Plasma Free Fatty Acid Concentrations Research Articles

Albumin is an important factor in the control of serum free fatty acid flux in both male and female mice.

Albumin knockout (Alb-/-) mice exhibit a low plasma free fatty acid (FFA) concentration, but it was not known if the suppressed concentration reflects a lower rate of appearance (Ra) of FFA in the circulation (i.e., lower FFA flux) or if the absence of albumin alters the relationship between FFA flux and concentration. For understanding the role of albumin in FFA transport through the bloodstream, it is not sufficient to rely on FFA concentration data alone. Therefore, we developed a method to study FFA kinetics in Alb-/- mice. Using an albumin-free formulation of [U-13C]palmitate tracer, serum FFA kinetics were tested in Alb-/- and wild-type (WT) mice. Results indicate that the flux of FFA in serum of Alb-/- mice was significantly lower than in WT mice (P < 0.05), while albumin deficiency did not alter the relationship between FFA flux and concentration. Next, to test if suppressed lipolysis might have also been involved in the suppressed FFA kinetics, gene expression of a lipolytic enzyme (adipose triglyceride lipase, Atgl) and a marker of lipolysis (phosphorylation of hormone-sensitive lipase, p-HSL) were measured in adipose tissue. In contrast to the low FFA flux in Alb-/-, both Atgl gene expression and p-HSL protein were significantly higher in adipose tissue of Alb-/- than in WT mice (P < 0.05). Thus, the low FFA flux in Alb-/- appeared to be driven by the absence of albumin's FFA binding functions rather than through regulation of lipolysis, indicating that albumin is an important factor in determining the flux of FFA in circulation.NEW & NOTEWORTHY To improve understanding of the albumin protein's function in vivo, we tested plasma free fatty acid kinetics in albumin knockout mice compared with wild-type mice. Using a new tracer formulation strategy, it was discovered that the appearance rate of free fatty acids in serum is lower in albumin knockout mice than in wild-type mice. The results indicate that albumin is a major controller of free fatty acid kinetics.

The association between plasma angiopoietin-like protein 4, glucose and lipid metabolism during pregnancy, placental function, and risk of delivering large-for-gestational-age neonates

BackgroundLarge-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. MethodsWe conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. ResultsAmong 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. ConclusionsPlasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA.

Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20mL) or high (≥20mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Acute Statin Withdrawal Does not Interfere With the Improvements of a Session of Exercise in Postprandial Metabolism.

The risk for atherogenic plaque formation is high after ingestion of meals in individuals with high blood lipid levels (ie, dyslipidemia). Statins and exercise reduce the rise of blood triglyceride concentrations after a meal, but the effect of their combination is unclear. In a randomized crossover design, 11 individuals with dyslipidemia and metabolic syndrome treated with statins underwent a mixed-meal (970 ± 111 kcal, 24% fat, and 34% carbohydrate) tolerance test. Plasma lipid concentrations, fat oxidation, glucose, and glycerol kinetics were monitored immediately prior and during the meal test. Trials were conducted with participants under their habitual statin treatment and 96 hours after blinded statin withdrawal. Trials were duplicated after a prolonged bout of low-intensity exercise (75 minutes at 53 ± 4% maximal oxygen consumption) to study the interactions between exercise and statins. Statins reduced postprandial plasma triglycerides from 3.03 ± 0.85 to 2.52 ± 0.86 mmol·L-1 (17%; P = .015) and plasma glycerol concentrations (ie, surrogate of whole-body lipolysis) without reducing plasma free fatty acid concentration or fat oxidation. Prior exercise increased postprandial plasma glycerol levels (P = .029) and fat oxidation rates (P = .024). Exercise decreased postprandial plasma insulin levels (241 ± 116 vs 301 ± 172 ρmol·L-1; P = .026) but not enough to increase insulin sensitivity (P = .614). Neither statins nor exercise affected plasma glucose appearance rates from exogenous or endogenous sources. In dyslipidemic individuals, statins reduce blood triglyceride concentrations after a meal, but without limiting fat oxidation. Statins do not interfere with exercise lowering the postprandial insulin that likely promotes fat oxidation. Last, statins do not restrict the rates of plasma incorporation or oxidation of the ingested glucose.

2'-fucosyllactose alone or combined with resistant starch increases circulating short-chain fatty acids in lean men and men with prediabetes and obesity.

Infusion of short-chain fatty acids (SCFA) to the distal colon beneficially affects human substrate and energy metabolism. Here, we hypothesized that the combination of 2'-fucosyllactose (2'-FL) with resistant starch (RS) increases distal colonic SCFA production and improves metabolic parameters. In this randomized, crossover study, 10 lean (BMI 20-24.9 kg/m2) and nine men with prediabetes and overweight/obesity (BMI 25-35 kg/m2) were supplemented with either 2'-FL, 2'-FL+RS, or placebo one day before a clinical investigation day (CID). During the CID, blood samples were collected after a overnight fast and after intake of a liquid high-fat mixed meal to determine plasma SCFA (primary outcomes). Secondary outcomes were fasting and postprandial plasma insulin, glucose, free fatty acid (FFA), glucagon-like peptide-1, and peptide YY concentrations. In addition, fecal SCFA and microbiota composition, energy expenditure and substrate oxidation (indirect calorimetry), and breath hydrogen excretion were determined. In lean men, supplementation with 2'-FL increased postprandial plasma acetate (P = 0.017) and fasting H2 excretion (P = 0.041) compared to placebo. Postprandial plasma butyrate concentration increased after 2'-FL and 2'-FL+RS as compared to placebo (P < 0.05) in lean men and men with prediabetes and overweight/obesity. Additionally, 2'-FL+RS decreased fasting and postprandial plasma FFA concentrations compared to placebo (P < 0.05) in lean men. Supplementation of 2'-FL with/without RS the day before investigation increased systemic butyrate concentrations in lean men as well as in men with prediabetes and obesity, while acetate only increased in lean men. The combination of 2'-FL with RS showed a putatively beneficial metabolic effect by lowering plasma FFA in lean men, indicating a phenotype-specific effect. nr. NCT04795804.

A new oral model of free fatty acid kinetics to assess lipolysis in subjects with and without type 2 diabetes.

Assessing free fatty acids (FFAs) kinetics and the role of insulin and glucose on FFA lipolysis and disposal may improve our understanding of the pathogenesis of type 2 diabetes (T2D). Some models have been proposed to describe FFA kinetics during an intravenous glucose tolerance test and only one during an oral glucose tolerance test. Here, we propose a model of FFA kinetics during a meal tolerance test and use it to assess possible differences in postprandial lipolysis in individuals with type 2 diabetes (T2D) and individuals with obesity without type 2 diabetes (ND). We studied 18 obese ND and 16 T2D undergoing three meal tolerance tests (MTT) on three occasions (breakfast, lunch, and dinner). We used plasma glucose, insulin, and FFA concentrations collected at breakfast to test a battery of models and selected the best one based on physiological plausibility, ability to fit the data, precision of parameter estimates, and the Akaike parsimony criterion. The best model assumes that the postprandial suppression of FFA lipolysis is proportional to the above basal insulin, while FFA disposal is proportional to FFA concentration. It was used to compare FFA kinetics in ND and T2D along the day. The maximum lipolysis suppression occurred significantly earlier in ND than T2D (39 ± 6 min vs. 102 ± 13 min, 36 ± 4 min vs. 78 ± 11 min, and 38 ± 6 min vs. 84 ± 13 min, P < 0.01, at breakfast, lunch, and dinner, respectively), making lipolysis significantly lower in ND than T2D. This is mainly attributable to the lower insulin concentration in the second group. This novel FFA model allows to assess lipolysis and insulin antilipolytic effect in postprandial conditions.NEW & NOTEWORTHY In this study, we propose a new mathematical model able to quantify postprandial FFA kinetics and adipose tissue insulin sensitivity in both subjects with obesity without type 2 diabetes (ND) and subjects with type 2 diabetes (T2D). Results show that the slower postprandial suppression of lipolysis in T2D contributes to the higher free fatty acid (FFA) concentration that, in turn, may contribute to hyperglycemia.

1502-P: Adipose Tissue Protein Response and Insulin Sensitivity in Obesity

Dysregulation of adipose tissue (AT) lipolysis, a hallmark of obesity and type 2 diabetes, results in elevated postabsorptive and postprandial plasma free fatty acid (FFA) concentrations. This is thought to be due to adipose insulin resistance with regards to anti-lipolysis effects. Alterations in intracellular adipocyte pathways and/or proteins that mediate this phenomenon in humans are poorly understood. To test the hypothesis that impaired insulin signaling is associated with adipose insulin resistance measured whole body insulin sensitivity (the insulin concentration that suppresses palmitate flux by 50% (IC50 FFA)) in 12 lean, 7 lower body obese and 15 upper body obese (n=15) volunteers using a single step hyperinsulinemic-euglycemic clamp. We also measured adipose pAkt/Akt (a measure of insulin signaling) and hormone sensitive lipase (pHSL/HSL) (a measure of lipolysis protein regulation) in biopsies of abdominal and thigh adipose obtained before and during the insulin clamp were measured. Contrary to our hypothesis, there was a positive relationship between IC50 FFA and insulin clamp fold change of pAkt/Akt in thigh samples (ρ = 0.38, p &amp;lt;0.05) and no relationship for abdominal adipose samples. There was good correlation between abdominal and thigh adipose samples in the fractional change in pAkt/Akt in response to insulin clamp (ρ= 0.49, p &amp;lt; 0.01). IC50 FFA was correlated to fractional decrease in HSL phosphorylation in both abdominal (r = 0.36, p&amp;lt; 0.05) and thigh (r = 0.41, p &amp;lt;0.05) Surprisingly, fold changes of pAKT/AKT in response to insulin clamp were positively correlated to fold change of pHSL/HSL in abdominal adipose tissue (ρ= 0.41, p &amp;lt; 0.05) but not thigh samples. In conclusion we found that insulin resistance in adipose is not related to canonical insulin signaling responses but is related to lipase responses. Disclosure K.Lytle: None. M.D.Jensen: Other Relationship; Novo Nordisk, Elsevier. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK40484)

Insulin Sensitivity and β-Cell Function During Early and Late Pregnancy in Women With and Without Gestational Diabetes Mellitus.

To evaluate the metabolic alterations associated with gestational diabetes mellitus (GDM) in women with overweight or obesity. We compared fasting and postprandial plasma glucose and free fatty acid (FFA) concentrations, insulin sensitivity (IS; Matsuda index), and β-cell function (i.e., β-cell responsiveness to glucose) by using a frequently sampled oral glucose tolerance test (OGTT) at 15 and 35 weeks' gestation in women with overweight or obesity who had GDM (n = 29) or did not have GDM (No-GDM; n = 164) at 35 weeks. At 15 weeks, IS and β-cell function were lower, and fasting, 1-h, and total area-under-the-curve plasma glucose concentrations during the OGTT were higher (all P < 0.05) in the GDM than in the No-GDM group. At 35 weeks compared with 15 weeks, IS decreased, β-cell function increased, and postprandial suppression of plasma FFA was blunted in both the GDM and No-GDM groups, but the decrease in IS and the increase in postprandial FFA concentration were greater and the increase in β-cell function was less (all P ≤ 0.05) in the GDM than in the No-GDM group. A receiver operating characteristic curve analysis showed that both fasting plasma glucose and 1-h OGTT glucose concentration at 15 weeks are predictors of GDM, but the predictive power was <30%. Women with overweight or obesity and GDM, compared with those without GDM, have worse IS and β-cell function early during pregnancy and a greater subsequent decline in IS and blunted increase in β-cell function. Increased fasting and 1-h OGTT plasma glucose concentration early during pregnancy are markers of increased GDM risk, albeit with weak predictive power.

Albumin Deficiency Reduces Hepatic Steatosis and Improves Glucose Metabolism in a Mouse Model of Diet-Induced Obesity.

Serum albumin facilitates the transport of free fatty acids (FFAs) from adipose tissue to other organs. It was not known if impeding this process could protect from hepatic steatosis and metabolic dysfunction in obesity. We tested whether albumin knockout (Alb-/-) mice would exhibit a reduction in plasma FFA concentration, reduced hepatic lipid accumulation, and improved glucoregulation as compared to wild-type (WT) mice. Male homozygous albumin knockout mice (Alb-/-) and WT controls were fed a low-fat diet (LFD) or high-fat diet (HFD). Alb-/- mice exhibited a similar body weight gain and body composition as WT on both diets. Despite HFD-induced obesity, Alb-/- mice were protected from various comorbidities. Compared to WT mice on the HFD, Alb-/- exhibited lower plasma FFA levels, lower blood glucose levels during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb-/- mice on HFD also exhibited elevated expression of multiple genes in the liver and adipose tissues, such as peroxisome proliferator-activated receptor α in both tissues, as well as glucose transporter-4 and adiponectin in adipose tissues. The results indicate that albumin's FFA transport function may be involved in the development of hepatic lipid accumulation and dysregulated glucose metabolism in obesity.

A cinnamaldehyde feed additive improved feed use-efficiency in lactating dairy cows

Dietary supplementation of essential oils (EO) may increase milk yield and feed use-efficiency in Holstein cattle. A study was conducted to determine the effect of EO feed additives in dairy cattle productivity. The hypothesis was that compared with cinnamaldehyde feed additive supplementation, the supplementation with an additive containing a blend of cinnamaldehyde and garlic oil would improve feed use-efficiency in lactating dairy cattle. Forty-eight lactating Holstein cows (34 multiparous, days in milk (DIM) 118 ± 31.1, and 14 primiparous, DIM 134 ± 38.8) were enroled and randomly assigned to one of three treatments for 8 weeks: 1) control diet (CTRL; no EO supplementation; n = 16), 2) supplementation with cinnamaldehyde (CIN; 600 mg of a prototype to provide 125 mg of cinnamaldehyde; Novus International Inc., St. Charles, MO; n = 16), or 3) supplementation with essential oil blend (EOB; Next Enhance® CGO feed additive, Novus International Inc., St. Charles, MO; to provide 125 mg of cinnamaldehyde and 10 mg of garlic oil; n = 16). Cows were housed in a free-stall barn and the diet was offered as total mixed ration (TMR) formulated with 36% forage and 64% concentrate. The TMR was fed individually and EO additives were top-dressed. Production data were collected and analyzed using the Mixed procedure of SAS (version 9.4) where the fixed effects of treatment, time (i.e., week or day, as repeated measurements), and all possible interactions were included in the model. Compared with CTRL, CIN and EOB decreased (P < 0.05) dry matter intake (DMI, 30.1, 28.2, and 29.6 kg/day respectively). Yields of milk, fat, protein and lactose, and percentage of fat, protein and lactose were not affected by treatments. Compared with CTRL, CIN and EOB decreased (P < 0.05) milk urea nitrogen (MUN) concentrations (11.8, 10.9 and 11.4 mg/dL, respectively). Compared with CTRL, EOB reduced (P < 0.05) somatic cell count (126 and 84 × 103 cells/mL, respectively). Body weight, body condition score, and plasma free fatty acid concentrations were not affected by treatments. Compared with CTRL and EOB, CIN increased (P < 0.05) energy-corrected milk yield (ECM) to DMI ratio (1.63, 1.64 and 1.68, respectively). Moreover, there was a tendency (P < 0.10) for EOB and CIN treatments to increase milk yield to DMI ratio. Compared with CTRL, CIN elicited an increase (P < 0.05) in the conversion efficiency of dietary nitrogen into milk protein (28.1 and 28.7%, respectively). In our study, CIN supplementation increased nitrogen use-efficiency to sustain synthesis of ECM. Therefore, dietary supplementation of cinnamaldehyde may be used to improve nitrogen metabolism and increase feed use-efficiency in lactating dairy cows.

Distinct Mechanisms Responsible for the Increase in Glucose Production and Ketone Formation Caused by Empagliflozin in T2DM Patients.

To examine the mechanisms responsible for the increase in glucose and ketone production caused by empagliflozin in patients with type 2 diabetes mellitus (T2DM). Twelve subjects with T2DM participated in two studies performed in random order. In study 1, endogenous glucose production (EGP) was measured with 8-h infusion of 6,6,D2-glucose. Three hours after the start of 6,6,D2-glucose infusion, subjects ingested 25 mg empagliflozin (n = 8) or placebo (n = 4), and norepinephrine (NE) turnover was measured before and after empagliflozin ingestion with 3H-NE infusion. Study 2 was similar to study 1 but performed under pancreatic clamp conditions. When empagliflozin was ingested under fasting conditions, EGP increased by 31% in association with a decrease in plasma glucose (-34 mg/dL) and insulin (-52%) concentrations and increases in plasma glucagon (+19%), free fatty acid (FFA) (+29%), and β-hydroxybutyrate (+48%) concentrations. When empagliflozin was ingested under pancreatic clamp conditions, plasma insulin and glucagon concentrations remained unchanged, and the increase in plasma FFA and ketone concentrations was completely blocked, while the increase in EGP persisted. Total-body NE turnover rate was greater in subjects receiving empagliflozin (+67%) compared with placebo under both fasting and pancreatic clamp conditions. No difference in plasma NE concentration was observed in either study. The decrease in plasma insulin and increase in plasma glucagon concentration caused by empagliflozin is responsible for the increase in plasma FFA concentration and ketone production. The increase in EGP caused by empagliflozin is independent of the change in plasma insulin or glucagon concentrations and is likely explained by the increase in NE turnover.

Feeding Status Affects Glucose Metabolism in Exercising Horses

Four standardbred horses were used in a Latin square design experiment to evaluate the effects of feeding status on metabolic response to exercise. Horses were deprived of food overnight and then fed 0 (control condition), 1, 2 or 3 kg of corn grain approximately 2.5-3 h before exercise. The exercise test consisted of a warm-up phase (heart rate mean = 144 beats/min) followed by 800 m of walking and then a high intensity work bout for 1600 m (heart rate mean = 206 beats/min). All tests were conducted on a high speed equine treadmill on which the horses had been previously conditioned. During exercise, the control treatment resulted in steady plasma glucose concentrations, whereas all other treatments (1, 2 or 3 kg corn) caused a decline in plasma glucose. Liver glycogen concentration was decreased by exercise in the horses only when they received the control treatment. Plasma lactate concentration was increased by exercise but was not affected by feeding state. Plasma free fatty acid concentrations were highest when the horses received the control treatment. In addition, when horses received the control treatment, plasma free fatty acid concentrations decreased during the warm-up and high intensity phases of the test and increased during the walk phase. Free fatty acid concentrations changed in the horses receiving 1, 2 or 3 kg of corn grain only during the high intensity phase of the exercise test. Feeding status affects the metabolic response of horses to exercise thus further studies are necessary to evaluate the effect of feeding status on exercise performance.

ANGPTL4, IL-6 and TNF-α as regulators of lipid metabolism during a marathon run

The aim of the study was to reveal whether marathon running influences regulators of lipid metabolism i.e. angiopoietin-like protein 4 (ANGPTL4), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α). Plasma concentration of ANGPTL4, IL-6, TNF-α and lipids were determined in samples collected from 11 male runners before the marathon, immediately after the run and at 90 min of recovery. Plasma ANGPTL4 increased during exercise from 55.5 ± 13.4 to 78.1 ± 15.0 ng/ml (P < 0.001). This was accompanied by a significant increase in IL-6, TNF-α, free fatty acids (FFA) and glycerol (Gly) and a decrease in triacylglycerols (TG). After 90 min of recovery ANGPTL4 and TG did not differ from the exercise values, while plasma IL-6, TNF-α, FFA and Gly concentration were significantly lower. The exercise-induced increase in plasma concentration of ANGPTL4 correlated positively with the rise in plasma IL-6, TNF-α, FFA and Gly and negatively with the duration of the run. The increase in plasma IL-6 and TNF-α correlated positively with the rise in Gly. Summarizing, marathon running induced an increase in plasma ANGPTL4 and the value was higher in faster runners. The increase in plasma FFA, IL-6 and TNF-α concentration during a marathon run may be involved in plasma ANGPTL4 release, which could be a compensatory mechanism against FFA-induced lipotoxicity and oxidative stress. All of the analyzed cytokines may stimulate lipolysis during exercise.

The effect of moderate energy and protein restriction during gilt development on changes in body weight and backfat depth and subsequent lactation performance.

Eighty-eight gilts [initial body weight (BW) 49.8 ± 0.8 kg] were recruited to determine the effects of moderate energy and protein restriction during the development period on changes in BW and backfat depth (BF) and subsequent lactation performance. Gilts were randomly assigned to one of four feeding programs: 1) standard commercial diet fed ad libitum (CON), 2) standard commercial diet fed 10% or 3) 20% below ad libitum, or 4) a high-fiber diet fed ad libitum [2.5 times more fiber (neutral detergent fiber) than the commercial diet to dilute net energy and crude protein by approximately 20% and 13%, respectively; FIB]. The gilts were housed individually and received the feeding programs between 90 and 190 (breeding) d of age and standard gestation and lactation diets thereafter. Litters were standardized to 12 ± 1 pigs within 48 h of farrowing; weaning occurred at 20.0 ± 0.4 d of age. Gilts that received the 20% restricted program had lower overall average daily feed intake (ADFI) during the development period (2.64 ± 0.04 kg; P < 0.05) versus all other feeding programs and gilts that received the 10% restricted program had lower ADFI than FIB and CON, which were not different (2.96 vs. 3.44 and 3.47 ± 0.04 kg for 10%, FIB and CON, respectively; P < 0.05). Plasma free fatty acid (FFA) concentrations on day 180 of age were lower for gilts that received the 10% and 20% restricted programs compared to gilts that received the FIB and CON programs, which were not different (97 and 86 vs. 220 and 149 ± 29 µEq/L, respectively; P < 0.05). Plasma concentrations of glucose, urea, prolactin, and IGF-1 were not different among feeding programs on day 180 of age. At breeding, gilts that received the FIB and 10% programs had lower BW and BF versus CON (145.7 and 144.8 vs. 155.2 ± 0.9 kg and 14.4 and 14.8 vs. 16.5 ± 0.2 mm for BW and BF, respectively; P < 0.05) but greater BW than gilts that received the 20% restricted program (137.9 kg; P < 0.05). The BW and BF of gilts did not differ at the end of gestation or at weaning. The ADFI of sows during lactation and offspring birth weight and growth rate during lactation and the 5-wk nursery period were not influenced by gilt development feeding program. Therefore, a high-fiber feeding program could be used in group-housing gilt-development scenarios, where feed is offered ad libitum, to control BW and BF prior to breeding without influencing milk production in the subsequent lactation period.

Differences in lipid metabolism in acquired versus preexisting glucose intolerance during gestation: role of free fatty acids and sphingosine-1-phosphate

BackgroundThe prevalence of gestational diabetes mellitus (GDM) is increasing worldwide. There is increasing evidence that GDM is a heterogeneous disease with different subtypes. An important question in this context is whether impaired glucose tolerance (IGT), which is a typical feature of the disease, may already be present before pregnancy and manifestation of the disease. The latter type resembles in its clinical manifestation prediabetes that has not yet manifested as type 2 diabetes (T2DM). Altered lipid metabolism plays a crucial role in the disorder's pathophysiology. The aim was to investigate the role of lipids which are relevant in diabetes-like phenotypes in these both models with different time of initial onset of IGT.MethodsTwo rodent models reflecting different characteristics of human GDM were used to characterize changes in lipid metabolism occurring during gestation. Since the New Zealand obese (NZO)-mice already exhibit IGT before and during gestation, they served as a subtype model for GDM with preexisting IGT (preIGT) and were compared with C57BL/6 N mice with transient IGT acquired during gestation (aqIGT). While the latter model does not develop manifest diabetes even under metabolic stress conditions, the NZO mouse is prone to severe disease progression later in life. Metabolically healthy Naval Medical Research Institute (NMRI) mice served as controls.ResultsIn contrast to the aqIGT model, preIGT mice showed hyperlipidemia during gestation with elevated free fatty acids (FFA), triglycerides (TG), and increased atherogenic index. Interestingly, sphingomyelin (SM) concentrations in the liver decreased during gestation concomitantly with an increase in the sphingosine-1-phosphate (S1P) concentration in plasma. Further, preIGT mice showed impaired hepatic weight adjustment and alterations in hepatic FFA metabolism during gestation. This was accompanied by decreased expression of peroxisome proliferator-activated receptor alpha (PPARα) and lack of translocation of fatty acid translocase (FAT/CD36) to the hepatocellular plasma membrane.ConclusionThe preIGT model showed impaired lipid metabolism both in plasma and liver, as well as features of insulin resistance consistent with increased S1P concentrations, and in these characteristics, the preIGT model differs from the common GDM subtype with aqIGT. Thus, concomitantly elevated plasma FFA and S1P concentrations, in addition to general shifts in sphingolipid fractions, could be an interesting signal that the metabolic disorder existed before gestation and that future pregnancies require more intensive monitoring to avoid complications.Graphical This graphical abstract was created with BioRender.com.

Physiological interindividual variability in endogenous estradiol concentration does not influence adipose tissue and hepatic lipid kinetics in women.

Increased triglyceride (TG) and apolipoprotein B-100 (apoB-100) concentrations in plasma are important risk factors for cardiovascular disease in women. Administration of some estrogen preparations raises plasma TG and apoB-100 concentrations by increasing hepatic very low-density lipoprotein (VLDL) TG and apoB-100 secretion rates. However, the influence of physiological variation in endogenous estradiol on VLDL-TG and VLDL-apoB-100 metabolism and on free fatty acid (FFA) release into plasma (the major source of fatty acids for VLDL-TG production) is not known. We measured basal VLDL-TG, VLDL-apoB-100, and plasma FFA kinetics by using stable isotopically labeled tracers in 36 eumenorrheic, premenopausal women (age: 33 ± 2 years, BMI: 31 ± 1 kg/m2; mean ± s.e.m.) during the follicular phase of the menstrual cycle; participants were divided into two groups based on low (n = 18) or high (n = 18) plasma estradiol concentrations (defined as below or above the median value of 140 pmol/L in the whole group). Mean plasma estradiol concentration was >3-fold higher in the high-estradiol than in the low-estradiol group (299 ± 37 and 96 ± 7 pmol/L, P < 0.001); there was no difference in plasma progesterone concentrations between the two groups (P = 0.976). There were no significant differences in plasma FFA concentration, FFA rate of appearance in plasma, VLDL-TG and VLDL-apoB-100 concentrations, hepatic VLDL-TG and VLDL-apoB-100 secretion rates, VLDL-TG and VLDL-apoB-100 plasma clearance rates, and mean residence times (all P ≥ 0.45). No significant associations were found between plasma estradiol concentration and FFA, VLDL-TG, and VLDL-apoB-100 concentrations and kinetics (all P > 0.19). Plasma estradiol concentration is not an important correlate of basal plasma FFA, VLDL-TG, and VLDL-apoB-100 kinetics in premenopausal women.

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

1411-P: Increased 24-Hour Plasma Free Fatty Acids in People with Obesity and Prediabetes

The importance of increased plasma free fatty acids (FFAs) in the pathogenesis of insulin resistance in people with prediabetes is unclear. It has been proposed that the increase in plasma insulin associated with obesity should be adequate to suppress adipose tissue lipolytic rates and maintain normal plasma FFA levels. We evaluated serial plasma FFA concentrations for 24 h in 20 adults with obesity and normal fasting glucose and glucose tolerance (metabolically healthy obesity [MHO]) and 20 adults with prediabetes, matched on age, sex, BMI and percent body fat with the MHO group. Insulin sensitivity, assessed as the glucose infusion rate during an insulin clamp, was greater in the MHO than the prediabetes group (48.1 ± 3.0 vs. 23.5 ± 1.3 μmol/kg fat-free mass/min, respectively, P &amp;lt; 0.0001) . Plasma FFA were greater throughout 24 h in the prediabetes group than the MHO group (Figure) . The 24-h areas under the curve were greater for plasma FFA (5.59 ± 0.37 vs. 4.58 ± 0.30 mmol/L x hour, P = 0.04) and plasma insulin (13,5± 1720 vs. 6,541 ± 558 pmol/L x hour, P = 0.0004) in the prediabetes group than the MHO group. We conclude that plasma FFA concentrations are greater throughout the day in people with prediabetes than those with MHO, despite a marked increase in plasma insulin concentration in those with prediabetes. These data support the notion that increased 24-h plasma FFAs contribute to insulin resistance associated with obesity. Disclosure M.C.Petersen: None. S.S.Farabi: n/a. G.Smith: None. S.Klein: Advisory Panel; Altimmune, Consultant; Janssen Research &amp; Development, LLC, ProSciento, Research Support; Janssen Research &amp; Development, LLC. Funding NIH T32DK007120Endocrine Fellows Foundation

Three hours of Moderate Intensity Exercise Training Reduces Glucose Tolerance in Endurance Trained Athletes

Objectives:It is well accepted that exercise training improves glucose uptake and insulin sensitivity, and that endurance trained athletes in general show a high capacity for these parameters. However, some studies have observed negative effects on glucose regulation in healthy, trained subjects the day after exercise. These, often unexpected, results have been postulated to be caused by excessive training loads, muscle damage, energy deficit, differences in glucose uptake in the exercised and non-exercised musculature and a metabolic interaction through increased fatty acid metabolism. The mode or volume of exercise that can lead to glucose intolerance in trained athletes as well as its relevance for health and performance are, however, not fully understood. We here studied the metabolic response to a glucose load the day after a session of high intensity interval training (HIIT) or three hours of continuous exercise (3h) in endurance trained athletes and compared the results with measurements during rest.Methods:Nine endurance trained athletes underwent oral glucose tolerance tests (OGTT) after rest and ˜14 hours after exercise on a cycle ergometer (HIIT 5x4 minutes at ˜95% of VO2max or 3h at 65% of VO2max). Concentrations of glucose, insulin, free fatty acids (FFA) and ketones (β-hydroxybutyrate) were measured. Statistical analysis was performed using a RM one-way ANOVA.Results:The area under the curve (AUC) during the OGTT increased greatly after 3h (668±124 mM · min) (p<0.01) compared to rest (532±89) but was found to be unchanged after HIIT (541±96). Resting values of FFA and ketones were increased after 3h (p<0.01 and p<0.05, respectively) but not after HIIT. Insulin was found to be unaltered during all conditions.Conclusion:Here, we show manifestation of glucose intolerance in endurance trained athletes together with concomitant increases in plasma concentrations of FFA and ketones the day after a session of prolonged exercise training but not after HIIT. This could be a protective response for securing glucose delivery to the brain and therefore have a positive effect on endurance. It also has the potential to reduce the recovery of glycogen depots, glucose uptake during exercise and performance at higher work rates.

Increased plasma fatty acid clearance, not fatty acid concentration, is associated with muscle insulin resistance in people with obesity

BackgroundAlthough it is well-accepted that increased plasma free fatty acid (FFA) concentration causes lipid overload and muscle insulin resistance in people with obesity, plasma FFA concentration poorly predicts insulin-resistant glucose metabolism. It has been proposed that hyperinsulinemia in people with obesity sufficiently inhibits adipose tissue triglyceride lipolysis to prevent FFA-induced insulin resistance. However, we hypothesized enhanced FFA clearance in people with obesity, compared with lean people, prevents a marked increase in plasma FFA even when FFA appearance is high. MethodsWe assessed FFA kinetics during basal conditions and during a hyperinsulinemic-euglycemic clamp procedure in 14 lean people and 46 people with obesity by using [13C]palmitate tracer infusion. Insulin-stimulated muscle glucose uptake rate was evaluated by dynamic PET-imaging of skeletal muscles after [18F]fluorodeoxyglucose injection. ResultsPlasma FFA clearance was accelerated in participants with obesity and correlated negatively with muscle insulin sensitivity without a difference between lean and obese participants. Furthermore, insulin infusion increased FFA clearance and the increase was greater in obese than lean participants. ConclusionsOur findings suggest plasma FFA extraction efficiency, not just plasma FFA concentration, is an important determinant of the cellular fatty acid load and the stimulatory effect of insulin on FFA clearance counteracts some of its antilipolytic effect.