Plasma Concentrations Of Fatty Acids Research Articles

Saturated fatty acid concentrations are predictive of insulin sensitivity and beta cell compensation in dogs

Chronic feeding of a high fat diet (HFD) in preclinical species induces broad metabolic dysfunction characterized by body weight gain, hyperinsulinemia, dyslipidemia and impaired insulin sensitivity. The plasma lipidome is not well characterized in dogs with HFD-induced metabolic dysfunction. We therefore aimed to describe the alterations that occur in the plasma lipid composition of dogs that are fed a HFD and examine the association of these changes with the clinical signs of metabolic dysfunction. Dogs were fed a normal diet (ND) or HFD for 12 weeks. Insulin sensitivity (SI) and beta cell compensation (AIRG) were assessed through an intravenous glucose tolerance test (IVGTT) and serum biochemistry was analyzed before the introduction of HFD and again after 12 weeks of continued ND or HFD feeding. Plasma lipidomics were conducted prior to the introduction of HFD and again at week 8 in both ND and HFD-fed dogs. 12 weeks of HFD feeding resulted in impaired insulin sensitivity and increased beta cell compensation measured by SI (ND mean: 11.5 [mU/l]–1 min–1, HFD mean: 4.7 [mU/l]–1 min–1) and AIRG (ND mean: 167.0 [mU/l]min, HFD mean: 260.2 [mU/l]min), respectively, compared to dogs fed ND over the same duration. Chronic HFD feeding increased concentrations of plasma lipid species and deleterious fatty acids compared to dogs fed a ND. Saturated fatty acid (SFA) concentrations were significantly associated with fasting insulin (R2 = 0.29), SI (R2 = 0.49) and AIRG (R2 = 0.37) in all dogs after 12 weeks, irrespective of diet. Our results demonstrate that chronic HFD feeding leads to significant changes in plasma lipid composition and fatty acid concentrations associated with metabolic dysfunction. High SFA concentrations may be predictive of deteriorated insulin sensitivity in dogs.

Increased hepatic glucagon sensitivity in totally pancreatectomised patients.

The metabolic phenotype of totally pancreatectomised patients includes hyperaminoacidaemia and predisposition to hypoglycaemia and hepatic lipid accumulation. We aimed to investigate whether the loss of pancreatic glucagon may be responsible for these changes. Nine middle-aged, normal-weight totally pancreatectomised patients, nine patients with type 1 diabetes (C-peptide negative), and nine matched controls underwent two separate experimental days, each involving a 150-min intravenous infusion of glucagon (4 ng/kg/min) or placebo (saline) under fasting conditions while any basal insulin treatment was continued. Glucagon infusion increased plasma glucagon to similar high physiological levels in all groups. The infusion increased hepatic glucose production and decreased plasma concentration of most amino acids in all groups, with more pronounced effects in the totally pancreatectomised patients compared with the other groups. Glucagon infusion diminished fatty acid re-esterification and tended to decrease plasma concentrations of fatty acids in the totally pancreatectomised patients but not in the type 1 diabetes patients. Totally pancreatectomised patients were characterised by increased sensitivity to exogenous glucagon at the level of hepatic glucose, amino acid, and lipid metabolism, suggesting that the metabolic disturbances characterising these patients may be rooted in perturbed hepatic processes normally controlled by pancreatic glucagon.

Metabolic flexibility in postmenopausal women: Hormone replacement therapy is associated with higher mitochondrial content, respiratory capacity, and lower total fat mass.

To investigate effects of hormone replacement therapy in postmenopausal women on factors associated with metabolic flexibility related to whole-body parameters including fat oxidation, resting energy expenditure, body composition and plasma concentrations of fatty acids, glucose, insulin, cortisol, and lipids, and for the mitochondrial level, including mitochondrial content, respiratory capacity, efficiency, and hydrogen peroxide emission. 22 postmenopausal women were included. 11 were undergoing estradiol and progestin treatment (HT), and 11 were matched non-treated controls (CONT). Peak oxygen consumption, maximal fat oxidation, glycated hemoglobin, body composition, and resting energy expenditure were measured. Blood samples were collected at rest and during 45 min of ergometer exercise (65% VO2peak). Muscle biopsies were obtained at rest and immediately post-exercise. Mitochondrial respiratory capacity, efficiency, and hydrogen peroxide emission in permeabilized fibers and isolated mitochondria were measured, and citrate synthase (CS) and 3-hydroxyacyl-CoA dehydrogenase (HAD) activity were assessed. HT showed higher absolute mitochondrial respiratory capacity and post-exercise hydrogen peroxide emission in permeabilized fibers and higher CS and HAD activities. All respiration normalized to CS activity showed no significant group differences in permeabilized fibers or isolated mitochondria. There were no differences in resting energy expenditure, maximal, and resting fat oxidation or plasma markers. HT had significantly lower visceral and total fat mass compared to CONT. Use of hormone therapy is associated with higher mitochondrial content and respiratory capacity and a lower visceral and total fat mass. Resting energy expenditure and fat oxidation did not differ between HT and CONT.

PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids.

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.

The Effect of Exercise Intensity on Carbohydrate Sparing Postexercise: Implications for Postexercise Hypoglycemia.

The purpose of this study was to determine the effect of exercise intensity on the proportion and rate of carbohydrate oxidation and glucoregulatory hormone responses during recovery from exercise. Six physically active participants completed 1hr of low-intensity (LI; 50% lactate threshold) or moderate-intensity (MI; 100% lactate threshold) exercise on separate days following a randomized counterbalanced design. During exercise and for 6hr of recovery, samples of expired air were collected to determine oxygen consumption, respiratory exchange ratio, energy expenditure, and substrate oxidation rates. Blood samples were also collected to measure glucoregulatory hormones (catecholamines, GH) and metabolites (glucose, free fatty acids, lactate, pH, and bicarbonate). During exercise, respiratory exchange ratio, energy expenditure, and the proportion and rate of carbohydrate (CHO) oxidation were higher during MI compared with LI. However, during recovery from MI, respiratory exchange ratio and the proportion and rate of CHO oxidation were lower than preexercise levels and corresponding LI. During exercise and early recovery, catecholamines and growth hormone were higher in MI than LI, and there was a trend for higher levels of free fatty acids in the early recovery from MI compared with LI. In summary, CHO oxidation during exercise increases with exercise intensity but there is a preference for CHO sparing (and fat oxidation) during recovery from MI exercise compared with LI exercise. This exercise intensity-dependent shift in substrate oxidation during recovery is explained, in part, by the pattern of change of key glucoregulatory hormones including catecholamines and growth hormone and plasma fatty acid concentrations.

The effect of dietary omega-3 fatty acid supplementation on fetal growth, piglet birth weight and plasma fatty acid concentrations, using docosahexaenoic acid in early gestation in sows

The objective of the study was to test the effect of the omega-3 fatty acid docosahexaenoic acid (DHA) on fetal and placental development as well as the birth weight of piglets. A total of 238 multiparous sows were allocated to either a control diet group or a DHA diet group with an omega-6 to omega-3 ratio of 9.8 and 2.4, respectively, from mating to day 43 of gestation. A blood sample was collected and back fat thickness was measured prior to mating, on days 14, 42 and 112 of gestation. On day 43 of gestation, 14 sows were slaughtered and measurements of fetuses and placentas were taken. Piglets in some litters were weighed individually at farrowing. Dietary treatment did not affect fetal characteristics and back fat thickness (P > 0.05). Dietary treatment increased the plasma concentrations of total omega-3 fatty acids in sows (P < 0.05). Sows fed the DHA diet had a shorter gestation length compared to the control sows (P < 0.05), but the number of born piglets was not affected (P > 0.05). The average piglet birth weight and the within-litter variation in birthweight were unaffected by dietary DHA (P > 0.05), however, sows fed DHA diet had fewer piglets under 800 g at birth compared to control sows (P < 0.05). In conclusion, addition of DHA decreased the dietary ratio of omega-6 to omega-3 fatty acids, increased plasma n-3 fatty acid concentrations in sows and decreased the number of piglets weighing under 800 g at birth.

Effects of dietary camelina, flaxseed, and canola oil supplementation on plasma fatty acid concentrations and health parameters in horses

Camelina (Camelina sativa) is a hardy, low-input oilseed crop that provides a rich source of the n-3 fatty acid, α-linolenic acid (ALA). The primary purpose of the present study was to assess the effects of dietary camelina oil (CAM) consumption on various health parameters, as compared to horses fed canola oil (OLA) or flax oil (FLX). Secondly, to determine how dietary CAM, FLX, and OLA alter circulating plasma total lipids across time. Thirty horses, from three separate herds, were used for this study [14.9 years ± 5.3 years; 544 ± 66 kg calculated BW (mean ± SD)]. After a 4-week gradual acclimation period using sunflower oil mixed with soaked hay cubes, horses were balanced by location, age, sex, weight, and breed and randomly allocated to one of three treatment oils (CAM, OLA, or FLX) at an inclusion of 370 mg of oil/kg BW/day. Horses had ad libitum access to hay and/or pasture for the duration of the study. Body condition score (BCS), BW, oil intake, complete blood counts, plasma biochemical profiles, and plasma total lipids were measured on weeks 0, 2, 4, 8, and 16 throughout the 16-week treatment period. BW, BCS, and oil intake were analyzed using an ANOVA using PROC GLIMMIX in SAS Studio. Complete blood counts and biochemical profiles were analyzed using an ANCOVA, and fatty acids were analyzed using an ANOVA in PROC MIXED in SAS Studio. No differences were observed among treatment groups for BW, BCS, oil intake, complete blood counts, and biochemical parameters. Individual fatty acids that differed among treatments and/or across time were largely reflective of the different FA profiles of the oils provided. Most notably, plasma ALA was greater for FLX than OLA, but neither differed from CAM (P = 0.01). Linoleic acid did not differ among treatments or over time (P > 0.05). The n-6:n-3 ratio decreased over time for both CAM and FLX, and ratios were lower for FLX than OLA at week 16, but not different from CAM (P = 0.02). These results suggest that dietary CAM had no adverse effects on health parameters and that daily supplementation of CAM and FLX at 370 mg of oil/kg BW/day induces positive changes (a decrease) in the n-6:n-3 status of the horse. Consequently, CAM may be considered as an alternative oil to FLX in equine diets.

Peripartum factors associated with variation in voluntary postpartum hay intake in dairy cows

The objective of this research was to assess variation in postpartum hay intake when offered alongside total mixed ration (TMR) as free choice, and identify factors related to the hay intake. Twenty multiparous cows were fed a closeup TMR (21.5% starch, 39.1% neutral detergent fiber [NDF] on a dry matter [DM] basis). After calving, cows were offered free choice timothy hay (61.6% NDF, 9.6% crude protein) in addition to a fresh cow TMR (26.8% starch, 33.0% NDF) for the first 5 d postpartum. Cows were fed individually with separate mangers for TMR and hay, each offered ad libitum. Prepartum DM intake (DMI) was recorded, and baseline blood samples were collected after calving, but before the first postpartum feeding. Free choice hay intake ranged from 0 to 4.7 kg/d (DM basis) or 0 to 55.2% (% of total DMI). Cows that consumed more hay (% of total DMI) from d 1 through 5 postpartum had lower DMI 2 d before calving (r = −0.63), and greater baseline concentrations of plasma β-hydroxybutyrate (r = 0.60) and serum haptoglobin (r = 0.68). Additionally, hay intake (% of total DMI) from d 1 through 5 postpartum tended to be positively related to baseline plasma fatty acid concentration (r = 0.41). These findings suggest that cows with lower intake before calving and cows with greater ketone production and inflammation at calving may consume more hay, when offered separate from TMR.

Air pollution exposure and plasma fatty acid profile in pregnant women: a cohort study.

Air pollution exposure was known to result in body impairments by inducing inflammation and oxidation. But little is known about the associations of air pollutants with plasma fatty acid profile which may play important roles in the impairment of air pollutants based on the related mechanism, especially in pregnant women. This study aimed to explore the relationships of air pollution exposure with plasma fatty acid profile and the potential effect modification by pre-pregnancy body mass index (BMI). Based on a cohort in Wuhan, China, we measured concentrations of plasma fatty acids of 519 pregnant women enrolled from 2013 to 2016 by gas chromatography-mass spectrometry (GC-MS). Levels of exposure to air pollutants (fine particulate matter (PM2.5), inhalable particles (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2), and carbon monoxide (CO)) were estimated by using spatial-temporal land use regression models and calculated in three periods (average concentrations during 1 day, 1 week, and 1 month before the phlebotomizing day in the first trimester). Per interquartile range increment of the levels of air pollution exposure 1 day before phlebotomizing was related to 1.21-2.01% increment of omega-6 polyunsaturated fatty acids (n-6PUFA) and 0.63-1.74% decrement of omega-3 polyunsaturated fatty acids (n-3PUFA). Besides, relationships above were kept robust in the analysis during 1 week and 1 month before phlebotomizing. In women with normal BMI, plasma fatty acid profile was observed to be more sensitive to air pollutants. Our study demonstrated that increment of exposure to air pollutants was associated with higher plasma n-6PUFA known to be pro-inflammatory and lower plasma n-3PUFA known to be anti-inflammatory, which was more sensitive in pregnant women with normal BMI. Our findings suggested that changes in plasma fatty acid profile should cause concerns and may serve as biomarkers in the further studies. Future studies are needed to validate our findings and elucidate the underlying mechanisms.

Inhibition of DHCR24 activates LXRα to ameliorate hepatic steatosis and inflammation.

Liver X receptor (LXR) agonism has theoretical potential for treating NAFLD/NASH, but synthetic agonists induce hyperlipidemia in preclinical models. Desmosterol, which is converted by Δ24-dehydrocholesterol reductase (DHCR24) into cholesterol, is a potent endogenous LXR agonist with anti-inflammatory properties. We aimed to investigate the effects of DHCR24 inhibition on NAFLD/NASH development. Here, by using APOE*3-Leiden. CETP mice, a well-established translational model that develops diet-induced human-like NAFLD/NASH characteristics, we report that SH42, a published DHCR24 inhibitor, markedly increases desmosterol levels in liver and plasma, reduces hepatic lipid content and the steatosis score, and decreases plasma fatty acid and cholesteryl ester concentrations. Flow cytometry showed that SH42 decreases liver inflammation by preventing Kupffer cell activation and monocyte infiltration. LXRα deficiency completely abolishes these beneficial effects of SH42. Together, the inhibition of DHCR24 by SH42 prevents diet-induced hepatic steatosis and inflammation in a strictly LXRα-dependent manner without causing hyperlipidemia. Finally, we also showed that SH42 treatment decreased liver collagen content and plasma alanine transaminase levels in an established NAFLD model. In conclusion, we anticipate that pharmacological DHCR24 inhibition may represent a novel therapeutic strategy for treatment of NAFLD/NASH.

Evaluation of plasma Short chain fatty acid levels as markers for Inflammatory bowel disease

Background Specific variations of short chain fatty acids in fecal samples have been shown for patients with inflammatory bowel disease. The aim of this study was to assess if Crohn’s disease and ulcerative colitis are associated with altered concentrations of short chain fatty acids also in blood plasma. Method Between 2016-2019, Swedish adults referred to a tertiary center for colonoscopy were asked to participate in a cross-sectional study. Individuals with Crohn’s disease or ulcerative colitis as well as individuals with no findings on the colonoscopy (defined as clean colon) were included in the study. Data on colonoscopy findings, blood samples (including haemoglobin, C-reactive protein and short chain fatty acid analysis) as well as a validated lifestyle questionnaire including 277 questions were collected from all participants. Linear regression was used to compare mean concentrations of short chain fatty acids between Crohn’s disease, ulcerative colitis and clean colon. Results The cohort consisted of 132 individuals with Crohn’s disease, 119 with ulcerative colitis and 205 with clean colon. In the crude model, succinic acid was significantly lower (p < 0.05) among patients with Crohn’s disease (mean 3.00 µM SE 0.10) and ulcerative colitis (mean 3.13 µM SE 0.10) in comparison to clean colon (mean 3.41 µM SE 0.08), however when adjusting for sex, age and diet the results did not remain statistically significant. No differences in plasma concentration of the other measured short chain fatty acids were detected. Conclusion Crohn’s disease and ulcerative colitis are not associated with altered short chain fatty acid concentrations in plasma. Further research is needed to confirm or refute our findings.

The Effect of Increasing Concentrations of Omega-3 Fatty Acids from either Flaxseed Oil or Preformed Docosahexaenoic Acid on Fatty Acid Composition, Plasma Oxylipin, and Immune Response of Laying Hens

BackgroundThere is a lack of nutrition guidelines for the feeding of omega-3 polyunsaturated fatty acids (PUFA) to laying hens. Knowledge as to whether the type and concentrations of α-linolenic acid (ALA) and/or docosahexaenoic acid (DHA) in the diet can make a difference to the birds’ immune responses when subjected to a lipopolysaccharide (LPS) challenge is limited. ObjectivesThe study was designed to determine the potential nutritional and health benefits to laying hens when receiving dietary omega-3 PUFA from either ALA or DHA. MethodsA total of 80 Lohmann LSL-Classic (white egg layer, 20 wk old) were randomly assigned to 1 of 8 treatment diets (10 hens/treatment), provided 0.2%, 0.4%, 0.6%, or 0.8% of total dietary omega-3 PUFA, provided as either ALA-rich flaxseed oil or DHA-enriched algal biomass. After an 8-wk feeding period, the birds were challenged with Escherichia coli-derived LPS (8 mg/kg; i.v. injection), with terminal sample collection 4 h after challenge. Egg yolk, plasma, liver, and spleen samples were collected for subsequent analyses. ResultsIncreasing dietary omega-3 supplementation yielded predictable responses in egg yolk, plasma, and liver fatty acid concentrations. Dietary intake of ALA contributed mainly to ALA-derived oxylipins. Meanwhile, eicosapentaenoic acid- and DHA-derived oxylipins were primarily influenced by DHA dietary intake. LPS increased the concentrations of almost all the omega-6 PUFA-, ALA-, and DHA-derived oxylipins in plasma and decreased hepatic mRNA expression of COX-2 and 5-LOX (P < 0.001) involved in the biosynthesis of oxylipins. LPS also increased mRNA expression of proinflammatory cytokine IFN-γ and receptor TLR-4 (P < 0.001) in the spleen. ConclusionsThese results revealed that dietary intake of ALA and DHA had unique impacts on fatty acid deposition and their derived oxylipins and inflammatory responses under the administration of LPS in laying hens.

Prospective Association Between Plasma Concentrations of Fatty Acids and Other Lipids, and Multimorbidity in Older Adults.

Biological mechanisms that lead to multimorbidity are mostly unknown, and metabolomic profiles are promising to explain different pathways in the aging process. The aim of this study was to assess the prospective association between plasma fatty acids and other lipids, and multimorbidity in older adults. Data were obtained from the Spanish Seniors-ENRICA 2 cohort, comprising noninstitutionalized adults ≥65 years old. Blood samples were obtained at baseline and after a 2-year follow-up period for a total of 1 488 subjects. Morbidity was also collected at baseline and end of the follow-up from electronic health records. Multimorbidity was defined as a quantitative score, after weighting morbidities (from a list of 60 mutually exclusive chronic conditions) by their regression coefficients on physical functioning. Generalized estimating equation models were employed to assess the longitudinal association between fatty acids and other lipids, and multimorbidity, and stratified analyses by diet quality, measured with the Alternative Healthy Eating Index-2010, were also conducted. Among study participants, higher concentrations of omega-6 fatty acids [coef. per 1-SD increase (95% CI) = -0.76 (-1.23, -0.30)], phosphoglycerides [-1.26 (-1.77, -0.74)], total cholines [-1.48 (-1.99, -0.96)], phosphatidylcholines [-1.23 (-1.74, -0.71)], and sphingomyelins [-1.65 (-2.12, -1.18)], were associated with lower multimorbidity scores. The strongest associations were observed for those with a higher diet quality. Higher plasma concentrations of omega-6 fatty acids, phosphoglycerides, total cholines, phosphatidylcholines, and sphingomyelins were prospectively associated with lower multimorbidity in older adults, although diet quality could modulate the associations found. These lipids may serve as risk markers for multimorbidity.

Microvascular constriction via fatty acid-mediated oxidative stress in humans

Purpose: Excess plasma lipids promote oxidative stress and impair vascular function. Herein, we examined microcirculatory blood flow and tested the hypothesis that a co-infusion of a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in retinal arteriole lumen diameter and increase resistance resulting from acutely elevated plasma lipids in healthy adults. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Retinal arteriole lumen diameter and resistance were assessed via Laser Speckle Flowgraphy at baseline and after infusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (lipid w/o AA: +36 ± 18 vs. lipid with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (lipid w/o AA: -1 ± 7 vs. lipid with AA: +26 ± 11 μmol/L, P=0.04). A significant increase in retinal arteriole resistance was observed following lipid infusion (lipid w/o AA: +20 ± 8 %, vs. lipid with AA: +17 ± 8 %, P=0.40). In accordance, lipid infusion significantly reduced retinal arteriole lumen diameter; however, co-infusion of AA reversed the lipid-mediated decrease in retinal arteriole diameter (lipid w/o AA: -3 ± 1 % vs. lipid with AA: +3 ± 2 %, P=0.01). Conclusions: Although microvascular resistance was increased, co-infusion of the antioxidant (ascorbic acid) reversed the fatty acid-mediated reduction in arteriole lumen diameter. Therefore, these preliminary findings suggest that acute elevations in plasma fatty acids induce microvascular constriction via an oxidative stress pathway. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 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.

Impaired endothelial function via fatty acids and the potential role of oxidative stress

Purpose: Excess plasma lipids promote oxidative stress and impaired vascular function. Therefore, we tested the hypothesis that a water-soluble antioxidant (ascorbic acid, AA) would attenuate reductions in endothelium-dependent dilation resulting from acutely elevated plasma fatty acids. Methods: A 20% IV fat emulsion (Intralipid) was administered for 2 hours to 8 healthy, middle-aged adults (2 men/6 women) with and without co-infusion of ascorbic acid (separate visits) in a double-blinded, crossover study design. Co-infusion of AA was administered at 0.06g/kg fat free mass in 100 ml saline at 5 mL/min over 20 min (bolus) followed by a drip infusion at 0.02 g/kg fat-free mass in 30 ml saline at 0.33 mL/min over 90 min. Endothelium-dependent dilation was assessed via brachial artery flow-mediated dilation (FMD) and expressed as % increase in diameter from baseline before forearm occlusion. Results: Lipid infusion significantly increase plasma fatty acid concentrations (w/o AA: +36 ± 18 vs. with AA: +41 ± 13 vs. μmol/L, P=0.84). AA infusion significantly increased plasma ascorbic acid concentrations (w/o AA: -1 ± 7 vs. with AA: +26 ± 11 μmol/L, P=0.04). Compared with baseline, FMD was significantly reduced following lipid infusion at (Baseline: 9.3 ± 1.1 vs. 20 min: 4.4 ± 1.3 vs. End: 5.3 ± 2.9 %, P=0.03), and when statistically adjusting for the stimulus (shear rate area under the curve) via analysis of covariance (P=0.02). FMD was also significantly reduced following lipid infusion with co-infusion of AA (Baseline: 8.9 ± 1.0 vs. 20 min: 5.3 ± 1.0 vs. End: 6.4 ± 3.8 %, P=0.02), but not when statistically adjusting for shear rate under the curve (P=0.08). Conclusions: Elevated plasma fatty acids impair endothelium-dependent dilation in healthy adults. However, co-administration of an antioxidant (ascorbic acid) limited the reduction in FMD when correcting for shear rate. Therefore, these preliminary data suggest that fatty acids may reduce endothelium-dependent dilation via an oxidative stress mechanism. Funding and support: R01HL159370-01 (S.W.H.). This work was also supported by a CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# UL1TR002366). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or CTSA. This is the full abstract presented at the American Physiology Summit 2023 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.

Effects of dietary organic acid and pure botanical supplementation on growth performance and circulating measures of metabolic health in Holstein calves challenged by heat stress

To evaluate the effects of heat stress environmental conditioning and dietary supplementation with organic acid and pure botanicals (OA/PB) on growth in dairy calves, we enrolled 62 bull (noncastrated) and heifer calves in a study with a completely randomized design. Calves were assigned to 1 of 5 groups (n = 11 to 14/group): (1) thermoneutral conditions (TN-Con), (2) HS conditions (HS-Con), (3) thermoneutral conditions and pair-fed to match nutrient intake with HS-Con (TN-PF), (4) HS with low-dose OA/PB [75 mg/kg of body weight (BW); 25% citric acid, 16.7% sorbic acid, 1.7% thymol, 1.0% vanillin, and 55.6% triglyceride; HS-Low], or (5) HS with high-dose OA/PB (150 mg/kg of BW; HS-High). Supplements were delivered as a twice-daily bolus via the esophagus from wk 1 through 13 of life; all calves, including those on the control treatments, received an equivalent amount of triglyceride used for microencapsulation. Calves were raised in TN conditions from birth until weaning. After weaning, calves (62 ± 2 d; 91 ± 10.9 kg of BW) were transported to a new facility and remained in TN conditions [temperature-humidity index (THI): 60 to 69] for a 7-d covariate period. Thereafter, calves remained in TN or were moved to HS conditions (THI: diurnal change 75 to 83 during night and day, respectively) for 19 d. Clinical assessments were performed thrice daily, BW was recorded weekly, and blood was sampled on d 1, 2, 3, 8, 15, and 19. Upon experiment completion, calves from HS-Con and TN-Con were euthanized, and hot carcass and visceral organ weights were recorded. The mixed model included calf as a random effect; treatment, day, hour (when appropriate) as fixed effects, and the interactions of treatment × day and treatment × hour (when appropriate). Rectal and skin temperatures and respiration rates were greater in HS-Con than in TN-Con. During heat stress exposure, dry matter intake (DMI), average daily gain (ADG), and gain to feed (G:F) were lower in HS-Con relative to TN-Con. Comparing HS-Con and TN-PF, ADG and G:F were similar. Plasma fatty acid concentrations were elevated in TN-PF compared with HS-Con and TN-Con. Despite tendencies for increased aspartate aminotransferase, HS conditions did not overtly influence liver and inflammation markers. Liver weights were lower in HS-Con relative to TN-Con. During the first week of heat exposure, DMI was greater for HS-Low relative to HS-Con. Supplementation of OA/PB at low and high levels had a similar G:F to HS-Con. We conclude that reductions in DMI accounted for production losses during HS conditioning and that dietary OA/PB supplementation was not able to improve growth performance in heat-stressed calves.

Glucose-Dependent Insulinotropic Polypeptide Plasma Level Influences the Effect of n-3 PUFA Supplementation

Elevated glucose-dependent insulinotropic peptide (GIP) levels in obesity may predict the metabolic benefits of n-3 PUFA supplementation. This placebo-controlled trial aimed to analyze fasting and postprandial GIP response to 3-month n-3 PUFA supplementation (1.8 g/d; DHA:EPA, 5:1) along with caloric restriction (1200–1500 kcal/d) in obese subjects. Compliance was confirmed by the incorporation of DHA and EPA into red blood cells (RBCs). Blood analyses of glucose, insulin, non-esterified fatty acids (NEFAs), GIP and triglycerides were performed at fasting, and during an oral glucose tolerance test and a high fat mixed-meal tolerance test. Fatty acid composition of RBC was assessed by gas chromatography and total plasma fatty acid content and composition was measured by gas–liquid chromatography. The DHA and EPA content in RBCs significantly increased due to n-3 PUFA supplementation vs. placebo (77% vs. −3%, respectively). N-3 PUFA supplementation improved glucose tolerance and decreased circulating NEFA levels (0.750 vs. 0.615 mmol/L), as well as decreasing plasma saturated (1390 vs. 1001 µg/mL) and monounsaturated (1135 vs. 790 µg/mL) fatty acids in patients with relatively high GIP levels. The effects of n-3 PUFAs were associated with the normalization of fasting (47 vs. 36 pg/mL) and postprandial GIP levels. Obese patients with elevated endogenous GIP could be a target group for n-3 PUFA supplementation in order to achieve effects that obese patients without GIP disturbances can achieve with only caloric restriction.

The association between heightened ADHD symptoms and cytokine and fatty acid concentrations during pregnancy.

ObjectivePrevious research conducted with samples of children suggest that individuals with attention-deficit/hyperactivity disorder (ADHD) have altered fatty acid concentrations and may have increased systemic inflammation. Whether these differences are also apparent in other populations of individuals with heightened ADHD symptoms (e.g., pregnant adults) is unknown. The goal of the current study was to examine whether there are ADHD-associated differences in polyunsaturated fatty acid concentrations or pro-inflammatory cytokine concentrations during pregnancy, a developmental period when fatty acid concentrations and systemic inflammation have implications for the health of both the pregnant person and the developing child. We hypothesized that plasma levels of the ratio of omega-6s to omega-3s (n-6:n-3) and plasma inflammatory cytokine levels would be higher in individuals with heightened ADHD symptoms, consistent with previous findings in children with ADHD.MethodsData (N = 68) came from a prospective study of pregnant community volunteers who were oversampled for ADHD symptoms. During the 3rd trimester, plasma concentrations of fatty acids and the pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were assessed. Dietary intake was examined in the 3rd trimester using three 24-h recalls conducted by trained dietitians and by examining plasma levels of conjugated linoleic acid (n-6) and α-linolenic acid (n-3), essential fatty acids that must come from dietary intake.ResultsThe group with heightened ADHD symptoms had higher n-6:n-3s (β = 0.30, p < 0.01) and higher TNF-α concentrations (β = 0.35, p < 0.001) relative to controls. There were no group differences in dietary variables, as assessed by self-report and via plasma concentrations of essential fatty acids. IL-6 was not reliably associated with ADHD status in this sample.ConclusionPregnant individuals with ADHD, on average, had higher plasma n-6:n-3s and higher TNF-α concentrations relative to controls. A difference was not detected in their dietary intake of fatty acids or other relevant nutrients. Though these null findings are inconclusive, they are consistent with the hypothesis that ADHD-associated differences in plasma fatty acid concentrations are the result of ADHD-associated differences in fatty acid metabolism, rather than simply differences in dietary intake.

Activated autophagy-lysosomal pathway in dairy cows with hyperketonemia is associated with lipolysis of adipose tissues

Activated autophagy-lysosomal pathway (ALP) can degrade virtually all kinds of cellular components, including intracellular lipid droplets, especially during catabolic conditions. Sustained lipolysis and increased plasma fatty acids concentrations are characteristic of dairy cows with hyperketonemia. However, the status of ALP in adipose tissue during this physiological condition is not well known. The present study aimed to ascertain whether lipolysis is associated with activation of ALP in adipose tissues of dairy cows with hyperketonemia and in calf adipocytes. In vivo, blood and subcutaneous adipose tissue (SAT) biopsies were collected from nonhyperketonemic (nonHYK) cows [blood β-hydroxybutyrate (BHB) concentration <1.2 mM, n = 10] and hyperketonemic (HYK) cows (blood BHB concentration 1.2-3.0 mM, n = 10) with similar days in milk (range: 3-9) and parity (range: 2-4). In vitro, calf adipocytes isolated from 5 healthy Holstein calves (1 d old, female, 30-40 kg) were differentiated and used for (1) treatment with lipolysis inducer isoproterenol (ISO, 10 µM, 3 h) or mammalian target of rapamycin inhibitor Torin1 (250 nM, 3 h), and (2) pretreatment with or without the ALP inhibitor leupeptin (10 μg/mL, 4 h) followed by ISO (10 µM, 3 h) treatment. Compared with nonHYK cows, serum concentration of free fatty acids was greater and serum glucose concentration, DMI, and milk yield were lower in HYK cows. In SAT of HYK cows, ratio of phosphorylated hormone-sensitive lipase to hormone-sensitive lipase, and protein abundance of adipose triacylglycerol lipase were greater, but protein abundance of perilipin 1 (PLIN1) and cell death-inducing DNA fragmentation factor-α-like effector c (CIDEC) was lower. In addition, mRNA abundance of autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), protein abundance of lysosome-associated membrane protein 1, and cathepsin D, and activity of β-N-acetylglucosaminidase were greater, whereas protein abundance of sequestosome-1 (p62) was lower in SAT of HYK cows. In calf adipocytes, treatment with ISO or Torin1 decreased protein abundance of PLIN1, and CIDEC, and triacylglycerol content in calf adipocytes, but increased glycerol content in the supernatant of calf adipocytes. Moreover, the mRNA abundance of ATG5, ATG7, and MAP1LC3B was upregulated, the protein abundance of lysosome-associated membrane protein 1, cathepsin D, and activity of β-N-acetylglucosaminidase were increased, whereas the protein abundance of p62 was decreased in calf adipocytes treated with ISO or Torin1 compared with control group. Compared with treatment with ISO alone, the protein abundance of p62, PLIN1, and CIDEC, and triacylglycerol content in calf adipocytes were higher, but the glycerol content in the supernatant of calf adipocytes was lower in ISO and leupeptin co-treated group. Overall, these data indicated that activated ALP is associated with increased lipolysis in adipose tissues of dairy cows with hyperketonemia and in calf adipocytes.

Associations of Plasma Fatty Acid Patterns During Pregnancy With Gestational Diabetes Mellitus.

BackgroundLimited studies have explored the difference of fatty acid profile between women with and without gestational diabetes mellitus (GDM), and the results were inconsistent. Individual fatty acids tend to be interrelated because of the shared food sources and metabolic pathways. Thus, whether fatty acid patters during pregnancy were related to GDM odds needs further exploration.ObjectiveTo identify plasma fatty acid patters during pregnancy and their associations with odds of GDM.MethodsA hospital-based case-control study including 217 GDM cases and 217 matched controls was carried out in urban Wuhan, China from August 2012 to April 2015. All the participants were enrolled at the time of GDM screening and provided fasting blood samples with informed consent. We measured plasma concentrations of fatty acids by gas chromatography–mass spectrometry, and derived potential fatty acid patterns (FAPs) through principal components analysis. Conditional logistic regression and restricted cubic spline model were used to evaluate the associations between individual fatty acids or FAPs and odds of GDM.ResultsTwenty individual fatty acids with relative concentrations ≥0.05% were included in the analyses. Compared with control group, GDM group had significantly higher concentrations of total fatty acids, 24:1n-9, and relatively lower levels of 14:0, 15:0, 17:0, 18:0, 24:0, 16:1n-7, 20:1n-9,18:3n-6, 20:2n-6, 18:3n-3, 20:3n-3, 22:5n-3. Two novel patterns of fatty acids were identified to be associated with lower odds of GDM: (1) relatively higher odd-chain fatty acids, 14:0, 18:0, 18:3n-3, 20:2n-6, 20:3n-6 and lower 24:1n-9 and 18:2n-6 [adjusted odds ratio (OR) (95% confidence interval) (CI) for quartiles 4 vs. 1: 0.42 (0.23–0.76), P-trend = 0.002], (2) relatively higher n-3 polyunsaturated fatty acids, 24:0, 18:3n-6 and lower 16:0 and 20:4n-6 [adjusted OR (95% CI) for quartiles 4 vs. 1: 0.48 (0.26–0.90), P-trend = 0.018].ConclusionOur findings suggested that two novel FAPs were inversely associated with GDM odds. The combination of circulating fatty acids could be a more significant marker of GDM development than individual fatty acids or their subgroups.