Odd-chain Fatty Acids Research Articles

Hidradenitis Suppurativa from a Multi-Omic Scope.

Hidradenitis suppurativa (HS) is recognized as a systemic immune-mediated disease (IMID), sharing genetic and environmental risk factors with other IMIDs such as inflammatory bowel disease and psoriasis. Over time, correlating clinical findings with genetic, proteomic, and metabolomic results has been challenging due to diverse sampling methods, analysis techniques, and the use of variable clinical phenotype descriptions across studies. This review aims to summarize the results from various omics fields to explore the etiopathology of HS. Genetic studies highlight defects in Notch and γ-secretase signaling and inflammasome function. Syndromic HS involves specific mutations in autoinflammatory syndromes such as pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) and pyoderma gangrenosum, acne, and HS (PASH). Proteomic analyses reveal key inflammatory pathways indicating activation of both innate and adaptive immunity. Additionally, microbiome studies show an increased presence of anaerobes like Prevotella in HS lesions and a decreased presence of commensals such as Staphylococcus epidermidis. Gut microbiota dysbiosis, particularly involving Ruminococcus gnavus and Clostridium ramosum, is associated with HS. Moreover, metabolomic profiling indicates dysregulated tryptophan catabolism and lipid metabolism, with increased 5-lipoxygenase-derived metabolites and odd-chain fatty acids suggesting bacterial involvement. In summary, despite advances, robust associations between genetics, proteomics, microbiome, and metabolomics in HS are still lacking. Integrating these datasets could identify new clinical phenotypes, genetic predispositions, microbial signatures, and therapeutic targets, enhancing personalized treatment strategies and biomarker discovery for HS classification, prognosis, and treatment response.

Galactooligosaccharides and Limosilactobacillus reuteri synergistically alleviate gut inflammation and barrier dysfunction by enriching Bacteroides acidifaciens for pentadecanoic acid biosynthesis

Ulcerative colitis (UC) is a debilitating inflammatory bowel disease characterized by intestinal inflammation, barrier dysfunction, and dysbiosis, with limited treatment options available. This study systematically investigates the therapeutic potential of a synbiotic composed of galactooligosaccharides (GOS) and Limosilactobacillus reuteri in a murine model of colitis, revealing that GOS and L. reuteri synergistically protect against intestinal inflammation and barrier dysfunction by promoting the synthesis of pentadecanoic acid, an odd-chain fatty acid, from Bacteroides acidifaciens. Notably, the synbiotic, B. acidifaciens, and pentadecanoic acid are each capable of suppressing intestinal inflammation and enhancing tight junction by inhibiting NF-κB activation. Furthermore, similar reduction in B. acidifaciens and pentadecanoic acid levels are also observed in the feces from both human UC patients and lipopolysaccharide-induced intestinal inflammation in pigs. Our findings elucidate the protective mechanism of the synbiotic and highlight its therapeutic potential, along with B. acidifaciens and pentadecanoic acid, for UC and other intestinal inflammatory disorders.

Supplementation of isoacids to lactating dairy cows fed low or high forage diets: Effects on performance, digestibility, and milk fatty acid profile

Our objective was to determine the effects of isoacids (ISO) on the lactation performance, digestibility, and milk fatty acid (FA) profile of Holstein cows fed 2 forage NDF levels (FL). The study was 10-wk long (including 2-wk for covariate) utilizing a randomized complete block design. Sixty-four mid-lactating Holstein cows [662 ± 71 kg BW, 119 ± 51 DIM, 2 ± 0.9 parity] were blocked by parity, DIM, and prior milk yield (MY) for multiparous cows or genetic merit for primiparous cows, and randomly assigned to 1 of the 4 diets (n = 16). Diets were arranged as a 2 × 2 factorial, with 2 FL containing 21 (HF) and 17% forage NDF (LF) without (WIA) or with ISO supplementation (IA, 7.85 mmol/kg DM and 3.44 mmol/kg DM for isobutyrate and 2-methylbutyrate, respectively). Diets were balanced for similar NEL (1.58 Mcal/kg DM), CP (16.0%) and total NDF (27.2%). Feed intake and MY were recorded daily. Nutrient digestibility for each cow was determined using indigestible NDF as a marker, and fecal samples were collected at 8-time points (4 h intervals between samples). Individual cow milk samples composited over a 10-wk period were analyzed using gas chromatography for FA profile. The statistical model included FL, ISO, and FL × ISO as fixed effects and block as a random effect (lme4 in R). The ISO did not affect DMI (P = 0.13), while LF had greater DMI than HF diets (27.8 vs. 26.0 kg/d; P < 0.01). However, ISO increased MY (34.7 vs. 37.2 kg/d; P < 0.01) and ECM (41.9 vs. 39.0 kg/d; P < 0.01) by 7% in HF but not in the LF diet, suggesting FL × ISO interaction (P = 0.04). Interestingly, ISO increased ADG (0.4 kg/d) but decreased MUN by 9% only in LF diet as indicated by FL × ISO interaction (P < 0.01). Additionally, ISO increased DM, OM, NDF, and CP digestibility by 10-24% in HF (P < 0.01), but not in LF (FL × ISO; P > 0.05). As expected, ISO increased milk odd chain FA profiles in the IA groups irrespective of FL, e.g., the IA had greater C15:0 (1.87 vs. 1.54 g/100g FA; P = 0.03) and a tendency to be greater C17:0 levels (0.86 vs. 0.76 g/100g FA; P = 0.05) compared with WIA groups. Overall, ISO improved MY and nutrient digestibility in the HF whereas it increased ADG and decreased MUN in LF diet. Additionally, ISO increased milk odd chain FA (C15:0 and C17:0) regardless of FL.

Relationship between pyrimidines, purines and fatty acids in milk of dairy cows fed distinct carbohydrate types: a metabolomic approach

The aim of this research was to evaluate changes in the milk metabolome of dairy cows fed different carbohydrate types from silages and concentrates, with special focus on purines and pyrimidines, likely associated with the microbial activity in the rumen. Furthermore, the relationship between the milk fatty acids and pyrimidine and purine metabolism retrieved in milk was investigated for potential correlations between these 2 groups of potential milk biomarkers. Twenty-four lactating dairy cows were used in a crossover design, where each cow received 2 of 4 diets. Diets were formulated based on a 2 by 2 factorial arrangement, using either grass-clover or corn silage as a forage source, and barley or dried beet pulp in the concentrate fraction. Fatty acids and LC-MS metabolome of the milk were analyzed. The milk metabolome and fatty acid concentration could differentiate the 4 diets used in the trial, while the milk metabolome alone could only differentiate the 2 silage types. Milk odd-chain fatty acids (C17:1 and C17:0) were correlated with pyrimidine and purine derivatives, with uric acid being significantly higher in milk samples associated with corn silage diets. Therefore, the results indicate potential differences in microbial protein synthesis between the diets, but a validation with actual ruminal microbial protein synthesis and investigation in digestive biofluids are necessary for further confirmation.

The Long-Term Effect of Kidney Transplantation on the Serum Fatty Acid Profile

Background: Epidemiologic evidence has demonstrated the prevalence of metabolic disorders and increased cardiovascular risk related to lipid metabolism disorders in kidney transplant recipients. Therefore, it is of great importance to understand lipid alterations and to look for ways to reduce cardiovascular risk in this patient group. Methods: Our study included 25 patients with chronic kidney disease undergoing kidney transplantation (KTx). Three blood samples were taken from each patient: before KTx, 3 months after KTx and 6–12 months after KTx. A series of biochemical blood tests and a detailed analysis of the serum fatty acid profile were performed. Results: In our previous study, the effects of kidney transplantation on serum fatty acid (FA) profile 3 months after the procedure were investigated. The current study shows the longer-term (6–12 months) effects of the procedure on the serum FA profile. We found that although n-3 polyunsaturated FA levels started to decrease 3 months after surgery, they normalized over a longer period of time (6–12 months). Furthermore, we observed a strong decrease in ultra-long-chain FAs and an increase in odd-chain FAs over a longer time after kidney transplantation. All of the above FAs may have an important impact on human health, including inflammation, cardiovascular risk or cancer risk. Conclusions: The changes in serum FA profiles after kidney transplantation are a dynamic process and that more detailed studies could provide an accurate indication for supplementation with some FAs or diet modification.

Cow's Milk Bioactive Molecules in the Regulation of Glucose Homeostasis in Human and Animal Studies.

Obesity disrupts glucose metabolism, leading to insulin resistance (IR) and cardiometabolic diseases. Consumption of cow's milk and other dairy products may influence glucose metabolism. Within the complex matrix of cow's milk, various carbohydrates, lipids, and peptides act as bioactive molecules to alter human metabolism. Here, we summarize data from human studies and rodent experiments illustrating how these bioactive molecules regulate insulin and glucose homeostasis, supplemented with in vitro studies of the mechanisms behind their effects. Bioactive carbohydrates, including lactose, galactose, and oligosaccharides, generally reduce hyperglycemia, possibly by preventing gut microbiota dysbiosis. Milk-derived lipids of the milk fat globular membrane improve activation of insulin signaling pathways in animal trials but seem to have little impact on glycemia in human studies. However, other lipids produced by ruminants, including polar lipids, odd-chain, trans-, and branched-chain fatty acids, produce neutral or contradictory effects on glucose metabolism. Bioactive peptides derived from whey and casein may exert their effects both directly through their insulinotropic effects or renin-angiotensin-aldosterone system inhibition and indirectly by the regulation of incretin hormones. Overall, the results bolster many observational studies in humans and suggest that cow's milk intake reduces the risk of, and can perhaps be used in treating, metabolic disorders. However, the mechanisms of action for most bioactive compounds in milk are still largely undiscovered.

Differential utilization of vitamin B12-dependent and independent pathways for propionate metabolism across human cells

Propionic acid links the oxidation of branched-chain amino acids and odd-chain fatty acids to the TCA cycle. Gut microbes ferment complex fiber remnants, generating high concentrations of short chain fatty acids, acetate, propionate and butyrate, which are shared with the host as fuel sources. Analysis of vitamin B12-dependent propionate utilization in skin biopsy samples has been used to characterize and diagnose underlying inborn errors of cobalamin (or B12) metabolism. In these cells, the B12-dependent enzyme, methylmalonyl-CoA mutase (MMUT), plays a central role in funneling propionate to the TCA cycle intermediate, succinate. Our understanding of the fate of propionate in other cell types, specifically, the involvement of the β-oxidation-like and methylcitrate pathways, is limited. In this study, we have used [14C]-propionate tracing in combination with genetic ablation or inhibition of MMUT, to reveal the differential utilization of the B12-dependent and independent pathways for propionate metabolism in fibroblast versus colon cell lines. We demonstrate that itaconate can be used as a tool to investigate MMUT-dependent propionate metabolism in cultured cell lines. While MMUT gates the entry of propionate carbons into the TCA cycle in fibroblasts, colon-derived cell lines exhibit a quantitatively significant or exclusive reliance on the β-oxidation-like pathway. Lipidomics and metabolomics analyses reveal that propionate elicits pleiotropic changes, including an increase in odd-chain glycerophospholipids, and perturbations in the purine nucleotide cycle and arginine/nitric oxide metabolism. The metabolic rationale and the regulatory mechanisms underlying the differential reliance on propionate utilization pathways at a cellular, and possibly tissue level, warrant further elucidation.

Novel odd-chain cyclopropane fatty acids: detection in a mammalian lipidome and uptake by hepatosplanchnic tissues

Microbe-produced molecules (xenometabolites) found in foods or produced by gut microbiota are increasingly implicated in microbe-microbe and microbe-host communication. Xenolipids, in particular, are a class of metabolites for which the full catalog remains to be elaborated in mammalian systems. We and others have observed that cis-3,4-methylene-heptanoylcarnitine is a lipid derivative that is one of the most abundant medium-chain acylcarnitines in human blood, hypothesized to be a product of incomplete β-oxidation of one or more “odd-chain” long-chain cyclopropane fatty acids (CpFAs). We deduced two possible candidates, cis-11,12-methylene-pentadecanoic acid (cis-11,12-MPD) and cis-13,14-methylene-heptadecanoic acid (cis-13,14-MHD). Authentic standards were synthesized: cis-11-pentadecenoic acid and cis-13-heptadecenoic acid were generated (using Jones reagent) from cis-11-pentadecene-1-ol and cis-13-heptadecene-1-ol, respectively, and these were converted to CpFAs via a reaction involving diiodomethane. Using these standards in mass spectrometry analyses, we determined the presence/absence of cis-11,12-MPD and cis-13,14-MHD in archived piglet biospecimens. Both CpFAs were detected in rectal contents of sow and soy-fed piglets. Archived mass spectra were analyzed post hoc from a second independent study that used tissue-specific catheterization to monitor net metabolite flux in growing pigs. This confirmed the presence of both CpFAs in plasma and revealed a significant net uptake of the odd-chain CpFAs across the splanchnic tissue bed and liver. The results confirm that the novel xenolipids cis-11,12-MPD and cis-13,14-MHD can be components of the mammalian lipidome and are viable candidate precursors of cis-3,4-methylene-heptanoylcarnitine produced from partial β-oxidation in liver or other tissues.

The attenuated hepatic clearance of propionate increases cardiac oxidative stress in propionic acidemia.

Propionic acidemia (PA), arising from PCCA or PCCB variants, manifests as life-threatening cardiomyopathy and arrhythmias, with unclear pathophysiology. In this work, propionyl-CoA metabolism in rodent hearts and human pluripotent stem cell-derived cardiomyocytes was investigated with stable isotope tracing analysis. Surprisingly, gut microbiome-derived propionate rather than the propiogenic amino acids (valine, isoleucine, threonine, and methionine) or odd-chain fatty acids was found to be the primary cardiac propionyl-CoA source. In a Pcca-/-(A138T) mouse model and PA patients, accumulated propionyl-CoA and diminished acyl-CoA synthetase short-chain family member 3 impede hepatic propionate disposal, elevating circulating propionate. Prolonged propionate exposure induced significant oxidative stress in PCCA knockdown HL-1 cells and the hearts of Pcca-/-(A138T) mice. Additionally, Pcca-/-(A138T) mice exhibited mild diastolic dysfunction after the propionate challenge. These findings suggest that elevated circulating propionate may cause oxidative damage and functional impairment in the hearts of patients with PA.

Use of crude glycerin in dairy goat feeding and its effects on milk and cheese performance and quality

This study aimed to assess the impact of stepwise dietary inclusion of crude glycerin (CG) on the productive traits of dairy goats and the quality of their milk and cheese. Sixteen Saanen goats, averaging 55 ± 6 kg live weight and 45 days in milk, were allocated into four simultaneous Latin squares (4×4) and fed on diets containing 0 (control), 50, 100, and 150 g/kg of CG in the dry matter (DM). A linear decrease (P < 0.05) was observed in DM, crude protein (CP), neutral detergent fiber (NDF), and non-fibrous carbohydrates intake with increasing CG levels in the diet, with a significant reduction (P < 0.05) noted at 100 and 150 g/kg of CG. Additionally, CP digestibility, nitrogen balance, and plasma urea nitrogen decreased (P < 0.05) with CG inclusion. Milk yield corrected for 3.5 % fat, total solids content, and total fatty acid (FA) amounts in goat milk decreased (P < 0.05) with 100 and 150 g/kg of CG. Furthermore, inclusion of 150 g/kg of CG decreased (P < 0.05) fat content in "coalho" cheese, although cheeses from goats fed up to 50 g/kg of CG showed superior (P < 0.05) appearance, global impression, and purchase intention. The CG inclusion increased (P < 0.05) short and odd-chain FA contents while decreasing (P < 0.05) long-chain and polyunsaturated FA levels in goat milk. Overall, we recommend incorporating up to 50 g/kg of CG in dairy goat diets as it does not affect milk and "coalho" cheese performance and quality.

Fasting alleviates metabolic alterations in mice with propionyl-CoA carboxylase deficiency due to Pcca mutation

Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca-/-(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca-/-(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.

Supplementing flaxseed meal with sucrose, flaxseed oil, or both: Effects on milk enterolactone, ruminal microbiota profile, production performance, and nutrient utilization in dairy cows

Flaxseed is the richest source of secoisolariciresinol diglucoside, which is converted by ruminal microorganisms primarily to the mammalian lignan enterolactone. Our objective was to investigate the effect of diets containing soybean meal or flaxseed meal (FM) supplemented with sucrose, flaxseed oil, or both, on milk enterolactone concentration yield, diversity, and relative abundance of ruminal bacterial taxa, ruminal fermentation profile, production performance, milk fatty acids (FA) yield, and nutrient utilization in dairy cows. Sixteen Holstein cows (8 multiparous [4 ruminally cannulated] and 8 primiparous) averaging (mean ± SD) 134 ± 54.1 DIM and 679 ± 78.9 kg of BW in the beginning of the study were assigned to treatment sequences in a replicated 4 × 4 Latin square design. Each experimental period lasted 25 d, with 18 d for diet adaptation and 7 d for data and sample collection. Diets were formulated to contain a 60:40 forage:concentrate ratio and included the following (DM basis): (1) 8% soybean meal and 23% ground corn (SBM); (2) 15% FM, 10.7% ground corn, and 5% sucrose (FLX+S); (3) 15% FM, 15.4% ground corn, and 3% flaxseed oil (FLX+O); and (4) 15% FM, 10.2% ground corn, 5% sucrose, and 3% flaxseed oil (FLX+SO). Compared with SBM, the concentration and yield of milk enterolactone increased in cows fed the FM diets but did not differ among FLX+S, FLX+O, and FLX+SO. The relative abundances of the phyla Firmicutes, Verrucomicrobiota, and Actinobacteriota, and those of the bacterial genera Lachnospiraceae NK3A20 group, Eubacterium coprostanoligenes group, Anaeromusa-Anaeroarcus, WCHB1-41, and p-251-o5 decreased, whereas Prevotella and NK4A214 group increased when comparing SBM against at least 1 diet containing FM. Furthermore, the relative abundances of Firmicutes and Actinobacteriota and those of Prevotella, Lachnospiraceae NK3A20 group, Eubacterium coprostanoligenes group, Acetitomaculum, Lachnospiraceae unclassified, NK4A214 group, and Anaeromusa-Anaeroarcus changed (increased or decreased) across the FLX+S, FLX+O, and FLX+SO diets. However, all these changes in the relative abundance of the ruminal bacterial taxa were not conclusively associated with the effect of diets on milk enterolactone. Diets did not affect ruminal pH and concentrations of NH3-N and total VFA. Dry matter intake and yields of milk, milk fat, and milk true protein all decreased in cows fed FLX+O or FLX+SO. Yields of milk total odd-chain FA, branched-chain FA, total <16C FA, and total 16C FA decreased with feeding FLX+O and FLX+SO. The apparent total-tract digestibilities of DM and OM were lowest in the FLX+S and FLX+O diets, with CP and ADF digestibilities lowest in cows receiving FLX+S or FLX+O, respectively. Urinary excretion of total N was lowest with feeding SBM. Contrarily, diets did not affect the urinary excretion of total purine derivatives. In brief, despite the effect of diets on the relative abundance of several ruminal microbiota phyla and genera, we were unable to conclusively associate these changes with increased milk enterolactone in FM-containing diets versus SBM.

Propionate prevents loss of the PDIM virulence lipid in Mycobacterium tuberculosis.

Phthiocerol dimycocerosate (PDIM) is an essential virulence lipid of Mycobacterium tuberculosis. In vitro culturing rapidly selects for spontaneous PDIM-negative mutants that have attenuated virulence and increased cell wall permeability, thus impacting the relevance of experimental findings. PDIM loss can also reduce the efficacy of the BCG Pasteur vaccine. Here we show that vancomycin susceptibility can rapidly screen for M. tuberculosis PDIM production. We find that metabolic deficiency of methylmalonyl-CoA impedes the growth of PDIM-producing bacilli, selecting for PDIM-negative variants. Supplementation with odd-chain fatty acids, cholesterol or vitamin B12 restores PDIM-positive bacterial growth. Specifically, we show that propionate supplementation enhances PDIM-producing bacterial growth and selects against PDIM-negative mutants, analogous to in vivo conditions. Our study provides a simple approach to screen for and maintain PDIM production, and reveals how discrepancies between the host and in vitro nutrient environments can attenuate bacterial pathogenicity.

Plasma Branched-Chain Fatty Acids Reflect Dairy-Fat Intake in a Pilot Clinical Trial in Individuals with Prediabetes

Epidemiological studies often rely on fatty acid (FA) biomarkers of dairy-fat intake to represent diet history and to establish associations with cardiometabolic risk factors. However, a more robust body of direct research is needed to validate the currently utilized FA biomarkers as accurate representations of dairy-fat intake. Thus, our objectives were to i) compare the plasma FA profile of individuals with prediabetes following the consumption of a diet with full-fat (3.25%) yogurt (FFY diet) or non-fat yogurt (NFY diet) to evaluate their validity of currently utilized biomarkers and ii) identify additional FAs to serve as potential biomarkers. We hypothesized that the proportion of the unique dairy-derived FAs including odd-chain FAs (13:0, 15:0, 17:0, 19:0, 21:0, 23:0), branched-chain FAs ( iso-13:0, anteiso-13:0, iso-14:0, iso-15:0, anteiso-15:0, iso-16:0, iso-17:0, anteiso-17:0, iso-18:0), and the trans-FAs 16:1 trans-9 and 18:1 trans-11 would increase in plasma total lipids following the consumption of three daily servings of full-fat yogurt for three weeks. Our 8-week randomized, double-masked, controlled crossover study included six men and seven women aged 45-75 years old. Each experimental diet period, NFY diet and FFY diet, was three weeks in length. The arithmetic difference in fat (8% energy) between the NFY diet (30% fat) and the FFY diet (38% fat) was solely due to the dairy fat in the full-fat yogurt. Following each experimental diet period, fasting plasma samples were taken and analyzed for FA composition of plasma total lipids using gas-liquid chromatography. Consumption of the FFY diet resulted in no change in the proportion of total odd-chain FAs or the individual FAs 16:1 trans-9 and 18:1 trans-11, but the proportion of total branched-chain FAs was greater in response to the FFY diet ( P &lt; 0.01). For individual odd-chain and branched-chain FAs, the proportions of iso-17:0 and anteiso-17:0 were greater in response to the FFY diet ( P &lt; 0.01 for both); however, there were no differences in anteiso-15:0 or iso-15:0 proportions by diet. Results from this pilot trial suggest that commonly utilized FA biomarkers may not be suffciently robust to represent dairy-fat intake. Branched-chain FAs should be further explored for alternatives. Funding for this project was provided by National Dairy Council Nutrition Research Funding, a USDA Agriculture and Food Research Initiative National Institute of Food and Agriculture Predoctoral Fellowship, and a fellowship from the University of Vermont’s Food Systems Research Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Fat and fatty acids - a scoping review for Nordic Nutrition Recommendations 2023.

Two de novo NNR2022 systematic reviews (SRs) as well as 21 qualified SRs (qSRs) were available. A literature search yielded an additional ~70 SRs, meta-analyses and biomarker papers. Diets lower in total fat are associated with reductions in body weight and blood pressure compared with diets higher in total fat in adults. Partial replacement of saturated fatty acid (SFA) with n-6 polyunsaturated fatty acid (PUFA) improves blood lipid profile, decreases the risk of cardiovascular disease (CVD), improves glucose-insulin homeostasis and may decrease the risk of total mortality. Long-chain n-3 PUFAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) decrease triglycerides and are associated with lower risk of CVD. Dietary PUFAs, both n-3 and n-6, may be associated with reduced risk of type 2 diabetes (T2D). There is inconclusive evidence to suggest that the type of dietary fat is associated with blood pressure, risk of hypertension or musculoskeletal health. Higher intake of total PUFA is associated with lower mortality from any cancer. Long-chain n-3 PUFA is associated with reduced risk of breast cancer, whereas biomarker levels of n-6 PUFA are associated with lower risk of any cancer. Intake of long-chain n-3 PUFA during pregnancy increases length of gestation and child birth weight and reduces the risk of preterm delivery, but there is inconclusive evidence to suggest that it may influence child neurodevelopment, growth or development of allergic disease. In studies with higher versus lower dietary cholesterol intake levels, total blood cholesterol increased or were unaffected by the dietary cholesterol, resulting in inconclusive results. Trans fatty acid (TFA), regardless of source, impairs blood lipid profile compared to unsaturated fat. In observational studies, TFA is positively associated with CVD and total mortality but whether associations differ by source is inconclusive. Ruminant TFA, as well as biomarker levels of odd-chain fatty acids, might be associated with lower risk of T2D.

Concentration and composition of odd-chain fatty acids in phospholipids and triacylglycerols in Chinese human milk throughout lactation.

Human milk represents the gold standard for infant nutrition, with approximately 50% of the energy in human milk derived from lipids. Odd-chain fatty acids (OCFAs) have been recognized as a category of bioactive milk fatty acids in recent research; however, limited data exist on OCFAs in human milk. This study collected human milk samples spanning the postpartum period from 0 to 400 days. Phospholipids containing OCFAs (PL-OCFAs) were determined in 486 human milk samples using hydrophilic liquid chromatography-electrospray ionization-triquadrupole-mass spectrometry. Triacylglycerols containing OCFAs (TAG-OCFAs) were analyzed in 296 human milk samples using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. The average total concentration of PL-OCFA ranged from 30.89 ± 14.27 mg L-1 to 93.48 ± 36.55 mg L-1 during lactation, and the average total TAG-OCFA content ranged from 103.1 ± 147.15 mg L-1 to 965.41 ± 651.67 mg L-1. Despite the lower absolute concentration of PL-OCFA, its relative concentration (8.75%-11.75%) was significantly higher than that of TAG-OCFA (0.37%-1.85%) throughout lactation. PC-OCFA, SM-OCFA and PE-OCFA are major sub-classes of PL-OCFA. Furthermore, C17:0 was the major chain length in both PL-OCFA and TAG-OCFA, followed by C15:0. C17:1 was characteristic of TAG-OCFA, while long-chain fatty acids C19:0, C21:0 and C23:0 were characteristic of PL-OCFA. Our findings highlighted the importance of bioactive lipids in human milk, suggesting that OCFAs could be targeted in future studies in relation to the health and development of infants.

Pentadecanoic acid (C15:0, PA) induces mild maternal glucose intolerance and promotes the growth of the offspring partly through up-regulating liver PPARα and MAPK signaling pathways.

Gestational diabetes mellitus (GDM) is one of the most common metabolic disturbances during pregnancy, which poses a serious threat to both maternal and offspring health. Pentadecanoic acid (C15:0, PA) is one of the most common odd-chain saturated fatty acids (OCS-FAs). However, its safety and nutritional value are yet to be verified. Herein, we provide a systematic assessment of the effects of PA on maternal and progeny health and insulin sensitivity for the first time. Our results showed that consumption of 1% PA during pregnancy could increase the contents of PA and heptadecanoic acid (C17:0) in maternal plasma, fetal tissue and offspring plasma, but it had no effect on embryonic development. During pregnancy, PA treatment caused mild insulin resistance, while it had little effect on the maternal body composition. During lactation, PA treatment caused mild insulin resistance and oxidative stress. Maternal body fat deposition was also reduced, but the growth rate of the offspring was faster. It is worth noting that PA treatment decreased plasma and liver TG content and increased the antioxidant capacity of the offspring. The effect of PA on the transcription and expression genes in the liver of pregnant mice was investigated using RNA-seq. PPARα and MAPK signaling pathways, both closely related to lipolysis, inflammation, oxidative stress, and insulin resistance were significantly increased. The expression of c-JUN, ERK, JNK and P65 proteins was also significantly up-regulated. In conclusion, our results suggest that 1% PA can induce a mild decrease in the maternal glucose tolerance and lipolysis mainly by activated MAPK and PPARα signaling. Moreover, low concentrations of PA may be an effective nutrient to alleviate the oxidative stress and reduce blood lipid levels of offspring.

Systemic analysis shows that cold exposure modulates triglyceride accumulation and phospholipid distribution in mice.

Environmental exposure to cold is increasingly being associated with changes in metabolism. We developed and tested the hypothesis that exposure to cold drives systemic effects in lipid metabolism. Specifically, (i) that energy storage and provision adapts to the cold by altering triglyceride distribution and (ii) that membranes adapt to cold conditions by becoming more unsaturated. These hypotheses were designed to identify the underlying mechanisms that govern the response of mammalian systems to cold. To test these hypotheses, we used a metabolic network analysis. An established model of cold exposure was used, from which lipidomics data that represents the system was collected. The network analysis showed that triglyceride metabolism is altered on exposure to cold, with several smaller effects that are not straightforward, such as changes to the abundance and distribution of odd chain fatty acids. The range and profile of phosphatidylcholine and phosphatidylinositol were modified, but there was little change in phosphatidylethanolamine or sphingomyelin. These results support the hypothesis, and show that exposure to cold is a system-wide phenomenon that requires or drives changes across a range of metabolic pathways.

Cola rostrata K. Schum. constituents induce cytotoxicity through reactive oxygen species generation and mitochondrial membrane depolarisation

Aim: While the traditional use of Cola rostrata in treating illnesses and diseases has not been reported, the presence of cytotoxic principles has been reported in phylogenetically and biogeographically related species within the Cola genus. This study, therefore, evaluated the cytotoxic potential of extracts of the plant, and the associated cellular and molecular mechanisms. Methods: Activity-based fractionation of the extracts was carried out and cytotoxicity was assessed in the human cervical cancer cell line, HeLa, and the transformed human lung cell line, MRC5-SV2, using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay complemented with brightfield imaging. The 2ʼ,7ʼ-dichlorofluorescein diacetate (DCFDA) assay was used to assess induction of cellular reactive oxygen species (ROS), while flow cytometry of 5,5ʼ,6,6ʼ-tetrachloro-1,1ʼ,3,3ʼ-tetraethyl-imidacarbocyanine iodide (JC-1)-stained cells assessed the loss of mitochondrial membrane potential (∆ΨM). Gas chromatography-mass spectrometry (GC-MS) analysis was carried out on an active fraction. Results: Extracts of the fruit epicarp and leaf were cytotoxic against the cell lines. Half-maximal inhibitory concentration (IC50) values for the 48 h cytotoxicity of the ethanol extract of the epicarp against HeLa and MRC5-SV2 cells were 48.0 μg/mL ± 12.1 μg/mL and 40.4 μg/mL ± 7.2 μg/mL, respectively, while fractions from second-level partitioning of the hexane fraction of the leaf extract elicited cytotoxicity with IC50 values ranging from 12.8 μg/mL ± 1.0 μg/mL to 39.6 μg/mL ± 7.2 μg/mL in both cell lines, following 48 h treatment. GC-MS revealed the presence of seventeen compounds in a hexane fraction of the leaf extract, including even- and odd-chain fatty acids, the most abundant of which were n-hexadecanoic acid, decanoic acid 10-(2-hexylcyclopropyl); and octadecanoic acid. The mechanisms of cytotoxicity of most active fractions involved generation of ROS and mitochondrial membrane depolarisation. Conclusions: The findings show that C. rostrata is rich in cytotoxic phytochemicals which could be isolated for developing new anti-cancer agents.

CytogeneticsRapid Resolution of Medically Relevant Polyunsaturated, Very Long-, Odd-, and Branched-Chain Fatty Acid Methyl Esters

Abstract Fatty acids play an important role in human health and disease. Nearly 100 years ago, the Burrs demonstrated that polyunsaturated fatty acids (PUFAs) were essential for development; subsequent work uncovered the role of PUFAs as precursors to important signaling molecules such as prostaglandins, leukotrienes, and thromboxanes. Very long chain fatty acids (VLCFAs) originally sparked interest over 40 years ago for being elevated in humans with peroxisomal disorders. More recent studies have shown that VLCFAs are elevated in healthy human controls, compared to their diabetic counterparts. In a similar vein, odd chain fatty acids (OCFAs) and branched-chain fatty acids (BCFAs) of the iso and anteiso variety are higher in humans with insulin sensitivity than in insulin resistant individuals. These families of fatty acids are most frequently analyzed as their fatty acid methyl esters (FAMEs) by gas chromatography (GC). Regrettably, even recently published methods resolving BCFAs from their linear correlates have run-times in excess of an hour and, in some cases, over 100 minutes. Objective: The goal of this study was to decrease the GC run-time for the analysis of FAMEs relevant to human health and disease. Methods: Baseline resolution of FAMEs required careful combination of the right gas chromatograph, column dimensions, stationary phase, carrier gas, and temperature programming. Results: We cleanly resolved the FAMEs of all common polyunsaturated, very long-, odd-, and branched-chain fatty acids with baseline separation in only ~15 minutes – a 4-fold improvement over many existing methods. Conclusion: This method will significantly improve analysis of fatty acids in health and disease, especially in large-scale, clinical studies, by quartering the run time necessary to resolve PUFAs, VLCFAs, OCFAs, and BCFAs.