Non-esterified Fatty Acid Kinetics Research Articles

Abnormal Non Esterified Fatty Acid Suppression After a Mixed Meal Test in Patients With Partial Lipodystrophy

Elevated levels of non-esterified fatty acids (NEFA) have been observed in individuals with several clinical scenarios of insulin resistance, such as in diabetes mellitus and lipodystrophy. Insulin is a well-known stimulator of de novo lipogenesis. Despite the reduction of adipose tissue mass, paradoxically elevated circulating NEFA concentrations have been observed in patients with different lipodystrophy syndromes. Aiming to understand the behavior of NEFA in lipodystrophy versus common Type 2 diabetes mellitus during feeding, we compared NEFA kinetics during a mixed meal test in patients with partial lipodystrophy (PL) and Type 2 diabetes mellitus (DM). We reviewed data from 17 PL patients (13F/4M, ages 12–64) matched by gender and BMI to 20 DM patients (13F/7M, ages 24–72). All patients were evaluated during fasting state and then underwent a mixed meal test (MMT). Blood samples were collected before (fasting) and at 30, 60, 90, 120, and 180 minutes post-meal to measure glucose, insulin, non-esterified free fatty acids (NEFA), and triglyceride levels. Adipose tissue insulin resistance (ADIPO-IR) and homeostatic model of insulin resistance (HOMA-IR) were calculated from the fasting measurements, and the area under the curve (AUC) and maximum percentage of change from baseline were calculated from the MMT data. Fasting insulin and triglyceride (Tg) levels were lower in the DM group compared to the PL group (Insulin: 24.4±13.7 vs. 68.0±67.2 pmol/L, p=0.003 and Tg: 168.0±107.7 vs. 1378.3±1927.3 mg/dL, p<0.001). HOMA-IR was significantly higher in the PL group compared to the DM group (6.0±2.1 vs. 3.3±1.5, p=0.005), as well as ADIPO-IR (297.0±241.1 vs. 115.3±80.1, p=0.03). NEFA, glucose and triglyceride AUC were significantly higher in the PL group compared to the DM group. Patients with PL had higher glucose and triglyceride levels throughout the MMT at all-time points. Interestingly, NEFA levels were similar in both groups at baseline, but the PL group suppressed NEFA less than DM group (54.9±13.3% vs. 69.2±11.1%, p=0.002) despite higher insulin levels. Additionally, we divided the PL group according to the presence of a pathogenic variant in the lamin A gene (n=8) versus those without mutations in this gene (n=9), but there were no notable differences among these subgroups with respect to NEFA levels at baseline or during the meal. These findings support the need to better understand and address the origins of abnormal NEFA kinetics and adipose tissue insulin resistance in PL patients.

Effect of liraglutide on estimates of lipolysis and lipid oxidation in obese patients with stable coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial.

Elevated levels of non-esterified fatty acids (NEFA) play a role in insulin resistance, impaired beta-cell function and they are a denominator of the abnormal atherogenic lipid profile that characterizes obese patients with type 2 diabetes (T2DM). We hypothesized that the GLP-1 receptor agonist liraglutide, in combination with metformin, would reduce lipolysis. In a randomized, double-blind, placebo-controlled, cross-over trial, 41 T2DM patients with coronary artery disease were randomized and treated with liraglutide-metformin vs placebo-metformin during 12- + 12-week periods with a wash-out period of at least 2 weeks before and between the intervention periods. NEFA kinetics were estimated using the Boston Minimal Model of NEFA metabolism, with plasma NEFA and glucose levels measured during a standard 180-minute frequently sampled intravenous glucose tolerance test. Liraglutide-metformin reduced estimates of lipolysis. Furthermore, placebo-metformin increased estimates of lipid oxidation, while treatment with liraglutide eliminated this effect. We conclude that liraglutide exerts a clinically relevant reduction in estimates of lipolysis and lipid oxidation which is explained, in part, by improved insulin secretion, as revealed by an intravenous glucose tolerance test.

Alterations in plasma non-esterified fatty acid (NEFA) kinetics and relationship with insulin resistance in polycystic ovary syndrome.

Are non-esterified fatty acid (NEFA) kinetics altered in women with polycystic ovary syndrome (PCOS)? Women with PCOS, particularly obese subjects, have dysregulated plasma NEFA kinetics in response to changes in plasma insulin and glucose levels, which are associated with insulin resistance (IR) independently of the fasting plasma NEFA levels. Elevated plasma NEFA levels are associated with IR in many disorders, although the homeostasis of NEFA kinetics and its relationship to IR in women with PCOS is unknown. We prospectively compared insulin sensitivity and NEFA kinetics in 29 PCOS and 29 healthy controls women matched for BMI. This study was conducted in a tertiary institution. Plasma NEFA, glucose and insulin levels were assessed during a modified frequently sampled intravenous glucose tolerance test (mFSIVGTT). Minimal models were used to assess insulin sensitivity (Si) and NEFA kinetics (i.e. model-derived initial plasma NEFA level [NEFA0], phi constant [Φ], reflecting glucose-mediated inhibition of lipolysis and measures of maximum rate of lipolysis [SFFA] and NEFA uptake from plasma [KFFA]). The study provides new evidence that women with PCOS have defective NEFA kinetics characterized by: (i) lower basal plasma NEFA levels, measured directly and modeled (NEFA0), and (ii) a greater glucose-mediated inhibition of lipolysis in the remote or interstitial space (reflected by a lower affinity constant [Φ]). There were no differences, however, in the maximal rates of adipose tissue lipolysis (SFFA) and the rate at which NEFA leaves the plasma pool (KFFA). The differences observed in NEFA kinetics were exacerbated, and almost exclusively observed, in the obese PCOS subjects. Our study did not study NEFA subtypes. It was also cross-sectional and based on women affected by PCOS as defined by the 1990 National Institutes of Health (NIH) criteria (i.e. Phenotypes A and B) and identified in the clinical setting. Consequently, extrapolation of the present data to other phenotypes of PCOS should be made with caution. Furthermore, our data is exploratory and therefore requires validation with a larger sample size. Dysfunction in NEFA kinetics may be a marker of metabolic dysfunction in nondiabetic obese women with PCOS and may be more important than simply assessing circulating NEFA levels at a single point in time for understanding the mechanism(s) underlying the IR of PCOS. This work was supported by NIH grants R01-DK073632 and R01-HD29364 to R.A.; a Career Development Award from MD Medical Group, Moscow, RF, to D.L. and Augusta University funds to Y.-H.C. RA serves as consultant to Ansh Labs, Medtronics, Spruce Biosciences and Latitude Capital. U.E., Z.A., D.L., R.M., Y.-H.C., R.C.B. and Y.D.I.C. have no competing interests to declare. Not applicable.

0071 ROLE OF SLEEP RESTRICTION IN ADIPOCYTE INSULIN SENSITIVITY DURING AN INTRAVENOUS GLUCOSE TOLERANCE TEST IN HEALTHY ADULT MEN

Sleep restriction, or chronic partial sleep loss, increases obesity and diabetes risk by disrupting glucose metabolism and reducing whole-body insulin sensitivity without a compensatory increase in insulin secretion. Healthy adipocytes suppress hormone sensitive lipase (HSL) activity in response to insulin, which severely limits non-esterified fatty acid (NEFA) release. Elevated overnight NEFA levels are correlated with the reduction in insulin sensitivity that occurs in sleep restriction. Additionally, subcutaneous adipose biopsies from sleep-restricted subjects have reduced pAKT, evidence that sleep restriction decreases insulin sensitivity in adipocytes. The objective of this pilot study was to extend previous findings of the effects of sleep restriction on plasma glucose to mechanistic shifts within adipocyte metabolism. Subjects (20–35 y/o) were enrolled in an 11-day in-lab protocol; light exposure, activity, temperature, and diet were carefully controlled. An intravenous glucose tolerance test (IVGTT) was performed at three time points: after three nights of baseline sleep (10 hrs/night), after five nights of sleep restriction (5 hrs/night), and after two nights of recovery sleep (10 hrs/night). NEFA were quantified (Wako Diagnostics) and parameters describing NEFA kinetics (i.e. rate of NEFA production, utilization, suppression threshold) in the Boston and Moate minimal model were calculated using WinSAAM Compartmental Modeling software. Five subjects completed the sleep restriction protocol; one did not complete IVGTT procedures for safety reasons. Preliminary results from four subjects show the fractional rate of NEFA utilization was increased by 0.024 [0.009, 0.039] min-1 in the restricted condition (p=0.008). Restriction also increased the modifier of the inhibitory effect of remote glucose on NEFA production by 4.3 fold [1.2, 15.9] from baseline (p=0.04). Sleep restriction induces symmetrical changes in both glucose and lipid markers of insulin sensitivity in vivo. Preliminary evidence indicates that NEFA rate of utilization is increased in response to sleep restriction. In the context of whole-body metabolism, this indicates a shift in Randle cycle fuel selection by metabolic tissues. Additionally, a greater concentration of glucose was required to initiate NEFA suppression, evidence that sleep restriction functionally impairs HSL activity. UL1TR000127 (Chang PI) T32GM108563 (to KMN; Korzick PI).

Abstract 610: Ineffective Suppression of Adipocyte Lipolysis in Metabolic Syndrome: An in vivo Test for Adipocyte Insulin Resistance

Background: Insulin resistance is a major contributor to metabolic syndrome, disrupting both glucose and non-esterified fatty acid (NEFA) dynamics through ineffective glucose clearance and decreased suppression of lipid droplet lipolysis. The minimal model of glucose dynamics is used for glycemic insulin sensitivity however it does not measure adipocyte insulin sensitivity, the primary determinant of plasma NEFA. An in-vivo approach to measuring adipocyte insulin sensitivity using NEFA is employed, comparing healthy and metabolic syndrome subjects. Both the models are employed to estimate insulin sensitivity and validate the NEFA approach. Objective: To test the use of NEFA kinetics to measure adipocyte insulin sensitivity compared to the glucose minimal model. Approach and results: Metabolic syndrome (n=56) and optimally healthy (n=14) subjects underwent a frequently sampled intravenous glucose tolerance test, and plasma analyzed for insulin, glucose, and NEFA. Insulin sensitivity ( S I ) and glucose effectiveness ( S G ) were calculated from the glucose minimal model. S I was 1.7 (mU/L) -1 min -1 and 0.40 (mU/L) -1 /min -1 and S G was 0.027 min -1 and 0.017 min -1 for the healthy and metabolic syndrome groups, respectively, indicating substantial glycemic insulin resistance in the latter. A model using glucose as the driver for NEFA kinetics was then applied. We found the initial rate of NEFA utilization by tissues (NU) was less, but the threshold glucose (tG) and glucose concentration required for a unit change in lipolysis inhibition ( G i ) were greater in metabolic syndrome verses healthy (NU: 0.050[0.045, 0.057] vs. 0.068[0.054, 0.086] p=0.03; tG: 6.7[6.2, 7.2] vs. 5.0[4.3, 5.9] p=0.001; G i : 0.30[0.25, 0.35] vs. 0.17[0.07, 0.27] p=0.02). No differences were found in initial rate of NEFA production or glucose utilization. Conclusion: Our results indicate that suppression of lipid-droplet lipolysis requires greater stimulus in metabolic syndrome compared to insulin sensitive adipocytes. Further, the rate of NEFA removal is less in metabolic syndrome. These results reveal components of insulin sensitivity not demonstrated by the glucose model. The NEFA model provides a measurement of adipocyte insulin sensitivity not captured by glycemic indices.

Identification of a model of non-esterified fatty acids dynamics through genetic algorithms: The case of women with a history of gestational diabetes

Elevation in non-esterified fatty acids ( NEFA) has been shown to modulate insulin secretion and it is considered as a risk factor for the development of type 2 diabetes. Here we present a method that complements a mathematical model of NEFA kinetics with genetic algorithms for model identification. The complemented strategy allowed to assess parameters of NEFA kinetics and to get insight into their relationship with insulin during oral glucose tolerance tests in women with former gestational diabetes: (i) providing a reliable estimation of the model parameters, (ii) assuring the usability of the model, and (iii) promoting and facilitating its application in a clinical context.

NEFA minimal model parameters estimated from the oral glucose tolerance test and the meal tolerance test

The kinetics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification to facilitate understanding of diseases like type 1 and 2 diabetes, metabolic syndrome, and obesity, and the mechanisms underpinning various interventions. Oral glucose tolerance tests (OGTT) and glucose meal tolerance tests (MTT) are potentially useful procedures for enabling quantification of NEFA kinetics because they both cause transitory, but substantial, declines and then rebounds in plasma NEFA concentrations in response to physiologically relevant increases in plasma glucose. The Boston MINIMAL model of NEFA kinetics was developed to analyze data from the intravenous glucose tolerance test (IVGTT), but in this work, we present for the first time its application to modeling NEFA data from both OGTT and MTT studies. This model enables estimation of SFFA (micromol.l(-1).min(-1)) (a parameter describing the maximum rate of lipolysis), and KFFA (%/min) (a parameter related to NEFA oxidation rate). The model could well describe the trajectories of NEFA concentrations following an OGTT (R2 in excess of 0.97) but was not as successful with the MTT (R2>0.65). Model parameters derived from analysis of OGTT and MTT data were well identified with coefficients of variation generally less than 15%. Type 2 diabetes, body mass index, and dietary treatment (high-fat vs. high-glycemic-index diets) were all shown to have significant effects on model parameters. Modeling plasma NEFA concentrations over 24 h has helped to identify and quantify the extent that periprandial NEFA peaks and nocturnal elevation in plasma NEFA can be accounted for by our model.

A novel minimal model to describe NEFA kinetics following an intravenous glucose challenge

Dynamics of nonesterified fatty acid (NEFA) metabolism in humans requires quantification if we are to understand the etiology of such diseases as type 1 and 2 diabetes, as well as metabolic syndrome and obesity, or if we are to elucidate the mechanism of action of various interventions. We present a new compartmental model that employs the pattern of plasma glucose concentrations in healthy young adults to predict dynamic changes that occur in plasma NEFA concentrations during either a glucose-only intravenous glucose tolerance test, or an insulin-modified intravenous tolerance test, or a modified protocol during which variable-rate glucose infusions were administered to prevent plasma glucose from declining below 100 mg/dl. The model described all of the major features of NEFA response to an intravenous glucose tolerance test, including an initial latency phase, a phase during which plasma NEFA concentrations plummet to a nadir, and a rebound phase during which plasma NEFA concentrations may rise to a plateau concentration, which may be substantially higher than the initial basal NEFA concentration. This model is consistent with physiological processes and provides seven adjustable parameters that can be used to quantify NEFA production (lipolysis) and utilization (oxidation). When tested on data from the scientific literature, the range in estimated rate of lipolysis was 24-36 micromol.l(-1).min(-1) and for NEFA oxidation rate was 25-54 micromol.l(-1).min(-1). All model parameters were well identified and had coefficients of variation < 15% of their estimated values. It is concluded that this model is suitable to describe NEFA kinetics in human subjects.

A novel minimal model to describe non-esterified fatty acid kinetics in Holstein dairy cows

The dynamics of non-esterified fatty acid (NEFA) metabolism in lactating dairy cows requires quantification if we are to understand how dietary treatments and disease influence changes in body condition (adipose reserves) and the production of milk fat. We present here a novel compartmental model that employs the pattern of plasma glucose concentrations to predict the dynamic changes that occur in plasma NEFA concentrations during an intravenous glucose tolerance test (IVGTT) in lactating dairy cows. The model was developed using data obtained from ten early-lactation, Holstein-Friesian cows given a standard IVGTT. The model described all of the major features of the NEFA response to an IVGTT; it was consistent with physiological processes and provided a number of parameters that can be used to quantify NEFA production and utilization. For all of the individual cows, all model parameters were well identified and usually had CV<10% of their estimated values. In the model, elevated plasma glucose concentrations cause an increase in the level of glucose in a remote compartment, which in turn suppresses the rate of entry of NEFA to the plasma compartment. The means (+/-sd) for the five adjustable parameters of the model were: rate of entry of NEFA to the plasma pool (SFFA) 183+/-71 [micromol l-1 min-1], rate of removal (oxidation, sequestration in adipose tissue and uptake by the mammary gland for milk production) of NEFA from the plasma pool (KFFA) 0.140+/-0.047 [min-1], a threshold parameter (gs) representing a plasma glucose concentration above which elevated levels of plasma glucose result in entry of glucose into a 'remote' or inaccessible glucose compartment, 3.30+/-0.52 [mmol/l], a rate constant (K) describing the movement of plasma glucose (above gs) into a remote compartment 0.063+/-0.033 [min-1] and a parameter Phi which is a Michaelis Menten type affinity constant which modulates the extent to which remote glucose inhibits the provision of NEFA to the plasma pool, 0.812+/-0.276 [mmol/l]. It is concluded that the model is suitable to describe NEFA kinetics in lactating dairy cows and it may have application in other species.

Evaluation of a compartmental model to describe non-esterified fatty acid kinetics in Holstein dairy cows

The dynamics of non-esterified fatty acid (NEFA) metabolism in lactating dairy cows requires quantification if we are to understand how dietary treatments and disease influence changes in body condition (adipose reserves) and the production of milk fat. Recently, Thomaseth & Pavan (2003) presented a compartmental model (Thomaseth model), which employs the pattern of plasma insulin concentrations in humans to predict the dynamic changes that occur in the plasma concentrations of glucose and NEFA during an intravenous glucose tolerance test (IVGTT). The Thomaseth model, or at least a similar model, could have potential application to the field of energy metabolism in ruminants because it would enable the estimation of parameters that describe the rates of whole body disposition of glucose, and the production and utilization of NEFA. In this study we investigated the suitability of the Thomaseth model to describe NEFA and glucose kinetics in 10 lactating Holstein-Friesian cows given a standard IVGTT in early lactation. The Thomaseth model described the general pattern of the NEFA response and, in particular, described the downward-slope and nadir in NEFA concentrations reasonably well. However, it failed to describe the initial latency period (the period before NEFA concentrations decline precipitously), and it could not describe terminal 'rebound' plateau in NEFA concentration. Because of these inherent problems, the parameters of the Thomaseth model cannot be considered to provide accurate estimates of rates of NEFA production or utilization. It is concluded that the Thomaseth model is not suitable for describing NEFA kinetics in lactating dairy cows.

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin.

Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [(3)H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion. Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours. Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake. These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.

Intramuscular fatty acid metabolism in contracting and non-contracting human skeletal muscle.

The present study was undertaken to investigate the fate of blood-borne non-esterified fatty acids (NEFA) entering contracting and non-contracting knee extensor muscles of healthy young individuals. [U-(13)C]-palmitate was infused into a forearm vein during 5 h of one-legged knee extensor exercise at 40 % of maximal work capacity and the NEFA kinetics, oxidation and rate of incorporation into intramuscular triacylglycerol (mTAG) were determined for the exercising and the non-exercising legs. During 4 h of one-legged knee extensor exercise, mTAG content decreased by 30 % (P < 0.05) in the contracting muscle, whereas it was unchanged in the non-contracting muscle. The uptake of plasma NEFA, as well as the proportion directed towards oxidation, was higher in the exercising compared to the non-exercising leg, whereas the rate of palmitate incorporation into mTAG was fourfold lower (0.70 +/- 0.14 vs. 0.17 +/- 0.04 micromol (g dry wt)(-1) h(-1); P < 0.05), resulting in fractional synthesis rates of 1.0 +/- 0.2 and 3.8 +/- 0.9 % h(-1) (P < 0.01) for the contracting and non-contracting muscle, respectively. These findings demonstrate that mTAG in human skeletal muscle is continuously synthesised and degraded and that the metabolic fate of plasma NEFA entering the muscle is influenced by muscle contraction, so that a higher proportion is directed towards oxidation at the expense of storage in mTAG.

Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans

To determine the effect of insulin and glucagon on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB), we measured simultaneously in normal subjects NEFA and KB kinetics at different NEFA levels in the presence of basal (control test) or increasing insulin concentrations with glucagopenia (somatostatin + insulin infusion, insulin test) and without glucagopenia (somatostatin + insulin + glucagon infusion, glucagon test). NEFA levels were controlled during these tests by an intravenous (IV) infusion of a triglyceride emulsion. During the control test, a moderate increase of NEFA (464 ± 30 to 715 ± 56 μmol/L) increased the percentage of NEFA converted into KB (13.3% ± 1.4% to 26.4% ± 2.1%, P < .05), and there was a linear relationship between this percentage and NEFA levels ( r = .788, P < .01). During the insulin and glucagon tests, the progressive increase in NEFA induced by the triglyceride emulsion infusion was associated, despite the increase of insulinemia, with an increase in KB production rate ( P < .05) and in the proportion of NEFA used for ketogenesis in the presence (8.1% ± 1.2% to 14.2% ± 6.3%, P < .05) and absence (15.7% ± 2.8% to 25.2% ± 3.99%, P < 0.05) of glucagopenia. In both tests, this percentage was always linearly related with NEFA levels ( P < .05) and the slopes of these relationships were comparable to that observed in the control test. However, the fraction of NEFA used for ketogenesis was always higher ( P < .05) during glucagon substitution than in its absence. Last, the study of type 1 diabetic patients with various degrees of metabolic control showed that this percentage of NEFA used for ketogenesis was rather related to increasing NEFA level ( P < .05) than to decreasing insulin concentration ( P>10). In conclusion, within the range of NEFA and insulin attained in this study, we did not obtain evidence for a direct hepatic antiketogenic action of insulin, whereas glucagon appears to stimulate ketogenesis at physiological concentrations.

Relations between plasma non-esterified fatty acid metabolism and body fat mobilization in primiparous lactating goats.

During early lactation ruminants can mobilize considerable amounts of body fat to maintain milk production. The aim of the present study was to evaluate the efficacy of tritiated water (TOH) and non-esterified fatty acid (NEFA) kinetics as means of monitoring adipose tissue fat mobilization in lactating goats. Body fat, as estimated by a two-pool model of TOH kinetics, and NEFA entry rate were measured in four primiparous goats at days 11, 37 and 72 post partum. Estimated body fat decreased by an average of 64 g/d between days 11 and 37 of lactation, tending to increase between days 37 and 72. Plasma NEFA concentrations and NEFA entry rate decreased as lactation advanced, being significantly lower at day 72 than at day 11 of lactation. Both plasma concentrations of NEFA and NEFA entry rate were negatively correlated with calculated energy balance. Plasma NEFA concentrations and NEFA entry rate at days 11 and 37 of lactation were positively related to average body fat losses over the subsequent stage of lactation. These results demonstrate that NEFA kinetics reflect fat mobilization in primiparous lactating goats, particularly during negative energy balance.

Relations between plasma non-esterified fatty acid metabolism and body tissue mobilization during chronic undernutrition in goats.

1. Eleven mature goats were offered 140 kJ metabolizable energy/kg per d (M) of lucerne (Medicago sativa) hay-oaten grain (1:1, w/w) for at least 1 month before plasma non-esterified fatty acid (NEFA) kinetics and tritiated water space (TS) were determined. 2. Goats were then fed at M, 0.5 M or 0.25 M for 34 (SE 6) d, at which time the experimental procedures were repeated. 3. Chronic undernutrition resulted in elevated NEFA concentrations and NEFA entry rate, with a tendency for the ratio plasma NEFA:glycerol to increase, suggesting that body-fat mobilization during prolonged underfeeding is due more to decreased lipogenesis and intracellular NEFA re-esterification rather than to increased lipolysis. 4. Plasma NEFA concentrations and NEFA entry rate, as well as being highly correlated with each other, were significantly related to calculated energy balance and body fat losses estimated from changes in live weight and TS. 5. Increases in NEFA entry rate were highly correlated with, and of the same magnitude as, body fat losses, confirming that NEFA kinetics do quantitatively reflect lipid mobilization.

Effect of epinephrine on the relationship between nonesterified fatty acid availability and ketone body production in postabsorptive man: evidence for a hepatic antiketogenic effect of epinephrine.

The effect of epinephrine (EPI) on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB) in normal subjects was determined by measuring simultaneously NEFA ([1-13C]palmitic acid) and KB ([3-13C]- or [3,4-13C2]acetoacetate) kinetics at different NEFA levels in the presence of basal (control test) or increased (EPI infusion test) EPI concentrations. During the control test the initial (postabsorptive state) concentrations and turnover rates of NEFA and KB were 476 +/- 47 (+/- SEM) and 4.30 +/- 0.17 mumol kg-1 min-1 (NEFA) and 126 +/- 17 and 2.49 +/- 0.07 mumol kg-1 min-1 (KB). The fraction of NEFA converted into KB was between 11.5-14.6%. Raising NEFA levels to about 650 mumol L-1 (iv infusion of a triglyceride emulsion) resulted in an increase in this fraction to between 26-30.3% (P less than 0.01). When NEFA concentrations were next abruptly raised to high levels (near 3 mmol L-1) by heparin injection this fraction returned to near the initial values (15-19.2%). During the EPI infusion test the initial (postabsorptive) concentrations and turnover rates of NEFA and KB as well as the fraction of NEFA converted into KB (10.5-11.5%) were comparable to the initial values of the control test. Intravenous infusion of EPI (10 ng kg-1 min-1) raised NEFA between 600 and 750 mumol L-1, comparable to values during the triglyceride test, but the fraction of NEFA converted into KB remained between 8.2-12% (P less than 0.05 vs. control test); when NEFA then were raised to even higher values (near 2.5 mmol L-1) by the infusion of a triglyceride emulsion and the injection of heparin, this fraction decreased to between 4-8% (P less than 0.05 vs. initial values of the EPI test and P less than 0.05 vs. the control test). In conclusion, 1) the fraction of NEFA converted into KB appears to depend in part on the NEFA concentration; and 2) the net effect of EPI infusion was to decrease the fraction of NEFA converted into KB.