Free Fatty Acid Mobilization Research Articles

Twelve Weeks Of Endurance Training Increases Free Fatty Acid Mobilization And Reesterification In Postmenopausal Women

Despite far-ranging interest in the metabolic consequences of aging, the effects of menopause on FFA mobilization (FFA Ra), reesterification (Rs) and oxidation have been little studied in humans. PURPOSE: We examined the effects of exercise intensity and training on rates of lipolysis, plasma free fatty acid (FFA) appearance (Ra), disappearance (Rd), Rs, and oxidation (Roxp) in postmenopausal (PM) women. METHODS: Ten sedentary but healthy women (55±0.6 yr) completed 12 wk of supervised endurance exercise training on a cycle ergometer [5 days/wk, 1 h/day, 65% peak oxygen consumption (VO2peak)]. Flux rates were determined by continuous infusion of [1-13C]palmitate and [1,1,2,3,3-2H5]glycerol during 90 min of rest and 60 min of cycle ergometer exercise during one pretraining exercise trial [65% VO2peak (PRE)] and two post-training exercise trials [at power outputs that elicited 65% pretraining VO2peak (ABT) and 65% post-training VO2peak (RLT)]. All flux data were compared using a repeated-measures ANOVA. RESULTS: Initial body weights (68.2±4.5 kg) were maintained over the course of study. Training increased VO2peak by 16.3±3.9% (1.69 ± 0.08 vs. 1.95 ± 0.08 L/min P<0.05) (Zarins ZA, Wallis GA, Faghihnia N, Johnson ML, Fattor JA, Horning MA and Brooks GA. Effects of endurance training on cardiorespiratory fitness and substrate partitioning in postmenopausal women. Metabolism 58: 9: 1338-1346, 2009). Glycerol Ra was elevated in the RLT trial (4.08 ± 0.45 vs. 5.3 ± 0.69 mmol kg-1 min-1 P<0.05), but not the ABT (4.16 ± 0.56 mmol kg−1 min-1) trial after training. Rates of plasma FFA Ra (5.7±0.8 vs 8.2±1.2 mmol kg-1 min-1), Rd (5.35 ± 0.8 vs 8.06 ± 1.3 mmol kg-1 min-1), and RoxP (3.1 ± 0.4 vs 4.9 ± 0.6 mmol kg-1 min-1) were elevated during the ABT compared to PRE trial (P<0.05). FFA Rs accounted for most (50-70%) of Rd during exercise; training reduced FFA Rs during ABT (8.1 ± 0.8 vs. 6.2 ± 1.2 umol kg-1 min-1), but not RLT (11.3 ± 2.0 umol kg-1 min-1 P<0.05) compared to PRE. CONCLUSIONS: We conclude that, in spite of the large age-related decrease in metabolic scope in PM women, endurance training increases the capacities for FFA mobilization and oxidation during exercises of a given power output. However, after menopause total lipid oxidation capacity remains low, with reesterification accounting for most of FFA Rd. Supported by NIH grant R01 AR042906

Twelve weeks of endurance training increases FFA mobilization and reesterification in postmenopausal women

We examined the effects of exercise intensity and training on rates of lipolysis, plasma free fatty acid (FFA) appearance (R(a)), disappearance (R(d)), reesterification (R(s)), and oxidation (R(oxP)) in postmenopausal (PM) women. Ten sedentary but healthy women (55 ± 0.6 yr) completed 12 wk of supervised endurance exercise training on a cycle ergometer [5 days/wk, 1 h/day, 65% peak oxygen consumption (Vo(2peak))]. Flux rates were determined by continuous infusion of [1-(13)C]palmitate and [1,1,2,3,3-(2)H(5)]glycerol during 90 min of rest and 60 min of cycle ergometer exercise during one pretraining exercise trial [65% Vo(2peak) (PRE)] and two posttraining exercise trials [at power outputs that elicited 65% pretraining Vo(2peak) (absolute training; ABT) and 65% posttraining Vo(2peak) (relative training; RLT)]. Initial body weights (68.2 ± 4.5 kg) were maintained over the course of study. Training increased Vo(2peak) by 16.3 ± 3.9% (P < 0.05) (Zarins ZA, Wallis GA, Faghihnia N, Johnson ML, Fattor JA, Horning MA and Brooks GA. Metabolism 58: 9: 1338-1346, 2009). Glycerol R(a) and R(d) were elevated in the RLT trial (P < 0.05), but not the ABT trial after training. Rates of plasma FFA R(a), R(d), and R(oxP) were elevated during the ABT compared with PRE trial (P < 0.05). FFA R(s) accounted for most (50-70%) of R(d) during exercise; training reduced FFA R(s) during ABT, but not RLT compared with PRE. We conclude that, despite the large age-related decrease in metabolic scope in PM women, endurance training increases the capacities for FFA mobilization and oxidation during exercises of a given power output. However, after menopause, total lipid oxidation capacity remains low, with reesterification accounting for most of FFA R(d).

Associations of Free Fatty Acids With Insulin Secretion and Action Among African‐American and European‐American Girls and Women

Ethnic differences in insulin secretion and action between African Americans (AAs) and European Americans (EAs) may influence mobilization of free fatty acids (FFAs). We tested the hypotheses that FFA concentrations would be associated with measures of insulin secretion and action before and during a glucose challenge test. Subjects were 48 prepubertal girls, 60 premenopausal women, and 46 postmenopausal women. Fasting insulin (insulin(0)), the acute insulin response to glucose (AIR(g)), the insulin sensitivity index (S(I)), basal and nadir FFA (FFA(0), FFA(nadir)), and nadir time (TIME(nadir)) were determined during an intravenous glucose tolerance test (IVGTT). Stepwise multiple linear regression (MLR) analysis was conducted to identify associations of FFA(0), FFA(nadir), and TIME(nadir) with ethnicity, age group, insulin measures, indexes of body composition from dual-energy X-ray absorptiometry, and measures of fat distribution from computed tomography scan. In this population, insulin(0) and AIR(g) were higher among AAs vs. EAs, whereas S(I) was lower, independent of age group. MLR analyses indicated that FFA(0) was best predicted by lean tissue mass (LTM), leg fat mass, ethnicity (lower in AAs), S(I), and insulin(0). FFA(nadir) was best predicted by FFA(0), age group, and intra-abdominal adipose tissue (IAAT). TIME(nadir) was best predicted by leg fat mass, AIR(g), and S(I). In conclusion, indexes of insulin secretion and action were associated with FFA dynamics in healthy girls and women. Lower FFA(0) among AAs was independent of insulin(0) and S(I). Whether lower FFA(0) is associated with substrate oxidation or risk for obesity remains to be determined.

Central angiotensin AT 1 receptors are involved in metabolic adjustments in response to graded exercise in rats

To investigate the influence of central angiotensin AT 1-receptors blockade on metabolic adjustments during graded exercise, Losartan (Los) was intracerebroventricularly injected in rats before running until fatigue. Oxygen consumption (VO 2) was measured ( n = 6) and blood samples collected ( n = 7) to determine variations of glucose, lactate and free fatty acids (FFA). Los-rats exhibited a hyperglycemic response, already observed at 20% of maximal work, followed by a higher lactate levels and FFA mobilization from adipose tissue. Despite the reduced total time to fatigue and the higher VO 2 associated with reduced mechanical efficiency, exercise led to the attainment of similar levels of effort in both groups. In summary, central AT 1-receptor blockade during graded exercise induces hyperglycemia and higher FFA mobilization from adipose tissue at low exercise intensities in rats running at the same absolute exercise intensity. These data suggest that the central angiotensinergic system is involved in metabolic adjustments during exercise since central blockade of AT 1-receptors shifts energy balance during graded exercise, similarly to situations of higher and premature sympathetic activation.

Free fatty acid kinetics in the late phase of postexercise recovery: importance of resting fatty acid metabolism and exercise-induced energy deficit

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope–labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 ± 7 years; body mass index, 25 ± 4 kg/m2) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P ≤ .008) and net energy expenditure of exercise (P ≤ .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.

INCREASED MOBILIZATION OF FREE FATTY ACIDS FROM ADIPOSE TISSUE IN DIABETES.

Increased Mobilization of Free Fatty Acids from Adipose Tissue in Diabetes Get access Nutrition Reviews, Volume 22, Issue 11, November 1964, Pages 334–337, https://doi.org/10.1111/j.1753-4887.1964.tb04834.x Published: 01 November 1964

Dysglycaemia, cardiovascular outcome and treatment. Is the jury still out?

Dale and co-workers have reported on the influence of glycaemic control on long-term mortality from ischaemic heart disease (IHD) in patients with asymptomatic newly detected diabetes mellitus participating in a population-wide health survey in Norway.1 The annual measurements of glycated haemoglobin A1c (HbA1c) in subjects with newly diagnosed diabetes during the 10 years following recruitment constitute a strength of this study allowing assessment of how risk may vary according to glycaemic burden over time. Considering the high prevalence of undetected diabetes mellitus among patients seen by cardiologists and the widespread dysglycaemia in the general population, the issue raised by this study is indeed relevant for everyday practice.2,3 The relationship between cardiovascular disease and glucose regulation abnormalities has been discussed since the first published report on glucosuria in patients with myocardial infarction in 1922.4 Thanks to individual and collaborative efforts of many research groups, the wealth of knowledge regarding association of dysglycaemia with the incidence of cardiovascular events has increased exponentially in the last decade. Several mechanisms may account for this relationship. Elevated glucose concentrations cause direct damage to vascular endothelium and other tissues owing to oxidative stress. Insulin resistance promotes mobilization of free fatty acids from adipose tissue which reduces HDL and increases LDL. Oxidative stress reduces insulin production by damaging insulin-secreting β-cells. All together these conditions promote pro-inflammatory and pro-thrombotic processes.5 Abnormal glucose regulation has serious prognostic implications in patients with coronary artery disease (CAD). Established diabetes is associated with impaired prognosis after myocardial infarction.6 According to more recent evidence, the increased risk is already apparent at modestly raised levels of blood glucose below the present threshold for diabetes.2,7–10 The progressive relationship between cardiovascular mortality and glycaemia is indeed independent of the classical cardiovascular risk factors as … Corresponding author. Tel: +39 06 33775561, Fax: +39 06 33775061, Email: f_cosentino{at}hotmail.com

Metabolic adjustments in response to graded exercise depends on central angiotensin AT1‐receptors

To asses the influence of central angiotensin AT1 receptors on metabolic adjustments in rats during graded exercise on a treadmill, 2 μL of NaCl (Sal) or losartan (Los; 60 nmol) were intracerebroventricularly injected before running until fatigue (starting at 10 m/min, 1 m/min increment every 3 min until fatigue, 10% inclination). Oxygen consumption (VO2) was measured and mechanical efficiency (ME) calculated (n=6). The same protocol was used to collect blood samples through a jugular catheter (n=7). Plasmatic concentrations of glucose, lactate and free fatty acids (FFAs) were determined. During the first two steps of exercise, a similar increase in VO2 and equal ME were observed in both groups. Thereafter, VO2 continued to increase, but at a higher rate in Los‐treated animals, leading to a 34% reduction in ME in these animals (p&lt;0.01). Los‐treated rats also showed a fast hyperglycemic response, already seen at low exercise intensities as 20% of maximal work. Higher lactate and FFAs levels followed this hyperglycemic response. The data shows that AT1‐receptor blockade during graded exercise increases metabolic cost, leading to decreased ME, hyperglycemia and higher FFA mobilization at lower levels of exercise intensities. We conclude that angiotensinergic blockade results in higher and premature sympathetic activation, shifting energy balance during graded exercise.Supported by CNPq, FAPEMIG

Acute Toxic Effects Of Fatty Acids

One of the main risk factors in the development of adiposity, type II diabetes, and some cardiovascular diseases is a chronic increase in the level of lipids and free fatty acids (FFA) circulating in the blood. In the acute variant, urgent mobilization of FFA may cause cell death in ischemia/reperfusion and microvesicular steatosis of the liver. It is believed that the main mechanism underlying the cell death in the presence of toxic FFA (primarily palmitic acid and myristic acid) levels is the mitochondrial energetics destabilization. But some data suggest that FFA and their derivatives (acylCoAs or acylcarnitines) may activate reticular Ca2+ channels. In this work we showed that the major cause of cell death induced by the acute toxic action of fatty acids is the destabilization of Ca2+ homeostasis of excitable or nonexcitable cells, which is associated with the activation of sarcoendoplasmic reticulum Ca2+ release channels (RyR and IP3). Under these conditions, the contribution of the activation of L-type Ca2+ channels, NMDA channels, the reversion of the Na+/Ca2+−exchanger of the plasmalemma of excitable cells and the store-operated calcium channels (SOC) of nonexcitable cells is small. In this case, mitochondria act as a Ca2+ buffer system, which is capable of accumulating Ca2+ until the deenergization of mitochondria and a fall of Δφ due to the inhibition of the energetics through AcylCoA or the exhaustion of the Ca2+ capacity of mitochondria and the release of Ca2+ into the cytoplasm (opening of mPTP) followed by the necrotic cell death.

Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes

The mobilization of free fatty acids (FFA) from adipose tissue to the bloodstream primarily depends on triacylglycerol lipolysis in adipocytes. Catecholamines are major hormones that govern lipolysis through elevating cellular cAMP production and activating protein kinase, cAMP dependent, catalytic, alpha (PKA) and mitogen-activated protein kinase 1/2 (MAPK1/3). Obesity and type 2 diabetes are associated with elevated levels of systemic FFA, which restricts glucose utilization and induces insulin resistance. The biguanide metformin exerts its antihyperglycemic effect by enhancing insulin sensitivity, which is associated with decreased levels of circulating FFA. In this study, we examined the characteristics and basis of the inhibitory effect of metformin on adrenergic-stimulated lipolysis in primary rat adipocytes. We measured the release of FFA and glycerol as an index of lipolysis and examined the major signalings of the lipolytic cascade in primary rat adipocytes. Metformin at 250-500 microM efficiently attenuated FFA and glycerol release from the adipocytes stimulated with 1 microM isoproterenol. To elucidate the basis for this antilipolytic action, we showed that metformin decreased cellular cAMP production, reduced the activities of PKA and MAPK1/3, and attenuated the phosphorylation of perilipin during isoproterenol-stimulated lipolysis. Further, metformin suppressed isoproterenol-promoted lipase activity but did not affect the translocation of lipase, hormone-sensitive from the cytosol to lipid droplets in adipocytes. This study provides evidence that metformin acts on adipocytes to suppress the lipolysis response to catecholamine. This antilipolytic effect could be a cellular basis for metformin decreasing plasma FFA levels and improving insulin sensitivity.

Mechanism of Action of Niacin

Nicotinic acid (niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B-containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I-containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of niacin and challenged older concepts. There are new data on (1) how niacin affects triglycerides (TGs) and apo B-containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific niacin receptor in adipocytes and immune cells, (5) how niacin causes flushing, and (6) the characterization of a niacin transport system in liver and intestinal cells. New findings indicate that niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase-2, a key enzyme for TG synthesis. The inhibition of TG synthesis by niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI-mediated cholesterol esters. Decreased HDL-apo A-I catabolism by niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that niacin, by inhibiting the hepatocyte surface expression of beta-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I. Recent studies indicate that niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The niacin flush results from the stimulation of prostaglandins D(2) and E(2) by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor has been a widely suggested mechanism of niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of niacin.

High Omega-3 Fat Intake Improves Insulin Sensitivity and Reduces CRP and IL6, but does not Affect Other Endocrine Axes in Healthy Older Adults

Aging diminishes hormone secretion and target cell responsiveness, possibly due to loss of cell membrane fluidity or alteration of membrane phospholipids affecting signal transduction. We investigated whether a high omega-3 polyunsaturated fatty acid diet would improve endocrine function in 6 men and 6 women aged over 60 years. Subjects first ate an isocaloric control diet for 6 weeks, followed by an 8-week experimental diet, which included 720 g of fatty fish weekly plus 15 ml of sardine oil daily. In the last week, we measured RBC membrane fatty acids on each diet, performed pituitary, adrenal, hepatic, and Leydig cell endocrine provocative testing, and assayed selected cytokines. We also assessed insulin sensitivity utilizing octreotide insulin suppression testing and assessed free fatty acid (FFA) responses to isoproteronol. Insulin sensitivity increased significantly after 8 weeks on the omega-3 diet and FFA responses trended lower. Serum C-reactive protein was significantly reduced and a trend towards lower IL-6 was noted. No differences were found in other metabolic parameters, adiponectin levels, or hormone responses. We conclude that, in older people, high omega-3 consumption increases insulin sensitivity, may reduce FFA mobilization by catecholamines, and reduces inflammatory markers, but did not alter endocrine responsiveness after 8 weeks.

Nicotinic Acid (Niacin) Receptor Agonists: Will They Be Useful Therapeutic Agents?

Nicotinic acid (niacin) favorably affects very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and lipoprotein (a) (LP[a]) and increases high-density lipoprotein (HDL). Emerging data indicates vascular anti-inflammatory properties to additionally account for niacin's proven effects in cardiovascular disease. Recent evidence indicates that niacin acts on GPR109A and GPR109B (HM74A and HM74, respectively), receptors expressed in adipocytes and immune cells. In adipocytes, GPR109A activation reduces triglyceride (TG) lipolysis, resulting in decreased free fatty acid (FFA) mobilization to the liver. In humans, this mechanism has yet to be confirmed because the plasma FFA decrease is transient and is followed by a rebound increase in FFA levels. New evidence indicates niacin directly inhibits diacylglycerol acyltransferase 2 (DGAT2) isolated from human hepatocytes, resulting in accelerated hepatic apolipoprotein (apo)B degradation and decreased apoB secretion, thus explaining reductions in VLDL and LDL. This raises important questions as to whether stimulation of GPR109A in adipocytes or inhibition of DGAT2 in liver by niacin best explain the reduction in VLDL and LDL in dyslipidemic patients. Kinetic and in vitro studies indicate that niacin retards the hepatic catabolism of apoA-I but not liver scavenger receptor B1-mediated cholesterol esters, suggesting that niacin inhibits hepatic holoparticle HDL removal. Indeed, recent preliminary evidence suggests that niacin decreases surface expression of hepatic beta-chain of adenosine triphosphate synthase, which has been implicated in apoA-I/HDL holoparticle catabolism. GPR109A-mediated production of prostaglandin D2 in macrophages and Langerhan cells causes skin capillary vasodilation and explains, in part, niacin's effect on flushing. Development of niacin receptor agonists would, theoretically, result in adipocyte TG accumulation (and clinical adiposity) and increased flushing. This raises questions about niacin receptor agonists as therapeutic agents. Several niacin receptor agonists have been developed and patented, but their clinical effects have not been described. Future research is needed to determine whether niacin receptor agonists will demonstrate all the beneficial properties of nicotinic acid on atherosclerosis and without significant adverse effects.

A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset™ or placebo

BackgroundCycloset™ is a quick-release formulation of bromocriptine mesylate, a dopamine agonist, which in animal models of insulin resistance and type 2 diabetes acts centrally to reduce resistance to insulin- mediated suppression of hepatic glucose output and tissue glucose disposal. In such animals, bromocriptine also reduces hepatic triglyceride synthesis and free fatty acid mobilization, manifesting decreases in both plasma triglycerides and free fatty acids. In clinical trials, morning administration of Cycloset™ either as monotherapy or adjunctive therapy to sulfonylurea or insulin reduces HbA1c levels relative to placebo by 0.55–1.2. Cycloset™ therapy also reduces plasma triglycerides and free fatty acid by approximately 25% and 20%, respectively, among those also receiving sulfonylurea therapies. The effects of once-daily morning Cycloset™ therapy on glycemic control and plasma lipids are demonstrable throughout the diurnal portion of the day (7 a.m. to 7 p.m.) across postprandial time points.Methods/Design3,095 individuals were randomized in a 2:1 ratio into a one year trial aimed to assess the safety and efficacy of Cycloset™ compared to placebo among individuals receiving a variety of treatments for type 2 diabetes. Eligibility criteria for this randomized placebo controlled trial included: age 30–80, HbA1c ≤ 10%, diabetes therapeutic regimen consisting of diet or no more than two hypoglycemic agents or insulin with or without one additional oral agent (usual diabetes therapy; UDT). The primary safety endpoint will test the hypothesis that the rate of all-cause serious adverse events after one year of usual diabetes therapy (UDT) plus Cycloset™ is not greater than that for UDT plus placebo by more than an acceptable margin defined as a hazard ratio of 1.5 with a secondary endpoint analysis of the difference in the rate of serious cardiovascular events, (myocardial infarction, stroke, coronary revascularization or hospitalization for or angina or congestive heart failure). Efficacy analyses will evaluate effects of Cycloset™ versus placebo on change from baseline in HbA1c, fasting glucose, body weight, waist circumference, blood pressure and plasma lipids.DiscussionThis study will extend the current data on Cycloset™ safety, tolerability and efficacy in individuals with type 2 diabetes to include its effects in combination with thiazolodinediones, insulin secretagogues, metformin, alpha-glucosidase inhibitors and exogenous insulin regimens.Trial registrationclinical trials.gov NCT00377676

Effect of subcutaneous injections of PYY1-36 and PYY3-36 on appetite, ad libitum energy intake, and plasma free fatty acid concentration in obese males

Intraveneous (i.v.) PYY(3-36) infusions have been reported to reduce energy intake (EI) in humans, whereas few studies exist on effects of PYY(1-36). The aim of the present study was to examine effects of subcutaneous (sc) injections of PYY(1-36) and PYY(3-36) on appetite, ad libitum EI, plasma concentrations of PYY and free fatty acids (FFA) in obese males. Twenty-four males (BMI 27-40 kg/m(2)) were randomly assigned to two groups receiving sc injections of either PYY(1-36) or PYY(3-36) in a blinded, placebo-controlled, dose-escalating, cross-over study. Subjects were studied 5 days in succession, with escalating doses of PYY(1-36) [saline, 50, 100, 150, and 200 pmol PYY(1-36)/kg lean body mass (LBM)], or PYY(3-36) (saline, 25, 50, 75, and 100 pmol PYY(3-36)/kg LBM), respectively. PYY injections resulted in dose-dependent increases in plasma PYY levels but no effect on EI in either the PYY(1-36) or the PYY(3-36) group. However, increasing doses of PYY(3-36), but not PYY(1-36), resulted in increased ratings of satiety and decreased ratings of hunger, thirst, and prospective food consumption. Although not dose dependently, significant elevation of plasma FFA was seen after injection of PYY(3-36), but not PYY(1-36). Although sc administration of PYY was well tolerated, it remains to be determined whether high-dose PYY(3-36) is sufficient in reducing EI in long-term trials, and if so, whether the reduction in EI occurs without nausea. PYY(1-36) is unlikely to be important in regulating energy intake. The PYY(3-36) administrations caused a non-dose-dependent mobilization of FFA, likely through a direct effect.

Adipose Triglyceride Lipase and Hormone-sensitive Lipase Are the Major Enzymes in Adipose Tissue Triacylglycerol Catabolism

The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis.

Maximal β3-Adrenergic Regulation of Lipolysis Involves Src and Epidermal Growth Factor Receptor-dependent ERK1/2 Activation

Catecholamine-stimulated lipolysis is primarily a beta-adrenergic and cAMP-dependent event. In previous studies we established that the beta(3)-adrenergic receptor (beta(3)AR) in adipocytes utilizes a unique mechanism to stimulate extracellular signal-regulated kinases 1 and 2 (ERK) by direct recruitment and activation of Src kinase. Therefore, we investigated the role of the ERK pathway in adipocyte metabolism and found that the beta(3)AR agonist CL316,243 regulates lipolysis through both cAMP-dependent protein kinase (PKA) and ERK. Inhibition of PKA activity completely eliminated lipolysis at low (subnanomolar) CL316,243 concentrations and by 75-80% at higher nanomolar concentrations. The remaining 20-25% of PKA-independent lipolysis, as well as ERK activation, was abolished by inhibiting the activity of either Src (PP2 or small interfering RNA), epidermal growth factor receptor (EGFR with AG1478 or small interfering RNA), or mitogen-activated protein kinase kinase 1 or 2 (MKK1/2 with PD098059). PD098059 inhibited lipolysis by 53% in mice as well. Finally, the effect of estradiol, a reported acute activator of ERK and lipolysis, was also totally prevented by PP2, AG1478, and PD098059. These results suggest that ERK activation by beta(3)AR depends upon Src and epidermal growth factor receptor kinase activities and is responsible for the PKA-independent portion of the lipolytic response. Together these results illustrate the distinct and complementary roles for PKA and ERK in catecholamine-stimulated lipolysis.

Metabolic clues regarding the enhanced performance of elite endurance athletes from orchiectomy-induced hormonal changes

This article examines the metabolic performance of an elite cyclist, Lance Armstrong, before and after his diagnosis with testicular cancer. Although a champion cyclist in 1-day events prior to his diagnosis of testicular cancer at age 25, he was not a contender in multi-day endurance cycle races such as the 3-week Tour de France. His genetic makeup and physiology (high VO2max, long femur, strong heavy build) coupled with his ambition and motivation enabled him at an early age to become one of the best 1-day cyclists in the world. Following his cancer diagnosis, he underwent a unilateral orchiectomy, brain surgery and four cycles of chemotherapy. After recovering, he returned to cycling and surprisingly excelled in the Tour de France, winning this hardest of endurance events 7 years running. This dramatic transformation from a 1-day to a 3-week endurance champion has led many to query how this is possible, and under the current climate, has led to suggestions of doping as to the answer to this metamorphosis. Physiological tests following his recovery indicated that physiological parameters such as VO2max were not affected by the unilateral orchiectomy and chemotherapy. We propose that his dramatic improvement in recovery between stages, the most important factor in winning multi-day stage races, is due to his unilateral orchiectomy, a procedure that results in permanent changes in serum hormones. These hormonal changes, specifically an increase in gonadotropins (and prolactin) required to maintain serum testosterone levels, alter fuel metabolism; increasing hormone sensitive lipase expression and activity, promoting increased free fatty acid (FFA) mobilization to, and utilization by, muscles, thereby decreasing the requirement to expend limiting glycogen stores before, during and after exercise. Such hormonal changes also have been associated with ketone body production, improvements in muscle repair and haematocrit levels and may facilitate the loss of body weight, thereby increasing power to weight ratio. Taken together, these hormonal changes act to limit glycogen utilization, delay fatigue and enhance recovery thereby allowing for optimal performances on a day-to-day basis. These insights provide the foundation for future studies on the endocrinology of exercise metabolism, and suggest that Lance Armstrong's athletic advantage was not due to drug use.

Central nitric oxide inhibition modifies metabolic adjustments induced by exercise in rats

The influence of the central nervous system on metabolic function is of interest in situations deviating from basal states, such as during exercise. Our previous study in rats demonstrated that central nitric oxide (NO) blockade increases metabolic rate, reducing mechanical efficiency during exercise. To assess the role of brain nitric oxide in the plasma glucose, lactate and free fatty acids (FFAs) concentrations of rats submitted to an incremental exercise protocol on a treadmill until fatigue, 1.43 μmol (2 μl) of N ω-nitro- l-arginine methyl ester ( l-NAME, n = 6), a NO synthase inhibitor, or 2 μl of 0.15 M NaCl (SAL, n = 6) was injected into the lateral cerebral ventricle (icv) of male Wistar rats immediately before exercise (starting at 10 m/min, with increments of 1 m/min every 3 min until fatigue, 10% inclination). Blood samples were collected through a chronic jugular catheter at rest and during exercise until fatigue. During exercise, the l-NAME-treated animals had the following metabolic response compared to controls: (1) an increased hyperglycemic response during the first 60% of time to fatigue; (2) higher plasma lactate levels; and (3) a significant transitory increase in plasma free fatty acids during the dynamic phase of exercise that returned to basal levels earlier than controls during the steady state phase of exercise. In addition l-NAME-treated rats fatigued earlier than controls. The data indicate that the inhibition of the brain nitrergic system induced by icv l-NAME treatment disrupted the accuracy of the neural mechanism that regulates plasma glucose and free fatty acids mobilization during exercise in rats.

HDL and the progression of atherosclerosis: new insights

Aims Lowering low-density lipoprotein (LDL) cholesterol or raising high-density lipoprotein (HDL) cholesterol can result in significant cardiovascular benefit, both in terms of reduction of events and also, to a variable extent, of atheromatous lesions. LDL and HDL have opposite roles in body cholesterol regulation and, both reduced deposition (LDL reduction) and increased removal (raised HDL) can improve vascular disease. Very recently, studies using recombinant apolipoprotein AI liposomes (in particular with the mutant apo AIMilano) have shown that direct infusion can effectively remove cellular cholesterol and dramatically reduce established atheromatous plaques in animals and in coronary patients. It has thus become of growing interest, the possibility of raising HDL by pharmacological treatments. This review will attempt to investigate existing and novel methodologies for HDL raising. Methods and results HDL raising can be achieved by using drugs active on the peroxisome proliferator activated receptor α (PPAR α) system, particularly using fibrates or n-3 fatty acids and, possibly more effectively, by using nicotinic acid. The activity of this agent has been traditionally linked to a reduced free fatty acid (FFA) mobilization from adipose tissue. More recently, it has been noted that nicotinic acid can activate the PPAR system, by stimulating all three PPAR isoforms (α, γ, δ). This mode of action seems to more effectively explain the striking HDL-raising properties of the drug. Conclusions Newly discovered mechanisms of nicotinic acid can explain, on the one hand, reduced atherosclerosis progression in secondary prevention patients treated with statins and, on the other hand, improved body cholesterol mobilization, effectively reducing cholesterol pool sizes.