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Gastrointestinal motility, gut hormone secretion, and energy intake after oral loads of free fatty acid or triglyceride in older and middle-aged men.
Madsen, JL, Damgaard, M, Fuglsang, S, Dirksen, C, Holst, JJ, Graff, J
Appetite. 2019;:18-24
Abstract
In young individuals, oral free fatty acid delays gastric emptying, promotes gut hormone release, and reduces energy intake more than an isocaloric load of triglyceride does. The objective of this study was to compare the effects of the free fatty acid oleic acid (OA) and the triglyceride olive oil (OO) on gastrointestinal motility, gut hormone secretion, and energy intake in older and middle-aged healthy volunteers. In a double-blind, randomized, cross-over, study 10 older (age 83.0 ± 3.4 (mean ± SD) years) and 10 middle-aged (age 43.1 ± 8.9 years) men were examined on two occasions to evaluate the effect of isocaloric and isovolaemic loads of radiolabelled OA or OO on gastric emptying, oro-caecal transit, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) secretions, and energy intake. Gastric emptying was slower in older than in middle-aged men (lipid p < 0.001, water p = 0.010), while no difference between these groups was found for oro-caecal transit. In comparison with OO, OA caused slower gastric emptying (lipid p < 0.001, water p = 0.020) and faster oro-caecal transit (p = 0.025). Postprandial secretion of GLP-1 and PYY was comparable for older and middle-aged men, as well as for OA and OO. Older men ingested less energy than middle-aged men did (p < 0.001) and their energy intake was lower after OA than OO (p = 0.002). Thus, gastric emptying of an oral lipid load is slower in older than in middle-aged men; gastric emptying is slower and oro-caecal transit faster after OA than OO in both age groups; and older men ingest less energy than middle-aged men and less energy after OA than OO.
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Effects of soybean lipid infusion on triglyceride and unbound free fatty acid levels in preterm infants.
Hegyi, T, Kleinfeld, A, Huber, A, Weinberger, B, Memon, N, Joe Shih, W, Carayannopoulos, M, Oh, W
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 2019;(19):3226-3231
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Abstract
Objective: To determine the plasma triglyceride (TG) and unbound free fatty acid (FFAu) levels in infants treated with increasing dosages of soybean lipid, intralipid (IL), infusion. Study design: TG and FFAu levels were measured in 78 preterm infants (BW 500-2000 g; GA 23-34 weeks) using the fluorescent probe ADIFAB2 and enzymatic method. Results: The infants' BW was 1266.2 ± 440.7 g and GA 28.8 ± 3.1 weeks. TG levels were 77.4 ± 50 mg/dL, 140.2 ± 188 mg/dL (p < .04 compared to levels during low dose IL infusion) and 135.6 ± 118 mg/dL (p < .004), respectively during increased IL rates. FFAu levels were 17.7 ± 13 nM, 47.3 ± 102.8 nM (p = .07) and 98 ± 234 nM (p = .03). TG levels correlated with IL dose, the rate of IL administration, and FFAu levels. TG and FFAu levels were higher in infants below 28 weeks' gestation Conclusions: Increasing dosage of IL is associated with increasing levels of TG and FFAu, especially in infants below 29 weeks of gestation. The increased level of FFAu suggests inefficient cellular utilization.
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β2-Agonist Induces Net Leg Glucose Uptake and Free Fatty Acid Release at Rest but Not During Exercise in Young Men.
Onslev, J, Jensen, J, Bangsbo, J, Wojtaszewski, J, Hostrup, M
The Journal of clinical endocrinology and metabolism. 2019;(3):647-657
Abstract
OBJECTIVE The role of selective β2-adrenergic stimulation in regulation of leg glucose uptake and free fatty acid (FFA) balance is inadequately explored in humans. The objective of this study was to investigate β2-adrenergic effects on net leg glucose uptake and clearance, as well as FFA balance at rest and during exercise. DESIGN The study was a randomized, placebo-controlled crossover trial where 10 healthy men received either infusion of β2-agonist terbutaline (0.2 to 0.4 mg) or placebo. Net leg glucose uptake and clearance and FFA balance were determined at rest and during 8 minutes of knee extensor exercise using Fick's principle. Vastus lateralis muscle biopsies were collected at rest and at cessation of exercise. The primary outcome measure was net leg glucose uptake. RESULTS At rest, net leg glucose uptake and clearance were 0.35 (±0.16) mmol/min and 41 (±17) mL/min (mean ± 95% CI) higher (P < 0.001) for terbutaline than placebo, corresponding to increases of 84% and 70%. During exercise, no treatment differences were observed in net leg glucose uptake, whereas clearance was 101 (±86) mL/min lower (P < 0.05) for terbutaline than placebo. At rest, terbutaline induced a net leg FFA release of 21 (±14) µmol/min, being different from placebo (P = 0.04). During exercise, net leg FFA uptake was not different between the treatments. CONCLUSIONS These observations indicate that β2-agonist alters net leg glucose uptake and clearance, as well as FFA balance in humans, which is associated with myocellular β2-adrenergic and insulin-dependent signaling. Furthermore, the study shows that exercise confounds the β2-adrenergic effect on net leg glucose uptake and FFA balance.
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Free Fatty Acids: Circulating Contributors of Metabolic Syndrome.
Suiter, C, Singha, SK, Khalili, R, Shariat-Madar, Z
Cardiovascular & hematological agents in medicinal chemistry. 2018;(1):20-34
Abstract
Metabolic syndrome induces an increased cardiovascular morbidity and mortality. Most importantly, the prevalence of metabolic syndrome in adult population is expanding. Both clinical and preclinical studies indicate that increased Free Fatty Acids (FFAs) are involved in the pathogenesis of insulin resistance and subsequent development of metabolic syndrome. The relevance of FFAs in protecting and restoring tissue function is quite vast. The search to correlate the functional deterioration of the tissues within the cardiovascular system and increased plasma concentrations of FFAs has been reported. The importance of reduction in the consumption of dietary fatty acids along with the identification of dysregulated genes responsible for persistent increased FFAs uptake and mitochondrial β-oxidation has been increasingly recognized. This review discusses the current empirical understanding of the different types of fatty acids and their metabolism and functions both in physiological and pathophysiological conditions. We also discuss in detail about the molecular and pathophysiological basis of increased FFAs, which augments Cardiovascular Disease (CVD).
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A pilot study of the effects of niacin administration on free fatty acid and growth hormone concentrations in children with obesity.
Galescu, OA, Crocker, MK, Altschul, AM, Marwitz, SE, Brady, SM, Yanovski, JA
Pediatric obesity. 2018;(1):30-37
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CONTEXT Children with obesity have low spontaneous growth hormone (GH) secretion. High circulating free fatty acid (FFA) concentration is believed to inhibit GH secretion in those with obesity. In adults, lipolytic inhibition with niacin lowers FFA and increases GH, but there are no prior studies in children with obesity. OBJECTIVE The objective of the study was to determine the dose and frequency of niacin administration required to lower FFA and stimulate GH in children with obesity. DESIGN Dose-finding study of nondiabetic children ages 6-12 years with body mass index (BMI) ≥ 95th percentile given niacin 250 mg q2h × 3 doses (n = 2), 500 mg q2h × 3 doses (n = 5) or 500 mg q1h × 4 doses (n = 5). PARTICIPANTS Eight boys and four girls (age 9.7 ± 1.8 years; BMI 26.4 ± 3.1 kg m-2 ; BMIz 2.2 ± .25) were studied. MAIN OUTCOME Percentage of serum FFA values that were below 0.2 mEq L-1 . GH, insulin and glucose were also measured serially. RESULTS FFA decreased as the dose and frequency of niacin increased (p = .01). Niacin 500 mg q1h 4 doses suppressed FFA < 0.2 mEq L-1 and significantly increased GH (p = .04). Adverse effects were flushing/warmth (100%), tingling (60%) and GI complaints (20-40%). CONCLUSIONS Niacin 500 mg q1h significantly lowered serum FFA and increased GH. These pilot data suggest that high FFA is an important suppressor of GH secretion in children with obesity.
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The acute effects of dietary carbohydrate reduction on postprandial responses of non-esterified fatty acids and triglycerides: a randomized trial.
Samkani, A, Skytte, MJ, Anholm, C, Astrup, A, Deacon, CF, Holst, JJ, Madsbad, S, Boston, R, Krarup, T, Haugaard, SB
Lipids in health and disease. 2018;(1):295
Abstract
BACKGROUND Postprandial non-esterified fatty acid (NEFA) and triglyceride (TG) responses are increased in subjects with type 2 diabetes mellitus (T2DM) and may impair insulin action and increase risk of cardiovascular disease and death. Dietary carbohydrate reduction has been suggested as non-pharmacological therapy for T2DM, but the acute effects on NEFA and TG during subsequent meals remain to be investigated. METHODS Postprandial NEFA and TG responses were assessed in subjects with T2DM by comparing a carbohydrate-reduced high-protein (CRHP) diet with a conventional diabetes (CD) diet in an open-label, randomized, cross-over study. Each diet was consumed on two consecutive days, separated by a wash-out period. The iso-caloric CRHP/CD diets contained 31/54 E% from carbohydrate, 29/16 E% energy from protein and 40/30 E% from fat, respectively. Sixteen subjects with well-controlled T2DM (median HbA1c 47 mmol/mol, (37-67 mmol/mol) and BMI 30 ± 4.4 kg/m2) participated in the study. NEFA and TG were evaluated following breakfast and lunch. RESULTS NEFA net area under curve (AUC) was increased by 97 ± 38 μmol/Lx270 min (p = 0.024) after breakfast but reduced by 141 ± 33 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. Likewise, TG net AUC was increased by 80 ± 28 μmol/Lx270 min (p = 0.012) after breakfast but reduced by 320 ± 60 μmol/Lx180 min (p < 0.001) after lunch on the CRHP compared with CD diet. CONCLUSIONS In well-controlled T2DM a modest reduction of dietary carbohydrate with a corresponding increase in protein and fat acutely reduced postprandial serum NEFA suppression and increased serum TG responses after a breakfast meal but had the opposite effect after a lunch meal. The mechanism behind this second-meal phenomenon of CRHP diet on important risk factors for aggravating T2DM and cardiovascular disease awaits further investigation. TRIAL REGISTRATION The study was registered at clinicaltrials.gov ID: NCT02472951. https://clinicaltrials.gov/ct2/show/NCT02472951 . Registered June 16, 2015.
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Metabolomics identifies increases in the acylcarnitine profiles in the plasma of overweight subjects in response to mild weight loss: a randomized, controlled design study.
Kang, M, Yoo, HJ, Kim, M, Kim, M, Lee, JH
Lipids in health and disease. 2018;(1):237
Abstract
BACKGROUND Using metabolomics technique to analyze the response to a dietary intervention generates valuable information concerning the effects of the prescribed diet on metabolic regulation. To determine whether low calorie diet (LCD)-induced weight reduction causes changes in plasma metabolites and metabolic characteristics. METHODS Overweight subjects consumed a LCD (n = 47) or a weight maintenance diet (control, n = 50) in a randomized, controlled design study with a 12-week clinical intervention period. Plasma samples were analyzed using an UPLC-LTQ-Orbitrap MS. RESULTS The 12-week LCD intervention resulted in significant mild weight loss, with an 8.3% and 10.6% reduction observed in the visceral fat area (VFA) at the level of the lumbar vertebrae L1 and L4, respectively. The LCD group showed a significant increase in the mean change of serum free fatty acids compared to the control group. In the LCD group, we observed a significant increase in the acylcarnitine (AC) levels, including hexanoylcarnitine, L-octanoylcarnitine, 9-decenoylcarnitine, trans-2-dodecenoylcanitine, dodecanoylcarnitine, 3,5-tetradecadiencarnitine, cis-5-tetradecenoylcarnitine, 9,12-hexadecadienoylcarnitine, and 9-hexadecenoylcarnitne at the 12-week follow-up assessment. When the plasma metabolite changes from baseline were compared between the control and LCD groups, the LCD group showed significant increases in hexanoylcarnitine, L-octanoylcarnitine, trans-2-dodecenoylcanitine, and 3,5-tetradecadiencarnitine than the control group. Additionally, the changes in these ACs in the LCD group strongly negatively correlated with the changes in the VFA at L1 and/or L4. CONCLUSION Mild weight loss from 12-week calorie restriction increased the plasma levels of medium- and long-chain ACs. These changes were coupled with a decrease in VFA and an increase in free fatty acids. TRIAL REGISTRATION NCT03135132 ; April 26, 2017.
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Plasma Palmitoyl-Carnitine (AC16:0) Is a Marker of Increased Postprandial Nonesterified Incomplete Fatty Acid Oxidation Rate in Adults With Type 2 Diabetes.
Bouchouirab, FZ, Fortin, M, Noll, C, Dubé, J, Carpentier, AC
Canadian journal of diabetes. 2018;(4):382-388.e1
Abstract
OBJECTIVES Enhanced mitochondrial fatty acid utilization is known to increase radical oxidative stress and induce insulin resistance. An increased level of plasma acylcarnitine (AC) has been proposed to indicate mitochondrial energy substrate overload, a possible mechanism leading to insulin resistance. The aim of our study was to determine fasting and postprandial plasma acetyl-carnitine (AC2:0), palmitoyl-carnitine (AC16:0), oleoyl-carnitine (AC18:1) and linoleoyl-carnitine (AC18:2) levels and their relationships with plasma nonesterified fatty acid appearance and oxidation rates and insulin sensitivity in participants with type 2 diabetes and normoglycemic offspring of 2 parents with type 2 diabetes (FH+) compared to healthy participants without family histories of type 2 diabetes (FH-). METHODS All participants underwent 3 metabolic protocols: 1) a euglycemic hyperinsulinemic clamp at fasting; 2) a 6-hour steady-state oral standard liquid meal and 3) an identical 6-hour steady-state meal intake study with a euglycemic hyperinsulinemic clamp. AC levels were measured by liquid chromatography with tandem mass spectrometry, and fatty acid oxidation (FAO) rates were measured by stable isotopic tracer techniques with indirect respiratory calorimetry. RESULTS During the insulin clamp at fasting, AC16:0 was significantly higher in the group with type 2 diabetes vs. FH- (p<0.05). In the postprandial state, AC2:0, AC16:0 and AC18:1 decreased significantly, but this reduction was blunted in type 2 diabetes, even during normalization of postprandial glucose levels during the insulin clamp. Fasting AC16:0 correlated with FAO (ρ=+0.604; p=0.0002); triacylglycerol (ρ=+0.427; p<0.02) and waist circumference (ρ=+0.416; p=0.02). CONCLUSIONS Spillover of AC occurs in type 2 diabetes but is not fully established in FH+. AC16:0 can be a useful biomarker of excessive FAO.
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Increased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular Remodeling.
Voros, G, Ector, J, Garweg, C, Droogne, W, Van Cleemput, J, Peersman, N, Vermeersch, P, Janssens, S
Circulation. Heart failure. 2018;(12):e004953
Abstract
BACKGROUND Deranged energy metabolism contributes to the pathophysiology of heart failure (HF). Recent studies showed diminished free fatty acid (FFA) oxidation in experimental HF models with a shift towards oxidation of ketone bodies. However, conflicting clinical data on FFA metabolism and limited knowledge on ketone body metabolism in human HF mandate additional metabolic profiling studies. We, therefore, investigated cardiac uptake of FFAs and ketone bodies (β-hydroxybutyrate and acetoacetate) in patients with HF with reduced ejection fraction (HFrEF) or with aortic stenosis (AS)-induced left ventricular hypertrophy. We hypothesized that FFA oxidation is impaired in HFrEF and in AS and results in decreased concentrations of free carnitine, the necessary carrier for mitochondrial entry of activated FFAs, and in accumulation of metabolic intermediates. METHODS AND RESULTS We collected arterial and coronary sinus blood samples in patients with HFrEF (n=15), in AS patients with preserved systolic function (n=15), and in control patients (n=15). Plasma concentration gradients across the heart show significantly greater uptake of ketone bodies in patients with HFrEF than in controls. Patients with AS show significantly increased uptake of β-hydroxybutyrate and FFAs. Free carnitine concentration and concentration gradients of intermediates of FFA oxidation were comparable between groups. CONCLUSIONS In conclusion, our results show significantly increased cardiac uptake of ketone bodies in patients with stable HFrEF and AS and increased uptake of FFAs in AS compared with control patients. The lack of myocardial release of acyl-carnitine species or change in free carnitine uptake suggests no impairment of FFA oxidation.
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Hormone, metabolic peptide, and nutrient levels in the earliest phases of rheumatoid arthritis-contribution of free fatty acids to an increased cardiovascular risk during very early disease.
Tang, MW, Koopman, FA, Visscher, JP, de Hair, MJ, Gerlag, DM, Tak, PP
Clinical rheumatology. 2017;(2):269-278
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Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with changes in several hormones and metabolic peptides. Crosstalk between these factors and the immune system may be important for homeostasis during inflammation. Here, we studied the levels of hormones, metabolic peptides, and nutrients in individuals at risk for developing RA (at risk). In total, 18 hormones, metabolic peptides, and nutrients were measured in fasting serum samples from 45 autoantibody-positive individuals at risk, 22 RA patients, and 16 healthy subjects. Triglyceride (TG) levels were also measured in an independent validation cohort of 32 individuals at risk, 20 early arthritis patients, and 20 healthy controls. We found an elevated TG level in individuals at risk and significantly higher TG levels in RA patients compared to healthy controls. These results were confirmed in the validation cohort. Similarly, free fatty acid (FFA) levels showed an increase in individuals at risk and were significantly higher in RA patients compared to healthy controls. In RA patients, FFA levels were positively correlated with disease activity. Pancreatic polypeptide (PP) and norepinephrine levels were highly significantly increased in individuals at risk and RA patients compared to healthy controls. TG and FFA levels are increased in RA patients and positively correlated with disease activity parameters. The results presented here suggest a role for FFAs in the pathogenesis of RA. Furthermore, PP and norepinephrine may be a biomarker that could assist in the identification of individuals at risk.