Influence of critical micelle concentration of choline-based long chain fatty acid soaps on their antibacterial activity against Methicillin resistant Staphylococcus aureus.

HYPOTHESIS: Antimicrobial resistance (AMR) is a pressing global health concern. ESKAPEE pathogens, such as Methicillin-resistant Staphylococcus aureus (MRSA) are notable of concern in healthcare settings due to their resistance to critical antibiotics. To combat AMR, the development of alternatives such as bacterial membrane-active agents is crucial. Fatty acids (FAs) have emerged as a sustainable, antibiotic-free solution with inherent antibacterial activity. However, long chain saturated fatty acids (LCFAs) sodium soaps exhibit poorly antibacterial properties in comparison to short chain FAs, believed to be linked to limited solubility in aqueous media. EXPERIMENTS: We employed choline as a chaotropic organic counter-ion to enhance the solubility of LCFAs and investigated their antibacterial effects against MRSA. The optimal medium conditions for micelle formation for LCFAs was first investigated. Then, we determined the critical micelle concentration (CMC), micellar morphology, and aggregation number through surface tension measurements and small angle neutron scattering experiments. Antimicrobial activity was assessed using minimum bactericidal concentration (MBC) assays and time-kill experiments. FINDINGS: We have identified conditions where LCFAs are effective against MRSA for the first time, providing valuable insights for developing new antibacterial agents to fight AMR. LCFAs need to be used above their Krafft temperatures and CMC to exhibit antibacterial efficacy.

Ceramides as the molecular link between impaired lipid metabolism, saturated fatty acid intake and insulin resistance: are all saturated fatty acids to be blamed for ceramide-mediated lipotoxicity?

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has reached epidemic proportions worldwide, posing a huge treat on people's health and quality of life. From a pathogenetic prospective, T2DM is driven by insulin resistance defined as a blunted response of tissues to insulin which leads to chronic hyperglycaemia. Mechanistically, lipotoxicity and particularly the intracellular accumulation of ceramides in the skeletal muscle and the liver, is a primary metabolic aberration underpinning insulin resistance. Indeed, intracellular ceramide accumulation can hamper insulin signal transduction pathway thereby promoting insulin resistance. This review will provide an updated overview of the metabolic defects underlaying ceramide buildup and the molecular mechanism by which ceramides imping upon insulin signalling. Additionally, the role of specific ceramide subspecies as potential biomarkers for T2DM and the role of both long- and medium-chain saturated fatty acids as a modulator of ceramide metabolism will be discussed.

Association of circulation very long chain saturated fatty acids with depression in NHANES 2011-2014.

BACKGROUND: Recent studies have shown that elevated levels of medium and long chain saturated fatty acids are associated with an increased risk of depression. However, little is known about the effect of very long chain saturated fatty acids (VLSFAs) on depression. Therefore, our study aimed to examine the association between VLSFAs and depression in the US adult population. METHODS: A total of 2706 participants with serum VLSFAs detection from NHANES 2011-2014 were included in the study. Logistic regression models were used to evaluate the association between quartile levels of serum VLSFAs (20:0, 22:0, 23:0, 24:0, and total VLSFA) and depression. RESULTS: After adjusting for multiple variables, we found that increased circulating levels of 22:0, 23:0, 24:0 and total VLSFA were linearly associated with a reduced risk of depression (model 3, Q4 OR: 0.658, 95 % CI: 0.438-0.989, P-trend = 0.023; OR: 0.515, 95 % CI: 0.339-0.782, P-trend<0.001; OR: 0.556, 95 % CI: 0.370-0.835, P-trend = 0.003; OR: 0.652, 95 % CI: 0.435-0.976, P-trend = 0.021, respectively). Additionally, individuals with the highest serum ratios of 22:0/16:0, 23:0/16:0, 24:0/16:0 and total VLSFA/16:0 also had a lower risk of depression after adjusting for multiple variables compared to the group with the lowest serum VLSFAs/16:0 (P-trend = 0.001, <0.001, 0.001 and 0.004, respectively). Moreover, the decreasing trend of depression associated with increased VLSFAs/18:0 remained significant. CONCLUSION: In conclusion, our findings suggest that increased circulating levels of 22:0, 23:0, 24:0 and total VLSFA may have a protective effect against the risk of depression.

Association between the circulating very long-chain saturated fatty acid and cognitive function in older adults: findings from the NHANES.

BACKGROUND: Age-related cognitive decline has a significant impact on the health and longevity of older adults. Circulating very long-chain saturated fatty acids (VLSFAs) may actively contribute to the improvement of cognitive function. The objective of this study was to investigate the associations between arachidic acid (20:0), docosanoic acid (22:0), tricosanoic acid (23:0), and lignoceric acid (24:0) with cognitive function in older adults. METHODS: This study used a dataset derived from the 2011-2014 National Health and Nutrition Examination Survey (NHANES). A total of 806 adults (≥ 60 years) were included who underwent comprehensive cognitive testing and plasma fatty acid measurements. Multivariable linear regression, restricted cubic spline (RCS), and interaction analyses were used to assess associations between VLSFAs and cognitive function. Partial Spearman' s correlation analysis was used to examine the correlations between VLSFAs and palmitic acid (16:0), high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, systemic inflammatory markers, and dietary nutrients. RESULTS: Multivariable linear regression analysis, adjusting for sociodemographic, clinical conditions, and lifestyle factors, showed that 22:0 and 24:0 levels were positively associated with better global cognitive function (ß = 0.37, 95% confidence interval [CI] = 0.01, 0.73; ß = 0.73, 95% CI = 0.29, 1.2, respectively) as well as better CEARD-DR Z-score (ß = 0.82, 95% CI = 0.36, 1.3 and ß = 1.2, 95% CI = 0.63, 1.8, respectively). RCS analysis showed linear associations between higher 22:0 and 24:0 levels and better cognitive performance in both global cognitive function and CERAD-DR tests. CONCLUSIONS: The study suggests that higher levels of 22:0 and 24:0 are associated with better global cognitive function in older adults. 22:0 and 24:0 may be important biomarkers for recognizing cognitive impairment, and supplementation with specific VLSFAs (22:0 and 24:0) may be an important intervention to improve cognitive function. Further studies are needed to elucidate the underlying biological mechanisms between VLSFAs and cognitive function.

Association of Circulating Very Long-Chain Saturated Fatty Acids With Cardiovascular Mortality in NHANES 2003-2004, 2011-2012.

CONTEXT: Limited studies have shown a protective effect of very long-chain saturated fatty acids (VLSFAs) on healthy aging, diabetes, heart failure, and risk factors related to cardiovascular disease (CVD), but the role of VLSFAs on mortality risk is unclear. OBJECTIVE: We aimed to investigate the association of serum docosanoic acid (C22:0) and serum lignoceric acid (C24:0) with all-cause and disease-specific mortality and to confirm the effect of VLSFAs on mortality risk in the whole, hyperlipidemia, and hypertensive populations. METHODS: A total of 4132 individuals from the 2003-2004, 2011-2012 National Health and Nutrition Examination Survey (NHANES) were included in this study. There were 1326 and 1456 participants in the hyperlipidemia and hypertensive population, respectively. Mortality information was confirmed using the National Death Index (NDI). Multiple model calibration was performed using Cox regression analysis for known risk factors to explore the association between circulating VLSFAs and all-cause or CVD or coronary heart disease (CHD) mortality. RESULTS: In the whole population, individuals with higher circulating C22:0 and C24:0 as a percentage of total serum fatty acid levels reduced the risks of mortality of all-cause (C22:0: HR = .409; 95% CI, 0.271-0.618; C24:0: HR = 0.430; 95% CI, 0.283-0.651), CVD (C22:0: HR = 0.286; 95% CI, 0.134-0.612; C24:0: HR = 0.233; 95% CI, 0.101-0.538), and CHD (C22:0: HR = 0.401; 95% CI, 0.187-0.913; C24:0: HR = 0.263; 95% CI, 0.082-0.846). Similar to the whole population, individuals with higher circulating C22:0 and C24:0 as a percentage of total serum fatty acid levels in the hyperlipidemia and hypertensive populations were also protective for all-cause, CHD, and CVD mortality. CONCLUSION: Our results confirm the protective effect of high levels of circulating VLSFAs (C22:0 and C24:0) on CVD, CHD, and all causes of death in the whole, hyperlipidemia, and hypertensive populations.

Saturated long chain fatty acids as possible natural alternative antibacterial agents: Opportunities and challenges.

The spread of new strains of antibiotic-resistant pathogenic microorganisms has led to the urgent need to discover and develop new antimicrobial systems. The antibacterial effects of fatty acids have been well-known and recognized since the first experiments of Robert Koch in 1881, and they are now used in diverse fields. Fatty acids can prevent the growth and directly kill bacteria by insertion into their membrane. For that, a sufficient amount of fatty acid molecules has to be solubilized in water to transfer from the aqueous phase to the cell membrane. Due to conflicting results in the literature and lack of standardization methods, it is very difficult to draw clear conclusions on the antibacterial effect of fatty acids. Most of the current studies link fatty acids' effectiveness against bacteria to their chemical structure, notably the alkyl chain length and the presence of double bonds in their chain. Furthermore, the solubility of fatty acids and their critical aggregation concentration is not only related to their structure, but also influenced by medium conditions (pH, temperature, ionic strength, etc.). There is a possibility that the antibacterial activity of saturated long chain fatty acids (LCFA) may be underestimated due to the lack of water solubility and the use of unsuitable methods to assess their antibacterial activity. Thus, enhancing the solubility of these long chain saturated fatty acids is the main goal before examining their antibacterial properties. To increase their water solubility and thereby improve their antibacterial efficacy, novel alternatives may be considered, including the use of organic positively charged counter-ions instead of the conventional sodium and potassium soaps, the formation of catanionic systems, the mixture with co-surfactants, and solubilization in emulsion systems. This review summarizes the latest findings on fatty acids as antibacterial agents, with a focus on long chain saturated fatty acids. Additionally, it highlights the different ways to improve their water solubility, which may be a crucial factor in increasing their antibacterial efficacy. We finish with a discussion on the challenges, strategies and opportunities for the formulation of LCFAs as antibacterial agents.

Serum Saturated Fatty Acids including Very Long-Chain Saturated Fatty Acids and Colorectal Cancer Risk among Chinese Population.

The association between circulating saturated fatty acids (SFAs) including very long-chain SFAs (VLCSFAs) and colorectal cancer (CRC) risk has not been clearly established. To investigate the association between serum SFAs and CRC risk in Chinese population, 680 CRC cases and 680 sex and age-matched (5-year interval) controls were recruited in our study. Serum levels of SFAs were detected by gas chromatography. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between serum SFAs and CRC risk. Results showed that total SFAs were positively associated with the risk of CRC (adjusted OR quartile 4 vs. 1 = 2.64, 95%CI: 1.47-4.74). However, VLCSFAs were inversely associated with CRC risk (adjusted OR quartile 4 vs. 1 = 0.51, 95%CI: 0.36-0.72). Specifically, lauric acid, myristic acid, palmitic acid, heptadecanoic acid, and arachidic acid were positively associated with CRC risk, while behenic acid and lignoceric acid were inversely associated with CRC risk. This study indicates that higher levels of total serum SFAs and lower levels of serum VLCSFAs were associated with an increased risk of CRC in Chinese population. To reduce the risk of CRC, we recommend reducing the intake of foods containing palmitic acid and heptadecanoic acid such as animal products and dairy products, and moderately increasing the intake of foods containing VLCSFAs such as peanuts and canola oil.

Lifestyle Factors Associated with Circulating Very Long-Chain Saturated Fatty Acids in Humans: A Systematic Review of Observational Studies.

Recent observational studies have documented inverse associations of circulating very long-chain saturated fatty acids (VLCSFAs), namely arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), with cardiometabolic outcomes. In addition to their endogenous production, it has been suggested that dietary intake or an overall healthier lifestyle may influence VLCSFA concentrations; however, a systematic review of the modifiable lifestyle contributors to circulating VLCSFAs is lacking. Therefore, this review aimed to systematically assess the effects of diet, physical activity, and smoking on circulating VLCSFAs. Following registration on PROSPERO (International Prospective Register of Systematic Reviews) (ID: CRD42021233550), a systematic search of observational studies was conducted in MEDLINE, EMBASE, and The Cochrane databases up to February 2022. A total of 12 studies consisting of mostly cross-sectional analyses were included in this review. The majority of the studies documented the associations of dietary intake with total plasma or red blood cell VLCSFAs, in which a range of macronutrients and food groups were examined. Two cross-sectional analyses showed a consistent positive association between total fat and peanut intake with 22:0 and 24:0 and an inverse association between alcohol intake and 20:0 and 22:0. Furthermore, a moderate positive association between physical activity and 22:0 and 24:0 was observed. Lastly, there were conflicting results on the effects of smoking on VLCSFA. Although most studies had a low risk of bias; the findings of this review are limited by the bi-variate analyses presented in the majority of the included studies, therefore, the impact of confounding is unclear. In conclusion, although the current observational literature examining lifestyle determinants of VLCSFAs is limited, existing evidence suggests that circulating 22:0 and 24:0 may be influenced by higher total and saturated fat consumption and nut intake.

Dietary fatty acid metabolism: New insights into the similarities of lipid metabolism in humans and hamsters.

Hamsters have been long accepted as animal models to study the lipid metabolism in humans. However, very few scientific works described in detail the fatty acid (FA) composition of plasma and erythrocytes in hamsters in relation to their dietary intake, and none work was found comparing them with that described in humans. Therefore, a study was carried out to compare the effect of ingesting olive oil or dairy fat, as part of an equilibrated diet in healthy subjects, on plasma and erythrocytes FA composition. More than 40 FA were detected in samples of both species. It was demonstrated that plasma total FA (TFA) concentration and FA profiles are similar in humans and hamsters. In both species linoleic, oleic and palmitic acids are the main FA and accounted for the 70% of TFA. Differences found between species can be explained by differences in the dietary intake and differences in the proportion of triglycerides, cholesteryl esters and phospholipid fractions in plasma of both species. Changes in dietary FA intake causes similar changes in FA concentration in the plasma of both species and can be explained by the same metabolic processes. The erythrocyte FA profile differs more between the two species. Moreover, unlike humans, the FA profile of hamster erythrocytes is more sensitive to changes in dietary FA than that of plasma.

Consumption of peanut products improves memory and stress response in healthy adults from the ARISTOTLE study: A 6-month randomized controlled trial.

BACKGROUND: Peanuts are rich in bioactive compounds that may have a positive impact on memory and stress response. OBJECTIVE: To evaluate the effect of regular consumption of peanut products on cognitive functions and stress response in healthy young adults. DESIGN: A three-arm parallel-group randomized controlled trial was conducted in 63 healthy young adults that consumed 25 g/day of skin roasted peanuts (SRP, n = 21), 32 g/d of peanut butter (PB, n = 23) or 32 g/d of a control butter made from peanut oil (free of phenolic compounds and fiber) (CB, n = 19) for six months. Polyphenol intake, cognitive functions, and anxiety and depression scores were evaluated using validated tests. Fecal short-chain fatty acids (SCFAs) and plasma and fecal fatty acids were assessed by chromatographic methods. Urinary cortisol was quantified by an enzymatic method. RESULTS: Comparing the two interventions with the control, a significant reduction in anxiety scores was observed in the SRP compared to the CB group. After the intervention, consumers of SRP and PB had an improved immediate memory (p = 0.046 and p = 0.011). Lower anxiety scores were associated with SRP and PB (p < 0.001 and p = 0.002, respectively) and lower depression scores with SRP, PB and CB (p = 0.007, p = 0.003 and p = 0.032, respectively). Memory functions and stress response were significantly correlated with polyphenol intake, fecal SCFAs, plasma and fecal very long chain saturated fatty acids (VLCSFAs). CONCLUSIONS: Regular peanut and peanut butter consumption may enhance memory function and stress response in a healthy young population. These effects seem to be associated with the intake of peanut polyphenols, increased levels of fecal SCFAs, and unexpectedly, VLCSFAs, which were also present in the control product.

Low Circulating Concentrations of Very Long Chain Saturated Fatty Acids Are Associated with High Risk of Mortality in Kidney Transplant Recipients.

Kidney transplant recipients (KTR) are at increased risk of mortality, particularly from infectious diseases, due to lifelong immunosuppression. Although very long chain saturated fatty acids (VLSFA) have been identified as crucial for phagocytosis and clearance of infections, their association with mortality in immunocompromised patient groups has not been studied. In this prospective cohort study we included 680 outpatient KTR with a functional graft ≥1 year and 193 healthy controls. Plasma VLSFA (arachidonic acid (C20:0), behenic acid (C22:0) and lignoceric acid (C24:0)) were measured by gas chromatography coupled with a flame ionization detector. Cox regression analyses was used to prospectively study the associations of VLSFA with all-cause and cause-specific mortality. All studied VLSFA were significantly lower in KTR compared to healthy controls (all p < 0.001). During a median (interquartile range) follow-up of 5.6 (5.2-6.3) years, 146 (21%) KTR died, of which 41 (28%) died due to infectious diseases. In KTR, C22:0 was inversely associated with risk of all-cause mortality, with a HR (95% CI) per 1-SD-increment of 0.79 (0.64-0.99), independent of adjustment for potential confounders. All studied VLSFA were particularly strongly associated with mortality from infectious causes, with respective HRs for C20:0, C22:0 and C24:0 of 0.53 (0.35-0.82), 0.48 (0.30-0.75), and 0.51 (0.33-0.80), independent of potential confounders. VLSFA are inversely associated with infectious disease mortality in KTR after adjustment, including HDL-cholesterol. Further studies are needed to assess the effect of VLSFA-containing foods on the risk of infectious diseases in immunocompromised patient groups.

Brain-sparing cord blood transplantation for the borderline stage of adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by rapidly progressive deterioration of neurocognitive functions and premature death. In addition to the difficulty in identifying the earliest signs of ALD, treatment-associated exacerbation of neurological symptoms has been an obstacle to achieve successful hematopoietic cell transplantation (HCT) for affected children. CASE REPORT: We report a 9-year-boy with ALD. He presented with impairment in social skills compatible to the diagnosis of autism spectrum disorder from 3 years of age. He showed progressive strabismus, slurred speech and dysmetria at 6 years of age. The head MRI showed symmetrical T2-hyperintense lesions in the occipital white matters with a gadolinium enhancement, which extended to the internal capsules. The Loes score was thus calculated as 13. Very-long-chain-fatty-acids were increased to 1.800 (C24:0/C22:0) and 0.077 (C26:0/C22:0) in leukocytes. Sanger sequencing confirmed the pathogenic variant in ABCD1 (NM_000033.4:p.Gly512Ser). After multidisciplinary discussions over the treatment options, we performed a cord blood HCT with a reduced intensity conditioning (fludarabine, melphalan and brain-sparing total body irradiation). He was fully recovered with >90% chimerism of donor leukocytes at 55 days after HCT. He experienced three times of generalized seizures after discharge, that has been well controlled for 2 years without other complications or neurocognitive deteriorations. CONCLUSION: For patients with ALD on a borderline indication for HCT, brain-sparing irradiation might be an alternative option in reduced intensity conditioning. Careful decision-making process and tailored conditioning are critical for the successful outcome of HCT for children with ALD.

The associations between individual plasma SFAs, serine palmitoyl-transferase long-chain base subunit 3 gene rs680379 polymorphism, and type 2 diabetes among Chinese adults.

BACKGROUND: Several individual studies have shown that circulating levels of odd-chain SFAs and very-long-chain SFAs (VLSFAs) may have beneficial effects, but the results are mixed. While the dietary and metabolic factors that may influence VLSFAs are not well-known, a previous study observed associations of VLSFA concentrations with variants in serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3) gene. OBJECTIVES: We investigated the associations of individual plasma SFAs and SPTLC3 gene rs680379 polymorphism with metabolic risk factors and type 2 diabetes (T2D). METHODS: We measured plasma SFAs using gas chromatography among 898 T2D cases and 1618 matched controls, and genotyped the SPTLC3 gene rs680379 polymorphism using the MassArray System among 1178 T2D cases and 1907 matched controls. Conditional logistic regression was used to estimate ORs and 95% CIs. RESULTS: We found that plasma odd-chain SFAs and VLSFAs were correlated with favorable blood lipids and insulin resistance marker profiles. After multivariable adjustment, pentadecanoic acid (15:0) was inversely associated with the odds of T2D (OR per 1 SD difference: 0.63; 95% CI: 0.57, 0.70), as were measurements of 3 individual VLSFAs [arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0)], with ORs ranging from 0.60 to 0.72 (95% CIs ranging between 0.52 and 0.79). The associations between 3 individual VLSFAs and T2D were attenuated after further adjustment for triglycerides. Meanwhile, compared with the rs680379 GG genotype carriers, the ORs of T2D for the GA and AA genotype carriers were 0.81 (95% CI: 0.68-0.97) and 0.76 (95% CI: 0.61-0.96), respectively. CONCLUSIONS: Plasma 15:0 and VLSFAs were inversely associated with T2D. Meanwhile, compared with the rs680379 GG genotype carriers, subjects with GA and AA genotypes were associated with decreased odds of T2D. More investigations are warranted to confirm our findings.

Very long chain fatty acid-containing lipids: a decade of novel insights from the study of ELOVL4.

Lipids play essential roles in maintaining cell structure and function by modulating membrane fluidity and cell signaling. The fatty acid elongase-4 (ELOVL4) protein, expressed in retina, brain, Meibomian glands, skin, testes and sperm, is an essential enzyme that mediates tissue-specific biosynthesis of both VLC-PUFA and VLC-saturated fatty acids (VLC-SFA). These fatty acids play critical roles in maintaining retina and brain function, neuroprotection, skin permeability barrier maintenance, and sperm function, among other important cellular processes. Mutations in ELOVL4 that affect biosynthesis of these fatty acids cause several distinct tissue-specific human disorders that include blindness, age-related cerebellar atrophy and ataxia, skin disorders, early-childhood seizures, mental retardation, and mortality, which underscores the essential roles of ELOVL4 products for life. However, the mechanisms by which one tissue makes VLC-PUFA and another makes VLC-SFA, and how these fatty acids exert their important functional roles in each tissue, remain unknown. This review summarizes research over that last decade that has contributed to our current understanding of the role of ELOVL4 and its products in cellular function. In the retina, VLC-PUFA and their bioactive "Elovanoids" are essential for retinal function. In the brain, VLC-SFA are enriched in synaptic vesicles and mediate neuronal signaling by determining the rate of neurotransmitter release essential for normal neuronal function. These findings point to ELOVL4 and its products as being essential for life. Therefore, mutations and/or age-related epigenetic modifications of fatty acid biosynthetic gene activity that affect VLC-SFA and VLC-PUFA biosynthesis contribute to age-related dysfunction of ELOVL4-expressing tissues.

Associations between red blood cells fatty acids, desaturases indices and metabolism of platelet activating factor in healthy volunteers.

INTRODUCTION: Platelet-activating-factor is an inflammatory lipid mediator. Key enzymes of its biosynthesis are CDP-choline:1-alkyl-2-acetyl-sn-glycerol-cholinephosphotransferase (PAF-CPT) and acetyl-CoA:lyso-PAF-acetyltransferases (Lyso-PAF-AT) while PAF-AH/Lp-PLA2 degrade PAF. The interplay between PAF and fatty acids metabolism was explored. MATERIAL AND METHODS: In a healthy population, PAF levels, its metabolic enzymes activity and RBC fatty acids were measured while desaturases indices (D) were estimated. A principal component analysis was also applied to assess patterns of RBC fatty acids. RESULTS: SFA were related to increased PAF biosynthesis and decreased Lp-PLA2 only in women. MUFA were inversely associated with PAF biosynthesis and positively with Lp-PLA2. Omega-6 fatty acids were positively correlated only with PAF-CPT while no significant correlations were observed with n3 fatty acids. D6 index was positively related with PAF biosynthetic enzymes and inversely with Lp-PLA2 while D9 correlated positively with Lp-PLA2. The pattern of high MUFA and low n6 was associated with reduced PAF biosynthesis and/or increased catabolism in both sexes. CONCLUSION: The role of fatty acids in amplifying or reducing inflammation seems to be also reflected in PAF metabolism.

Lauric Acid versus Palmitic Acid: Effects on Adipose Tissue Inflammation, Insulin Resistance, and Non-Alcoholic Fatty Liver Disease in Obesity.

Coconut oil, rich in medium-chain saturated fatty acids (MCSFA), in particular, lauric acid (LA), is known to exert beneficial metabolic effects. Although LA is the most abundant saturated fatty acid in coconut oil, the specific role of LA in altering obesity-related metabolic disorders remains unknown. Here, we examined the effects of supplementing a high fat (HF) diet with purified LA on obesity-associated metabolic derangements in comparison with palmitic acid (PA), a long-chain saturated fatty acid. Male C57BL/6 mice were fed a control chow diet (CD) or an HF diet supplemented with 3% LA (HF + LA) or PA (HF + PA) for 12 wk. Markers of adipose tissue (AT) inflammation, systemic insulin resistance (IR), and hepatic steatosis, were assessed. The body weight and total fat mass were significantly higher in both HF + LA and HF + PA diet-fed groups compared to CD controls. However, the visceral adipose tissue (VAT) mass was significantly higher (p < 0.001) in HF + LA-fed mice compared to both CD as well as HF + PA-fed mice. Interestingly, markers of AT inflammation were promoted to a lesser extent in HF + LA-fed mice compared to HF + PA-fed mice. Thus, immunohistochemical analysis of VAT showed an increase in MCP-1 and IL-6 staining in HF + PA-fed mice but not in HF + LA-fed mice compared to CD controls. Further, the mRNA levels of macrophage and inflammatory markers were significantly higher in HF + PA-fed mice (p < 0.001) whereas these markers were increased to a lesser extent in HF + LA-fed group. Of note, the insulin tolerance test revealed that IR was significantly increased only in HF + PA-fed mice but not in HF + LA-fed group compared to CD controls. While liver triglycerides were increased significantly in both HF + PA and HF + LA-fed mice, liver weight and plasma markers of liver injury such as alanine aminotransferase and aspartate aminotransferase were increased significantly only in HF + PA-fed mice but not in HF + LA-fed mice. Taken together, our data suggest that although both LA and PA increased AT inflammation, systemic IR, and liver injury, the extent of metabolic derangements caused by LA was less compared to PA in the setting of high fat feeding.

Plasma phospholipid very-long-chain SFAs in midlife and 20-year cognitive change in the Atherosclerosis Risk in Communities (ARIC): a cohort study.

BACKGROUND: Very-long-chain SFAs (VLSFAs) have recently gained considerable attention as having beneficial effects on health and aging. OBJECTIVES: The objective of this study was to assess the associations of plasma phospholipid VLSFAs [arachidic acid (20:0), behenic acid (22:0), tricosanoic acid (23:0), and lignoceric acid (24:0)] with 20-y cognitive decline in the Atherosclerosis Risk in Communities (ARIC) participants. Furthermore, this study compared the associations of plasma phospholipid VLSFAs with 5 common groups of fatty acids [i.e., total SFAs, total MUFAs, total ω-3 (n-3) PUFAs, total marine-derived ω-3 PUFAs, total ω-6 PUFAs]. METHODS: This study used a cohort study design of 3229 ARIC participants enrolled at the Minnesota field center. Fatty acids were measured at visit 1 (1987-1989); and cognition was assessed at visits 2 (1990-1992), 4 (1996-1998), and 5 (2011-2013) using 3 tests: the Delayed Word Recall Test (DWRT), the Digit-Symbol Substitution Test (DSST), and the Word Fluency Test (WFT). RESULTS: Higher proportions of plasma phospholipid total VLSFAs and each individual VLSFA were associated with less decline in WFT, a test of verbal fluency. For example, 1 SD higher in total VLSFAs at baseline was associated with 0.057 SD (95% CI: 0.018, 0.096, P = 0.004) less cognitive decline over 20 y as measured by WFT score. None of the 5 common fatty acid groups were associated with change in WFT, but a higher proportion of plasma phospholipid total MUFAs was associated with greater decline in DWRT; higher total ω-6 PUFAs with less decline in DWRT; and higher total ω-3 and total marine-derived ω-3 PUFAs with less decline in DSST. CONCLUSIONS: This study suggests that higher proportions of plasma phospholipid VLSFAs in midlife may be associated with less 20-y cognitive decline.

Potential relationship between dietary long-chain saturated fatty acids and hypothalamic dysfunction in obesity.

Diet-induced hypothalamic inflammation, which leads to hypothalamic dysfunction and a loss of regulation of energy balance, is emerging as a potential driver of obesity. Excessive intake of long-chain saturated fatty acids is held to be the causative dietary component in hypothalamic inflammation. This review summarizes current evidence on the role of long-chain saturated fatty acids in promoting hypothalamic inflammation and the related induction of central insulin and leptin insensitivity. Particularly, the present review focuses on the molecular mechanisms linking long-chain saturated fatty acids and hypothalamic inflammation, emphasizing the metabolic fate of fatty acids and the resulting lipotoxicity, which is a key driver of hypothalamic dysfunction. In conclusion, long-chain saturated fatty acids are key nutrients that promote hypothalamic inflammation and dysfunction by fostering the build-up of lipotoxic lipid species, such as ceramide. Furthermore, when long-chain saturated fatty acids are consumed in combination with high levels of refined carbohydrates, the proinflammatory effects are exacerbated via a mechanism that relies on the formation of advanced glycation end products.

Circulating Very-Long-Chain SFA Concentrations Are Inversely Associated with Incident Type 2 Diabetes in US Men and Women.

BACKGROUND: Very-long-chain SFAs (VLCSFAs), such as arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0), have demonstrated inverse associations with cardiometabolic conditions, although more evidence is needed to characterize their relation with risk of type 2 diabetes (T2D). In addition, little is known regarding their potential dietary and lifestyle predictors. OBJECTIVE: We aimed to examine the association of plasma and erythrocyte concentrations of VLCSFAs with incident T2D risk. METHODS: We used existing measurements of fatty acid concentrations in plasma and erythrocytes among 2854 and 2831 participants in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS), respectively. VLCSFAs were measured using GLC, and individual fatty acid concentrations were expressed as a percentage of total fatty acids. Incident T2D cases were identified by self-reports and confirmed by a validated supplementary questionnaire. Cox proportional hazards regression was used to evaluate the association between VLCSFAs and T2D, adjusting for demographic, lifestyle, and dietary variables. RESULTS: During 39,941 person-years of follow-up, we documented 243 cases of T2D. Intakes of peanuts, peanut butter, vegetable fat, dairy fat, and palmitic/stearic (16:0-18:0) fatty acids were significantly, albeit weakly, correlated with plasma and erythrocyte VLCSFA concentrations (|rs| ≤ 0.19). Comparing the highest with the lowest quartiles of plasma concentrations, pooled HRs (95% CIs) were 0.51 (0.35, 0.75) for arachidic acid, 0.43 (0.28, 0.64) for behenic acid, 0.40 (0.27, 0.61) for lignoceric acid, and 0.41 (0.27, 0.61) for the sum of VLCSFAs, after multivariate adjustments for demographic, lifestyle, and dietary factors. For erythrocyte VLCSFAs, only arachidic acid and behenic acid concentrations were inversely associated with T2D risk. CONCLUSIONS: Our findings suggest that, in US men and women, higher plasma concentrations of VLCSFAs are associated with lower risk of T2D. More research is needed to understand the mechanistic pathways underlying these associations.

Associations of circulating very-long-chain saturated fatty acids and incident type 2 diabetes: a pooled analysis of prospective cohort studies.

BACKGROUND: Saturated fatty acids (SFAs) of different chain lengths have unique metabolic and biological effects, and a small number of recent studies suggest that higher circulating concentrations of the very-long-chain SFAs (VLSFAs) arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) are associated with a lower risk of diabetes. Confirmation of these findings in a large and diverse population is needed. OBJECTIVE: We investigated the associations of circulating VLSFAs 20:0, 22:0, and 24:0 with incident type 2 diabetes in prospective studies. METHODS: Twelve studies that are part of the Fatty Acids and Outcomes Research Consortium participated in the analysis. Using Cox or logistic regression within studies and an inverse-variance-weighted meta-analysis across studies, we examined the associations of VLSFAs 20:0, 22:0, and 24:0 with incident diabetes among 51,431 participants. RESULTS: There were 14,276 cases of incident diabetes across participating studies. Higher circulating concentrations of 20:0, 22:0, and 24:0 were each associated with a lower risk of incident diabetes. Pooling across cohorts, the RR (95% CI) for incident diabetes comparing the 90th percentile to the 10th percentile was 0.78 (0.70, 0.87) for 20:0, 0.84 (0.77, 0.91) for 22:0, and 0.75 (0.69, 0.83) for 24:0 after adjustment for demographic, lifestyle, adiposity, and other health factors. Results were fully attenuated in exploratory models that adjusted for circulating 16:0 and triglycerides. CONCLUSIONS: Results from this pooled analysis indicate that higher concentrations of circulating VLSFAs 20:0, 22:0, and 24:0 are each associated with a lower risk of diabetes.