Changes In Non-esterified Fatty Acids Research Articles

Associations of Early Pregnancy Metabolite Profiles with Gestational Blood Pressure Development.

Blood pressure development plays a major role in both the etiology and prediction of gestational hypertensive disorders. Metabolomics might serve as a tool to identify underlying metabolic mechanisms in the etiology of hypertension in pregnancy and lead to the identification of novel metabolites useful for the prediction of gestational hypertensive disorders. In a population-based, prospective cohort study among 803 pregnant women, liquid chromatography—mass spectrometry was used to determine serum concentrations of amino-acids, non-esterified fatty acids, phospholipids and carnitines in early pregnancy. Blood pressure was measured in each trimester of pregnancy. Information on gestational hypertensive disorders was obtained from medical records. Higher individual metabolite concentrations of the diacyl-phosphatidylcholines and acyl-lysophosphatidylcholines group were associated with higher systolic blood pressure throughout pregnancy (Federal Discovery Rate (FDR)-adjusted p-values < 0.05). Higher concentrations of one non-esterified fatty acid were associated with higher diastolic blood pressure throughout pregnancy (FDR-adjusted p-value < 0.05). Using penalized regression, we identified 12 individual early-pregnancy amino-acids, non-esterified fatty acids, diacyl-phosphatidylcholines and acyl-carnitines and the glutamine/glutamic acid ratio, that were jointly associated with larger changes in systolic and diastolic blood pressure from first to third trimester. These metabolites did not improve the prediction of gestational hypertensive disorders in addition to clinical markers. In conclusion, altered early pregnancy serum metabolite profiles mainly characterized by changes in non-esterified fatty acids and phospholipids metabolites are associated with higher gestational blood pressure throughout pregnancy within the physiological ranges. These findings are important from an etiological perspective and, after further replication, might improve the early identification of women at increased risk of gestational hypertensive disorders.

Acute Echocardiographic Effects of Exogenous Ketone Administration in Healthy Participants

Interest in therapeutic applications of exogenous ketones has grown significantly, spanning patients with heart failure to endurance athletes. Exogenous ketones engender significant effects on cardiac function in heart failure and provide an ergogenic benefit in athletes. The aim of this study was to assess the effects of exogenous ketones on cardiac function in healthy participants. In a single-arm intervention study, 20 fasting, healthy participants underwent comprehensive echocardiography (two-dimensional, Doppler, and strain) before and 30min after weight-based oral ketone ester administration. The relationship between changes in log-transformed biomarker levels and change in absolute global longitudinal strain (GLS) was assessed using linear regression. The mean age was 30±7years, 50% were women, 45% were nonwhite, and the average body mass index was 24.3±3.1kg/m2. Ketone ingestion acutely elevated β-hydroxybutyrate levels from a median of 0.13mmol/L (interquartile range, 0.10-0.37mmol/L) to 3.23mmol/L (interquartile range, 2.40-4.97mmol/L) (P<.001). After ketone ester consumption, systolic blood pressure, heart rate, biventricular function, left ventricular GLS, and left atrial (LA) strain all augmented, while systemic vascular resistance decreased. Displayed as mean change, increases in ejection fraction (3.1%; 95% CI, 2.0%-4.2%; P<.001), GLS (2.0%; 95% CI, 1.4%-2.7%; P<.001), right ventricular S' (1.1cm/sec; 95% CI, 0.4-1.8cm/sec; P=.004), LA reservoir strain (7%; 95% CI, 3%-12%; P=.005), and LA contractile strain (4%; 2%-6%; P=.001) were observed. During robustly achieved ketosis, change in GLS was inversely associated with change in nonesterified fatty acids (P=.019). In a single-arm study, systolic blood pressure, heart rate, biventricular function, and LV and LA strain acutely augmented after ketone ester ingestion in healthy, fasting participants, similar to several effects observed in the failing heart. These data may provide supporting data for the ergogenic benefits observed in athletes and may become increasingly relevant with exogenous ketone consumption across a variety of cardiovascular and noncardiovascular applications.

Markers of adipose tissue inflammation are transiently elevated during intermittent fasting in women who are overweight or obese

ObjectiveThis study compared the effects of daily calorie restriction (DR) versus intermittent fasting (IF) on markers of inflammation and extracellular matrix deposition in adipose tissue and skeletal muscle in a controlled feeding trial in women with overweight or obesity. MethodsWomen (N = 76) were randomised to one of three diets and provided with all foods at 100% (IF100) or 70% (IF70 and DR70) of calculated energy requirements for 8 weeks. IF groups ate breakfast prior to fasting for 24-h on 3 non-consecutive days/week. Weight, body composition, serum non-esterified fatty acids (NEFA), tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-10 (IL-10), M1- and M2-macrophage markers by qPCR and immunohistochemistry in adipose tissue and skeletal muscle were measured following a 12-h overnight fast (fed day, all groups) and a 24-h fast (IF groups only). ResultsIF70 resulted in greater weight and fat losses and reductions in serum NEFA versus DR70 and IF100 (P < 0.05) after fed days. Markers of inflammation in serum (TNFα, IL6 and IL10), subcutaneous adipose tissue and skeletal muscle (CD68, CD40 and CD163) were unchanged by DR or IF after fed days. After fasting, NEFA, M1-macrophages (CD40+) in adipose tissue, and M2-macrophages (CD163+) in muscle were increased in IF70 and IF100 (all P < 0.05) and the changes in NEFA and mRNA of pan-macrophage marker CD68 in adipose tissue were positively correlated (r = 0.56, P = 0.002). ConclusionsUnlike caloric restriction, IF transiently elevated markers of macrophage infiltration in adipose tissue and skeletal muscle, possibly in response to marked increases in adipose tissue lipolysis.

A high-MUFA diet alone does not affect ketone body metabolism, but reduces glycated hemoglobin when combined with exercise training in diabetic rats

Abstract Background Monounsaturated fat (MUFA) also has glucose-lowering action, but its effect on ketone bodies is unknown. Objectives To examine the effects of high-MUFA diet alone or in combination with exercise training, which can improve glucose and ketone body metabolism, in a rat model of diabetes. Methods Wistar rats were administered streptozotocin to induce diabetes and then randomly divided into five groups: sedentary rats fed a regular diet (1), a high-saturated-fat diet (2), a high-MUFA diet (3); and exercisetrained rats fed a regular diet (4), and a high-MUFA diet (5). Training was by a treadmill twice daily, 5 days/week. At 12 weeks, glucose, glycated hemoglobin (HbA1c), insulin, nonesterified fatty acids (NEFA), and β-hydroxybutyrate levels were measured in cardiac blood. Activity of the overall ketone synthesis pathway was determined in liver and 3-ketoacyl-CoA transferase activity determined in gastrocnemius muscle. Results A high-MUFA diet tended to lower plasma glucose without affecting other biochemical variables. Training did not change glucose metabolism, but significantly reduced serum NEFA. Only the high-MUFA diet plus training significantly decreased HbA1c levels. Hepatic ketone synthesis was decreased and 3-ketoacyl-CoA transferase activity was increased by training alone or in combination with a high-MUFA diet. Changes in NEFA, β-hydroxybutyrate, and the enzymatic activities in response to training plus a high-MUFA diet were comparable to those caused by training alone. Conclusion A high-MUFA diet alone does not alter ketone body metabolism. Combination of a MUFA-rich diet and exercise training is more effective than either MUFA or exercise alone for lowering HbA1c.

Acute Changes in Non-esterified Fatty Acids in Patients with Type 2 Diabetes Receiving Bariatric Surgery

The purpose of this study was to compare acute changes of non-esterified fatty acids (NEFA) in relation to beta cell function (BCF) and insulin resistance in obese patients with type 2 diabetes (T2D) who underwent laparoscopic gastric bypass (GBP), laparoscopic sleeve gastrectomy (SG) or very low calorie diet (VLCD). In a non-randomised study, fasting plasma samples were collected from 38 obese patients with T2D, matched for age, body mass index (BMI) and glycaemic control, who underwent GBP (11) or SG (14) or VLCD (13). Samples were collected the day before and 3days after the intervention, during a 75-g oral glucose tolerance test. Glucose, insulin, c-peptide, glucagon like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured, and individual NEFAs were measured using a triple-quadrupole liquid chromatography-mass spectrometry (LC-MS/MS). BCF by mathematical modelling and insulin resistance were estimated. Palmitic acid significantly decreased after each intervention. Monounsaturated/polyunsaturated ratio (MUFA/PUFA) and unsaturated/saturated fat ratios increased after each intervention. BCF was improved only after VLCD. Linoleic acid was positively correlated with total insulin secretion (p=0.03). Glucose sensitivity correlated with palmitic acid (p=0.01), unsaturated/saturated ratio (p=0.0008) and MUFA/PUFA (p=0.009). HOMA-IR correlated with stearic acid (p=0.03), unsaturated/saturated ratio (p=0.005) and MUFA/PUFA (p=0.009). GIP AUC0-120 correlated with stearic acid (p=0.04), but not GLP-1. GBP, SG and VLCD have similar acute effects on decreasing palmitic acid. Several NEFAs correlated with BCF parameters and HOMA-IR.

Metabolic profiles of high-yielding dairy cows with ovarian cysts formation

Background: Ovarian cysts are among the diseases which cause reproductive failure and economic losses in dairy herds. High yelding dairy cattles are suseptable to reproductive failure caused by ovarian cysts, as a result of their exposure to stressful coditions during lactation. OBJECTIVES: This study aimed to monitor metabolic profile tests in dairy cows with ovarian cysts in comparison with cycling cows. METHODS: Forty high-yelding Holstein dairy cows were enrolled for this study (20 cows with ovarian cysts and 20 cyclic cows). Seven weeks after parturation, 40 cows without retained placenta, including healthy ones were selected. Ovarian cysts were detected as follicular-like structures, >20 mm in diameter, persisting for at least 7 days, without corpus luteum and were monitored by ultrasound examination. Blood samples were collected from the jugular vein and delivered to the laboratory for measurement of calcium, magnesium, phosphorus, sodium, potassium, beta-hydroxy butyric acid, non esterified fatty acids (NEFA), glucose, cortisol, insulin and BUN. RESULTS: In this study, when serum calcium, phosphorus, sodium, potassium, magnesium and glucose of cows with ovarian cysts were compared with cows that had normal ovarian status, there was no significant difference. BUN, beta-hydroxy butyrate, NEFA and cortisol of cows with ovarian follicular cysts as compared to the cows with normal ovaries, showed a significant increase. Serum insulin values decreased significantly in ovarian follicular cystic cows than in cyclic cows. CONCLUSIONS: Increasing blood cortisol and decreasing blood insulin may play a major role in the formation of ovarian cyst and any detectable change in NEFA, BHBA and BUN.

Sex-related differences in the effects of the mediterranean diet on glucose and insulin homeostasis.

Objective. To document sex differences in the impact of the Mediterranean diet (MedDiet) on glucose/insulin homeostasis and to verify whether these sex-related effects were associated with changes in nonesterified fatty acids (NEFA). Methods. All foods were provided to 38 men and 32 premenopausal women (24–53 y) during 4 weeks. Variables were measured during a 180 min OGTT before and after the MedDiet. Results. A sex-by-time interaction for plasma insulin iAUC was found (men: −17.8%, P = 0.02; women: +9.4%, P = 0.63; P for sex-by-time interaction = 0.005). A sex-by-time interaction was also observed for insulin sensitivity (Cederholm index, P = 0.03), for which only men experienced improvements (men: +8.1%, P = 0.047; women: −5.9%, P = 0.94). No sex difference was observed for glucose and C-peptide responses. Trends toward a decrease in NEFA AUC (P = 0.06) and an increase in NEFA suppression rate (P = 0.06) were noted, with no sex difference. Changes in NEFA were not associated with change in insulin sensitivity. Conclusions. Results suggest that the more favorable changes in glucose/insulin homeostasis observed in men compared to women in response to the MedDiet are not explained by sex differences in NEFA response. This clinical trial is registered with clinicaltrials.gov NCT01293344.

Challenges of a mechanistic feedback model describing nicotinic acid-induced changes in non-esterified fatty acids in rats

Previously, we developed a feedback model to describe the tolerance and oscillatory rebound of non-esterified fatty acid (NEFA) plasma concentrations in male Sprague Dawley rats after intravenous infusions of nicotinic acid (NiAc). This study challenges that model, using the following regimens of intravenous and oral NiAc dosing in male Sprague Dawley rats (n = 95) to create different patterns of exposure: (A) 30 min infusion at 0, 1, 5 or 20 μmol kg(-1) body weight; (B) 300 min infusion at 0, 5, 10 or 51 μmol kg(-1); (C) 30 min infusion at 5 μmol kg(-1), followed by a stepwise decrease in rate every 10 min for 180 min; (D) 30 min infusion at 5 μmol kg(-1), followed by a stepwise decrease in rate every 10 min for 180 min and another 30 min infusion at 5 μmol kg(-1) from 210 to 240 min; (E) an oral dose of 0, 24.4, 81.2 or 812 μmol kg(-1). Serial arterial blood samples were taken for measurement of plasma NiAc and NEFA concentrations. The gradual decrease in infusion rate in (C) and (D) were also designed to test the hypothesis that a gradual reduction in NiAc plasma concentration may be expected to reduce or prevent rebound. The absorption of NiAc was described by parallel linear and non-linear processes and the disposition of NiAc by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. NEFA (R) turnover, which was driven by the plasma concentration of NiAc via an inhibitory drug-mechanism function acting on NEFA formation, was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M 1) inhibited the formation of R and the last compartment (M N ) stimulated the loss of R. All processes regulating the plasma NEFA concentration were assumed to be captured by the moderator function. Data were analyzed using non-linear mixed effects modeling (NONMEM). The potency IC 50 of NiAc was 68 nmol L(-1), the fractional turnover rate k out 0.27 L mmol(-1) min(-1), and the turnover rate of moderator k tol 0.023 min(-1). The lower physiological limit of NEFA, which was modeled as a NiAc-independent release (k cap ) of NEFA into plasma, was estimated to 0.023 mmol L(-1) min(-1). The parameter estimates derived in this study were consistent with our previous estimates, suggesting that the model may be used for prediction of the NEFA response time-course following different modes and routes administration of NiAc or NiAc analogues. In order to avoid NiAc-induced NEFA rebound, a slow decline in the NiAc exposure pattern is needed at or below IC (50).

Type 2 Diabetes Associated Changes in the Plasma Non-Esterified Fatty Acids, Oxylipins and Endocannabinoids

Type 2 diabetes has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well-described in diabetes, effects on signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of bioactive fatty acid metabolites with many structural members that influence insulin signaling, adipose function and inflammation through autocrine, paracrine and endocrine mechanisms. To link diabetes-associated changes in plasma NEFA and signaling lipids, we quantitatively targeted >150 plasma lipidome components in age- and body mass index-matched, overweight to obese, non-diabetic (n = 12) and type 2 diabetic (n = 43) African-American women. Diabetes related NEFA patterns indicated ∼60% increase in steroyl-CoA desaturase activity and ∼40% decrease in very long chain polyunsaturated fatty acid chain shortening, patterns previously associated with the development of nonalcoholic fatty liver disease. Further, epoxides and ketones of eighteen carbon polyunsaturated fatty acids were elevated >80% in diabetes and strongly correlated with changes in NEFA, consistent with their liberation during adipose lipolysis. Endocannabinoid behavior differed by class with diabetes increasing an array of N-acylethanolamides which were positively correlated with pro-inflammatory 5-lipooxygenase-derived metabolites, while monoacylglycerols were negatively correlated with body mass. These results clearly show that diabetes not only results in an increase in plasma NEFA, but shifts the plasma lipidomic profiles in ways that reflect the biochemical and physiological changes of this pathological state which are independent of obesity associated changes.

Quercetin alters energy metabolism in swimming mice

Quercetin has been demonstrated to be effective in increasing physical endurance in mice and humans. However, the mechanisms involved are not fully understood. In this study, male Kunming mice were fed a diet containing 0.1% quercetin for 14 days before swimming for 60 min. The overall serum metabolic profile was investigated by a ¹H nuclear magnetic resonance-based metabolomic approach. Serum glucose, lactate, nonesterified fatty acids (NEFA), and nonprotein nitrogen (NPN), as well as hepatic and muscular glycogen were measured biochemically. The results of metabolomic analysis showed that swimming induced a significant change in serum metabolic profile. Relative increases in the levels of lactate, alanine, low-density lipoprotein-very low-density lipoprotein, and unsaturated fatty acids, and decreases in choline, phosphocholine, and glucose were observed after swimming. With quercetin supplementation, these changes were attenuated. The results of biochemical assays were consistent with the data obtained from metabolomic analysis, in that serum NEFA was increased while lactate and NPN decreased after exposed to quercetin in swimming mice. Similar change in NEFA was also found in liver and gastrocnemius muscle tissues. Our current findings suggest that quercetin alters energy metabolism in swimming mice and increased lipolysis may contribute to the actions of quercetin on physical endurance.

Quantitative analysis of rate and extent of tolerance of biomarkers: Application to nicotinic acid-induced changes in non-esterified fatty acids in rats

In this paper we quantitatively evaluate two feedback systems with a focus on rate and extent of tolerance and rebound development. In the two feedback systems, the regulation of turnover of response is governed by one or several moderators. In the basic system, one single moderator inhibits the formation of response. This system has been applied to cortisol secretion and serotonin reuptake inhibition. The basic system has been extended to adequately describe nicotinic acid (NiAc)-induced changes in non-esterified fatty acids (NEFA). In the extended system, the feedback is described by a cascade of moderators where the first inhibits formation of response and the last stimulates loss of response. The objectives of this paper were to analyze these systems from a mathematical/analytical and quantitative point of view and to present simulations with different parameter settings and dosing regimens in order to highlight the intrinsic behaviour of these systems and to present expressions and graphs that are applicable for quantification of rate and extent of tolerance and rebound. The dynamics of the moderators ( k tol ) compared to the dynamics of the response ( k out ), was shown to be important for the behaviour of both systems. For instance, slow dynamics of the moderator compared to the response ( k tol << k out ), resulted in overshoot and pronounced rebound. The extent of tolerance was studied over time at a single constant drug concentration and at steady state for different drug concentrations and was found to be largest at drug concentrations close to IC 50. An upper limit for the response could be identified and included in the quantification of extent of rebound. Especially, for the extended system, the duration of exposure was an important factor affecting size of rebound. The rate of tolerance development was addressed by quantitatively estimating the time to steady state for the two systems, in which the value of k tol and the length of the cascade were critical.

Activity of hepatic but not skeletal muscle carnitine palmitoyltransferase enzyme is depressed by intravenous glucose infusions in lactating dairy cows*

A positive energy balance in dairy cows pre-partum may decrease hepatic carnitine palmitoyltransferase (CPT) enzyme activity, which might contribute to disturbances of lipid metabolism post-partum. The purpose of this study was to investigate whether skeletal muscle CPT activity can also be downregulated during positive energy balance. Mid-lactating dairy cows were maintained on intravenous infusion of either saline (control) or glucose solutions that increased linearly over 24 days, remained at the 24-day level until day 28 and were suspended thereafter. Liver and skeletal muscle biopsies, as well as four diurnal blood samples, were taken on days 0, 8, 16, 24, and 32, representing infusion levels equivalent to 0%, 10%, 20%, 30% and 0% of the net energy for lactation (NE(L)) requirement respectively. Glucose infusion increased serum insulin concentrations on day 16 and 24 while plasma glucose levels were increased at only a single time point on day 24. Serum beta-hydroxybutyric acid concentrations decreased between day 8 and 24; whereas changes in non-esterified fatty acids were mostly insignificant. Total lipid contents of liver and skeletal muscle were not affected by treatment. Hepatic CPT activity decreased with glucose infusion (by 35% on day 24) and remained decreased on day 32. Hepatic expression levels of CPT-1A and CPT-2 mRNA were not significantly altered but tended to reflect the changes in enzyme activity. In contrast to the liver, no effect of glucose infusion was observed on skeletal muscle CPT activity. We conclude that suppression of CPT activity by positive energy balance appears to be specific for the liver in mid-lactating dairy cows.

Acute endurance exercise increases skeletal muscle uncoupling protein-3 gene expression in untrained but not trained humans

In rodents, acute exercise increases skeletal muscle uncoupling protein (UCP) gene expression and is associated with elevations in serum nonesterified fatty acids (NEFA). To test whether contractions increase UCP mRNA levels in humans, vastus lateralis biopsies were obtained 1 hour postexercise from untrained and trained subjects and analyzed for UCP-2 and UCP-3 long (UCP-3L) and short (UCP-3S) isoforms. The acute exercise bout (graded cycling protocol; 65% to 85% relative V̇o2max) induced significant (P <.01) elevations in serum NEFA in both untrained and trained subjects, but the increase in untrained subjects was significantly (P <.05) greater (60% v 30%). Ribonuclease protection assay demonstrated that basal levels of all UCP isoforms measured were similar between the 2 groups. However, acute exercise induced a significant increase (P <.02) in both UCP-3L and UCP-3S, but not UCP-2 mRNA levels in untrained, but not trained subjects. Correlation analysis did not show a significant relationship between exercise-induced changes in NEFA and UCP-3 levels. These results demonstrate that acute endurance exercise increases UCP-3 gene expression only in untrained skeletal muscle, but this effect does not seem to be tightly linked to the exercise-induced fluctuations in serum NEFA levels. Copyright 2003, Elsevier Science (USA). All rights reserved.

Increasing plasma fatty acids elevates F2-isoprostanes in humans: implications for the cardiovascular risk factor cluster.

To determine whether raised concentrations of non-esterified fatty acids (NEFAs) may contribute to the cardiovascular risk factor cluster by increasing oxidative stress in vivo. Plasma and urine F2-isoprostanes, biomarkers of oxidative stress, were measured after an overnight fast and during a 4 h infusion of Intralipid and heparin to increase NEFAs in 10 obese hypertensive patients with and 12 healthy normotensive individuals without evidence of insulin resistance. A time-control group of nine healthy normotensive individuals received saline and heparin. Plasma F2-isoprostanes increased more in obese hypertensive individuals than in lean normotensive individuals after 2 h (14.9 +/- 2.8 ng/ml compared with 4.6 +/- 2.8 ng/ml; P < 0.05) but not after 4 h (10.3 +/- 2.5 ng/ml compared with 8.1 +/- 4.1 ng/ml; NS) of the Intralipid and heparin infusion. When obese and lean individuals were combined, plasma (+9.1 +/- 2.5 ng/ml; P < 0.05) and urine (+0.7 +/- 0.3 ng/mg creatinine; P < 0.05) F2-isoprostanes increased by about 20% after 4 h of Intralipid and heparin, whereas plasma F2-isoprostanes decreased by approximately 20% (-9.7 +/- 4.5 ng/ml; P < 0.05) after 4 h of saline and heparin. When individuals from both infusions were combined, the correlation between changes in plasma NEFAs and F2-isoprostanes after 4 h persisted after controlling for changes in triglyceride concentrations (partial r = 0.49; P < 0.01), whereas the correlation between changes in triglycerides and F2-isoprostanes did not persist after controlling for changes in NEFA concentrations (partial r = 0.33, NS). The findings indicate that an acute increase in plasma lipids increases the concentration of F2-isoprostanes, biomarkers of oxidative stress, especially in obese hypertensive individuals. The observations raise the possibility that increased concentrations of NEFAs contribute to the cardiovascular risk factor cluster through oxidative-stress-sensitive mechanisms.

Effects of phenylalanine and tyrosine on cold acclimation in mice

The effects of phenylalanine (PHE) and tyrosine (TYR) on cold acclimation were studied in mice of the ddY strain. At 5 weeks of age, mice were maintained at 4 degrees C for 4 weeks. Test groups of mice were supplied with a 0.05% (w/v) solution of PHE or TYR as drinking water in addition to water. We measured changes in body weight, intake of water and food, rectal temperature upon acute exposure to -20 degrees C, weight of interscapular brown adipose tissue (BAT) and the levels of glucose, nonesterified fatty acids (NEFA) and 3H-butyrate in the blood prior to and after exposure to the lower temperature of -20 degrees C. Chronic exposure to cold (4 degrees C) reduced body-weight gain for the first two weeks but weight gain recovered within the next two weeks. PHE and TYR partially inhibited the gain in body weight under exposing to cold. TYR reduced the gain of body weight under room temperature. Exposure to cold stimulated the daily consumption of food. Both PHE and TYR somewhat enhanced the food intake when exposed to cold. Exposure to cold rendered mice resistant to severe cold (-20 degrees C). Both PHE and TYR did not reduce this resistance except in the early state in the case of TYR. Exposure to cold increased the weight of BAT but both PHE and TYR prevented this increase. The effect of TYR was determined in the case fed under room temperature. Cold exposure changed the utilization of glucose, NEFA and 3H-butyrate in the blood when exposed to severe cold (-20 degrees C). Both PHE and TYR prevented the change in NEFA. It remains to be confirmed whether the growth of brown adipocytes is always necessary when mice acclimate to cold.

Changes in serum free thyroxine, free tri-iodothyronine and thyroid stimulating hormone reference intervals in normal term pregnant women

SummaryQuantitation of serum free thyroxine (free T4) and free tri-iodothyronine (free T3) concentrations in pregnancy should theoretically avoid such confounding factors as low serum albumin, pregnancy changes in non-esterified fatty acids, and changes in thyroid binding globulin. The purpose of this study was to establish reference intervals for serum free T4 and T3, and thyroid stimulating hormone (TSH) in 120 healthy pregnant women during the third trimester, using assays unaffected by these factors. Reference intervals were determined as the central 95th centile confidence interval using non-parametric rank number analysis. Serum free T4 and T3 reference intervals both decreased, and the serum TSH reference interval increased when compared with non-pregnant levels. These changes are physiological, and show the importance of using pregnancy specific reference intervals for serum free T3 and T4 and TSH measurement when assessing thyroid function in the pregnant patient.

Effects of recombinant human IGF-I on glucose and leucine kinetics in men.

To examine the effects of recombinant human (rh) insulin-like growth factor I (IGF-I), insulin, and saline on metabolic parameters, we studied 20 young nonobese healthy men. Euglycemic clamps with 240-min IGF-I infusions at two doses (49 and 33 pmol.kg-1 x min-1, n = 8 and 12 subjects) were performed and compared with hyperinsulinemic-euglycemic clamps (2.25 pmol.kg-1 x min-1, n = 9). Leucine and glucose kinetics were examined with L-[1-13C]leucine and [3-3H]glucose. Glucose rate of appearance (Ra) declined equivalently in the 49 pmol.kg-1.min-1 IGF-I and insulin clamps but remained at basal levels during the 33 pmol.kg-1 x min-1 IGF-I infusions. In contrast, Rd of glucose was increased by 176% in the 49 pmol.kg-1 x min-1 IGF-I and 78% in the 33 pmol.kg-1 x min-1 IGF-I infusions. Furthermore, to prevent hypoglycemia after the termination of both rhIGF-I infusions, it was necessary to infuse glucose for an additional 2-20 h. Ra of leucine was suppressed significantly by both IGF-I and insulin, whereas leucine oxidation was not affected by either hormone. Therefore, the rate of disappearance of leucine expressed as the difference between Ra and oxidation rates was significantly reduced in all clamps. In addition, IGF-I significantly suppressed beta-cell secretion without affecting the other glucoregulatory hormones. In contrast to insulin, IGF-I had no apparent effect on lipolysis, as measured by changes in nonesterified fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute inhibition of lipolysis on operation of the glucose-fatty acid cycle in hepatic cirrhosis

Hepatic cirrhosis is frequently associated with glucose intolerance and insulin resistance, but the mechanisms underlying the insulin insensitivity are unknown. Plasma concentrations of nonesterified fatty acids (NEFA) are typically elevated in cirrhosis, and the glucose-fatty acid cycle provides a mechanism by which fatty acids may play a role in regulating glucose metabolism. We have therefore investigated the effect of acute inhibition of lipolysis, using the nicotinic acid analogue, acipimox, in 10 male patients with cirrhosis. All subjects were studied in the postabsorptive state after a 10- to 12-hour fast and were given either acipimox 250 mg or a placebo orally 2 hours before a 75-g oral glucose tolerance test (OGTT) and an infusion of insulin (50 mU/kg/h) and glucose (6 mg/kg/min) (insulin sensitivity tests [IST]). The drug was taken in a double-blind crossover design for each test. During the 2 hours following acipimox, there were rapid decreases in plasma NEFA, glycerol, and 3-hydroxybutyrate, confirming inhibition of lipolysis, while there were significant decreases in glucose, insulin, and C-peptide ( P < .001) compared with patients receiving the placebo. Acipimox blunted the increase in glucose after oral glucose loading and decreased incremental glucose concentration (from 579 ± 76 to 445 ± 65 mmol/min/L, P < .02) and incremental insulin concentration (from 13.4 ± 2.5 to 9.0 ± 1.4 U/min/L, P = .056) in the OGTT. Improvements in classification of glucose tolerance were seen in five subjects. During the IST, significant reductions occurred in steady-state blood glucose (to 8.8 ± 1 mmol/L, P < .02) and C-peptide (to 3.0 ± 0.5 nmol/L, P < .05). A significant correlation was seen between the change in NEFA incremental area in the basal period and the change in incremental glucose area of the OGTT, in response to acipimox. Although these findings support the operation of the glucose-fatty acid cycle in cirrhosis, the metabolic clearance for glucose and the insulin sensitivity index were not significantly improved when free fatty acid concentrations were fully suppressed, and thus gross insulin resistance persisted. The modulation of carbohydrate metabolism by short-term changes in NEFA is insufficient to account for the glucose intolerance of cirrhosis.

Effect of lidocaine on the accumulation of non-esterified fatty acids in the ischemic perfused rat heart

The effect of lidocaine on the accumulation of non-esterified fatty acids (NEFA) was investigated in the isolated, perfused working rat heart. Ischemia was induced by loweering the afterload pressrre to 0 mm Hg for 20 min, and reperfusion was induced by raising the pressure to the pre-ischemia value (60 mm Hg) for 20 min. The heart was frozen for biochemical studies immediately after ischemia or reperfusion. Ischmiia decreased the mechanical function, increased the levels of palmitoleic, arachidonic and linoleic acids, left unchanged the levels of oleic, lauric, myristic, palmitic and stearic acids, decreased the levels of adenosine triphosphate (ATP), creatine phosphate (CrP), decreased the energy charge potential (ECP) and increased the level of lactate. Lidocaine (10 −5 or 3 × 10 −5 M) improved the mechanical function and attenuated the changes in NEFA, ATP, CrP, and ECP caused by ischemia. These findings suggest that lidocaine attenuates the ischemia- and reperfusion-induced metabolic changes in the myocardium.

Effect of propranolol on accumulation of NEFA in the ischemic perfused rat heart

The effect of propranolol on the accumulation of non-esterified fatty acids (NEFA) in the isolated, perfused working rat heart was investigated. Ischemia was induced by lowering the afterload pressure to 0 mm Hg for 20 min and for reperfusion, the pressure was raised to the pre-ischemic pressure (60 mm Hg) for 20 min. The heart was frozen for biochemical studies immediately after ischemia or reperfusion. Ischemia decreased mechanical function, increased the levels of palmitoleic, arachidonic and linoleic acids, left oleic, lauric, myristic, palmitic and stearic acids unchanged, decreased the levels of adenosine triphosphate (ATP), creatine phosphate (CrP) and the energy charge potential (ECP), and increased the level of lactate. Propranolol (10 −5 or 3 × 10 −5 M) restored mechanical function and inhibited the changes in NEFA, ATP and ECP caused by ischemia. It is suggested that propranolol inhibits the decrease in mechanical function and high energy phosphates caused by ischemia, and thereby inhibits the accumulation of NEFA, especially of the unsaturated fatty acids such as arachidonic acid, during ischemia.