in randomized order. For one group (n = 8), the high-fat diet was enriched with saturated long-chain FAs (LCSFA-HFD), while the other group (n = 9) ingested a matched diet, but with ∼30 g (5E%) saturated MCFAs (MCSFA-HFD) in substitution for a corresponding fraction of the saturated long-chain fatty acids (LCFAs). A hyperinsulinemic-euglycemic clamp with femoral arteriovenous balance and glucose tracer was applied after the control and hypercaloric diets. In LCSFA-HFD, whole-body insulin sensitivity and peripheral insulin-stimulated glucose disposal were reduced. These impairments were prevented in MCSFA-HFD, accompanied by increased basal fatty acid oxidation, maintained glucose metabolic flexibility, increased nonoxidative glucose disposal related to lower starting glycogen content, and increased glycogen synthase activity, together with increased muscle lactate production. In conclusion, substitution of a small amount of dietary LCFAs with MCFAs rescues insulin action in conditions of lipid-induced energy excess.

The effects of dietary medium-chain fatty acids on ruminal methanogenesis and fermentation in vitro and in vivo: A meta-analysis.

The efficacy of methane (CH4 ) suppression using medium-chain fatty acids (MCFA) remains inconclusive, despite a number of studies on this topic are available. We thus carried out a meta-analysis to integrate the published data on different concentrations and types of MCFA such as lauric acid and myristic acid, which investigated ruminal methanogenesis and fermentation in in vitro and in vivo experiments. In vitro MCFA sources were classified either as pure MCFA (lauric acid, myristic acid and their combinations) or as natural MCFA-rich oils (canola oil enriched with lauric acids, coconut oil, krabok oil and palm kernel oil). The MCFA sources used in the in vivo studies were coconut oil, lauric acid, myristic acid and the combination of lauric and myristic acids. A total of 41 studies (20 in vitro and 21 in vivo studies) were compiled in our database, which included the data on CH4 emission, digestibility, ruminal fermentation products and microbial populations. The results showed that the amount of CH4 production per unit of digested organic matter decreased linearly under in vitro conditions (p < .01) and tended to decrease quadratically under in vivo conditions (p < .07) with increasing doses of MCFA. Populations of protozoa (p < .01) in both in vitro and in vivo responded negatively in a linear manner, whereas Archaea population diminished quadratically (p = .04) only in the in vitro conditions with increasing doses of MCFA. Increasing dietary MCFA concentrations also reduced the fibre digestibility linearly (p < .05) in both in vitro and in vivo conditions. CH4 production for different sources of MCFA decreased in following order: coconut oil>lauric acid>myristic acid>mixed lauric and myristic acids>palm kernel oil>canola oil enriched with lauric acids>krabok oil. It can be concluded that the effect of MCFA on ruminal methanogenesis depends on the amount and type of MCFA.

Dietary Fatty Acid Composition Influences Growth Performance and Hepatic Metabolism in Neonatal Pigs

Medium‐chain fatty acids (MCFA) are often included in neonatal milk formulas as a more readily oxidized source of energy compared with long‐chain fatty acids (LCFA). This rapid oxidation of MCFA is thought to enhance growth. Thus, the objectives of this study were to evaluate the effect of energy supplementation and fat source on growth and body composition, and determine the rate of Krebs Cycle substrate utilization in neonatal pigs. Eleven three‐day‐old pigs were allocated to one of three sow milk replacer formulas: a control (CONT) and diets rich in either LCFA or MCFA. The CONT formula provided 80%, whereas the MCFA and LCFA formulas provided 120%, of the metabolizable energy requirements of neonatal pigs. Pigs were fed for 20 days and body composition measured by DXA before initiation and on day 20 of feeding. At the end of the study, pigs were euthanized and muscles and organs collected and weighed. Livers were digested with collagenase and isolated hepatocytes were incubated in media containing all amino acids, glucose, and short‐chain fatty acids in the presence of [U13C] labeled alanine, glucose, propionate, and glutamate for 90 min. The enrichment of Krebs Cycle intermediates was determined using gas chromatography/mass spectrometry. Body weight of pigs in the LCFA group was greater than those in the MCFA and CONT groups on days 18 and 20. In addition, percent fat measured by DXA was greater for MCFA (8%) and LCFA (7%) than those in the CONT (4%) group, and this increase in fat deposition occurred at the expense of lean tissue (P &lt; 0.05). Longissimus dorsi and heart weights as percent of body weight were similar for all groups; however, soleus weight was less for MCFA compared with those in the CONT and LCFA groups. In addition, liver and kidney weights as a percentage of body weight were greater for pigs in the MCFA group compared with those in the CONT group with LCFA being intermediate (P&lt; 0.05). There was no effect of formula feeding on glucose and alanine contribution to lactate synthesis in isolated hepatocytes, but this contribution was greater for glucose (36%) than for alanine (15%) (P&lt;0.05). Conversely, the contribution of alanine (35%) carbon to pyruvate was greater than the contribution of glucose (7%) (P&lt;0.05). Furthermore, in hepatocytes of pigs fed CONT formula 39% of pyruvate carbon was derived from alanine and 31–34% for pigs in the LCFA and MCFA groups (P&lt;0.05). Lastly, glutamate contributed 64% of α‐ketoglutarate carbon in hepatocytes of CONT and MCFA and only 40% for LCFA pigs. These data suggest that dietary MCFA increase body fat without increasing lean tissue accretion compared with CONT. In addition, anaplerosis from glutamate was greater for pigs fed MCFA and CONT than for those fed LCFA.

Effect of dietary medium-chain fatty acids on nursery pig growth performance, fecal microbial composition, and mitigation properties against porcine epidemic diarrhea virus following storage.

An experiment was conducted to evaluate the effect of dietary medium-chain fatty acid (MCFA) addition on nursery pig growth performance, fecal microbial composition, and mitigation of porcine epidemic diarrhea virus (PEDV) following storage. A total of 360 pigs (DNA 400 × 200, Columbus, NE; initially 6.7 ± 0.07 kg) were randomized to pens (5 pigs per pen) on the day of weaning (approximately 20 d of age), allowed a 6-d acclimation, blocked by BW, and randomized to dietary treatment (9 pens per treatment). All MCFA (Sigma-Aldrich, St. Louis, MO) were guaranteed ≥98% purity, including hexanoic (C6:0), octanoic (C8:0), and decanoic (C10:0) acids. Treatment diets were formulated in 2 phases (7 to 11 and 11 to 23 kg BW) and formulated to meet or exceed NRC requirement estimates. Treatments (n = 8) were a dose response including 0%, 0.25%, 0.5%, 1.0%, and 1.5% added MCFA blend (1:1:1 ratio C6:0, C8:0, and C10:0), as well as treatments with individual additions of 0.5% C6:0, C8:0, or C10:0. Fecal samples were collected from pigs fed control and 1.5% MCFA blend diets on days 0 and 14 and analyzed using 16s rDNA sequencing. Following feed manufacture, feed was stored in bags at barn temperature and humidity for 40 d before laboratory inoculation with PEDV. Subsamples of retained feed were inoculated with PEDV to achieve a titer of 104 TCID50/g and separate sample bottles were analyzed on 0 and 3 d post-inoculation (dpi). Overall, ADG and ADFI were increased (linear, P ≤ 0.010) and feed efficiency (G:F) improved (linear, P = 0.004) with increasing MCFA blend. Pigs fed 0.5% C8:0 had greater (P = 0.038) ADG compared with pigs fed the control diet, and G:F was improved (P ≤ 0.024) when pigs were fed 0.5% C6:0, 0.5% C8:0, or 0.5% C10:0 compared with control. An inclusion level × day interaction was observed (quadratic, P = 0.023), where PEDV Ct values increased (quadratic, P = 0.001) on 0 dpi with increasing levels of MCFA blend inclusion and also increased on 3 dpi (linear, P < 0.001). Fecal microbial diversity and composition were similar between control and 1.5% MCFA blend. In summary, the use of MCFA in nursery pig diets improves growth performance, provides residual mitigation activity against PEDV, and does not significantly alter fecal microbial composition.

Effect of Acrocomia aculeata Kernel Oil on Adiposity in Type 2 Diabetic Rats.

The macauba palm (Acrocomia aculeata) is native of tropical America and is found mostly in the Cerrados and Pantanal biomes. The fruits provide an oily pulp, rich in long chain fatty acids, and a kernel that encompass more than 50% of lipids rich in medium chain fatty acids (MCFA). Based on biochemical and nutritional evidences MCFA is readily catabolized and can reduce body fat accumulation. In this study, an animal model was employed to evaluate the effect of Acrocomia aculeata kernel oil (AKO) on the blood glucose level and the fatty acid deposit in the epididymal adipose tissue. The A. aculeata kernel oil obtained by cold pressing presented suitable quality as edible oil. Its fatty acid profile indicates high concentration of MCFA, mainly lauric, capric and caprilic. Type 2 diabetic rats fed with that kernel oil showed reduction of blood glucose level in comparison with the diabetic control group. Acrocomia aculeata kernel oil showed hypoglycemic effect. A small fraction of total dietary medium chain fatty acid was accumulated in the epididymal adipose tissue of rats fed with AKO at both low and high doses and caprilic acid did not deposit at all.

Increasing Dietary Medium-Chain Fatty Acid Ratio Mitigates High-fat Diet-Induced Non-Alcoholic Steatohepatitis by Regulating Autophagy

Previous studies have demonstrated that saturated fatty acids (SFAs) are more lipotoxic than unsaturated fatty acids (UFAs) in inhibiting hepatic autophagy and promoting non-alcoholic steatohepatitis (NASH). However, there have been few studies have investigated the effects of carbon chain length on SFA-induced autophagy impairment and lipotoxicity. To investigate whether SFAs with shorter carbon chain lengths have differential effects on hepatic autophagy and NASH development, we partially replaced lard with coconut oil to elevate the ratio of medium-chain fatty acids (MCFAs) to long-chain fatty acids (LCFAs) in a mouse high-fat diet (HFD) and fed mice for 16 weeks. In addition, we treated HepG2 cells with different combinations of fatty acids to study the mechanisms of MCFAs-mediated hepatic protections. Our results showed that increasing dietary MCFA/LCFA ratio mitigated HFD-induced Type 2 diabetes and NASH in mice. Importantly, we demonstrated that increased MCFA ratio exerted its protective effects by restoring Rubicon-suppressed autophagy. Our study suggests that the relative amount of LCFAs and MCFAs in the diet, in addition to the amount of SFAs, can significantly contribute to autophagy impairment and hepatic lipotoxicity. Collectively, we propose that increasing dietary MCFAs could be an alternative therapeutic and prevention strategy for Type 2 diabetes and NASH.