The impact of 60 days of -6° head down tilt bed rest on mitochondrial content, respiration and regulators of mitochondrial dynamics.

It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal muscle mitochondrial function and dynamics and (2) to determine whether micronutrient supplementation would mitigate the adverse metabolic effect of bed rest. Participants were maintained in energy balance throughout 60 days of bed rest with micronutrient supplementation (INT) (body mass index: 23.747 ± 1.877 kg m-2 ; 34.80 ± 7.451 years; n = 10) or without (control) (body mass index: 24.087 ± 2.088 kg m-2 ; 33.50 ± 8.541 years; n = 10). Indirect calorimetry and dual-energy x-ray absorptiometry were used for measures of energy expenditure, exercise capacity and body composition. Mitochondrial respiration was determined by high-resolution respirometry in permeabilized muscle fibre bundles from vastus lateralis biopsies. Protein and mRNA analysis further examined the metabolic changes relating to regulators of mitochondrial dynamics induced by bed rest. INT was not sufficient in preserving whole body metabolic changes conducive of a decrease in body mass, fat-free mass and exercise capacity within both groups. Mitochondrial respiration, OPA1 and Drp1 protein expression decreased with bed rest, with an increase pDrp1s616 . This reduction in mitochondrial respiration was explained through an observed decrease in mitochondrial content (mtDNA:nDNA). Changes in regulators of mitochondrial dynamics indicate an increase in mitochondrial fission driven by a decrease in inner mitochondrial membrane fusion (OPA1) and increased pDrp1s616 . KEY POINTS: Sixty days of -6° head down tilt bed rest leads to significant changes in body composition, exercise capacity and whole-body substrate metabolism. Micronutrient supplementation throughout bed rest did not preserve whole body metabolic changes. Bed rest results in a decrease in skeletal muscle mitochondrial respiratory capacity, mainly as a result of an observed decrease in mitochondrial content. Prolonged bed rest ensues changes in key regulators of mitochondrial dynamics. OPA1 and Drp1 are significantly reduced, with an increase in pDrp1s616 following bed rest indicative of an increase in mitochondrial fission. Given the reduction in mitochondrial content following 60 days of bed rest, the maintenance of regulators of mitophagy in line with the increase in regulators of mitochondrial fission may act to maintain mitochondrial respiration to meet energy demands.

Effect of increased protein intake and exogenous ketosis on body composition, energy expenditure and exercise capacity during a hypocaloric diet in recreational female athletes.

Introduction: Since low body weight is an important determinant of success in many sports such as gymnastics, martial arts and figure skating, athletes can benefit from effective weight loss strategies that preserve muscle mass and athletic performance. The present study investigates the effects of increased protein intake and exogenous ketosis on body composition, energy expenditure, exercise capacity, and perceptions of appetite and well-being during a hypocaloric diet in females. Methods: Thirty-two female recreational athletes (age: 22.2 ± .5 years; body weight: 58.3 ± .8 kg; BMI: 20.8 ± .2 kg·m-2) underwent 4 weeks of 30% caloric restriction and were randomized to receive either an increased daily amount of dietary protein (PROT, ∼2.0-2.2 g protein·kg-1·day-1), 3 × 20 g·day-1 of a ketone ester (KE), or an isocaloric placebo (PLA). Body composition was measured by DXA, resting energy expenditure (REE) by indirect calorimetry, exercise capacity during a VO2max test, appetite hormones were measured in serum, and perceptions of general well-being were evaluated via questionnaires. Results: The hypocaloric diet reduced body weight by 3.8 ± .3 kg in PLA, 3.2 ± .3 kg in KE and 2.4 ± .2 kg in PROT (Ptime<.0001). The drop in fat mass was similar between treatments (average: 2.6 ± .1 kg, Ptime<.0001), while muscle mass was only reduced in PLA and KE (average: .8 ± .2 kg, Ptime<.05), and remained preserved in PROT (Pinteraction<.01). REE [adjusted for lean mass] was reduced after caloric restriction in PLA (pre: 32.7 ± .5, post: 28.5 ± .6 kcal·day-1·kg-1) and PROT (pre: 32.9 ± 1.0, post: 28.4 ± 1.0 kcal·day-1·kg-1), but not in KE (pre: 31.8 ± .9, post: 30.4 ± .8 kcal·day-1·kg-1) (Pinteraction<.005). Furthermore, time to exhaustion during the VO2max test decreased in PLA (by 2.5 ± .7%, p < .05) but not in KE and PROT (Pinteraction<.05). Lastly, the perception of overall stress increased in PLA and PROT (p < .05), but not in KE (Pinteraction<.05). Conclusion: Increased protein intake effectively prevented muscle wasting and maintained exercise capacity during a period of caloric restriction in female recreational athletes. Furthermore, exogenous ketosis did not affect body composition, but showed its potential in weight management by preserving a drop in exercise capacity and REE and by improving overall stress parameters during a period of caloric restriction.

A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study.

Physical inactivity and sedentary behaviors are independent risk factors for numerous diseases. We examined the ability of a nutrient cocktail composed of polyphenols, omega-3 fatty acids, vitamin E, and selenium to prevent the expected metabolic alterations induced by physical inactivity and sedentary behaviors. Healthy trained men ( n = 20) (averaging ∼14,000 steps/day and engaged in sports) were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise and decreased their daily steps (averaging ∼3,000 steps/day). During the last 10 days, metabolic changes were further triggered by fructose overfeeding. On days 0, 10, and 20, body composition (dual energy X-ray), blood chemistry, glucose tolerance [oral glucose tolerance test (OGTT)], and substrate oxidation (indirect calorimetry) were measured. OGTT included 1% fructose labeled with (U-13C) fructose to assess liver de novo lipogenesis. Histological changes and related cellular markers were assessed from muscle biopsies collected on days 0 and 20. While the cocktail did not prevent the decrease in insulin sensitivity and its muscular correlates induced by the intervention, it fully prevented the hypertriglyceridemia, the drop in fasting HDL and total fat oxidation, and the increase in de novo lipogenesis. The cocktail further prevented the decrease in the type-IIa muscle fiber cross-sectional area and was associated with lower protein ubiquitination content. The circulating antioxidant capacity was improved by the cocktail following the OGTT. In conclusion, a cocktail of nutrient compounds from dietary origin protects against the alterations in lipid metabolism induced by physical inactivity and fructose overfeeding. NEW & NOTEWORTHY This is the first study to test the efficacy of a novel dietary nutrient cocktail on the metabolic and physiological changes occurring during 20 days of physical inactivity along with fructose overfeeding. The main findings of this study are that 1) reduction in daily steps leads to decreased insulin sensitivity and total fat oxidation, resulting in hyperlipemia and increased de novo lipogenesis and 2) a cocktail supplement prevents the alterations on lipid metabolism.

Lipid mobilization in subcutaneous adipose tissue during exercise in lean and obese humans. Roles of insulin and natriuretic peptides.

The aim of this study was to evaluate the relative contributions of various hormones involved in the regulation of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise and to assess the impact of obesity on this regulation. Eight lean and eight obese men performed a 60-min cycle exercise bout at 50% of their peak oxygen uptake on two occasions: during intravenous infusion of octreotide (a somatostatin analog) or physiological saline (control condition). Lipolysis in SCAT was evaluated using in situ microdialysis. One microdialysis probe was perfused with the adrenergic blockers phentolamine and propranolol while another probe was perfused with the phosphodiesterase and adenosine receptor inhibitor aminophylline. Compared with the control condition, infusion of octreotide reduced plasma insulin levels in lean (from approximately 3.5 to 0.5 microU/ml) and in obese (from approximately 9 to 2 microU/ml), blunted the exercise-induced rise in plasma GH and epinephrine levels in both groups, and enhanced the exercise-induced natriuretic peptide (NP) levels in lean but not in obese subjects. In both groups, octreotide infusion resulted in higher exercise-induced increases in dialysate glycerol concentrations in the phentolamine-containing probe while no difference in lipolytic response was found in the aminophylline-containing probe. The results suggest that insulin antilipolytic action plays a role in the regulation of lipolysis during exercise in lean as well as in obese subjects. The octreotide-induced enhancement of exercise lipolysis in lean subjects was associated with an increased exercise-induced plasma NP response. Adenosine may contribute to the inhibition of basal lipolysis in both subject groups.

Lipid oxidation in overweight men after exercise and food intake.

Fat oxidation (FO) is optimized during low- to moderate-intensity exercise in lean and obese subjects, whereas high-intensity exercise induces preferential FO during the recovery period. After food intake during the postexercise period, it is unknown if FO differs according to the intensity exercise in overweight subjects. Fat oxidation was thus evaluated in overweight men after low- and high-intensity exercise during the recovery period before and after food intake as well as during a control session. Ten healthy, sedentary, overweight men (age, 27.9 +/- 5.6 years; body mass index, 27.8 +/- 1.3 kg m(-2); maximal oxygen consumption, 37 +/- 3.9 mL min(-1) kg(-1)) exercised on a cycloergometer (energy expenditure = 300 kcal) at 35% (E35) or 70% (E70) maximal oxygen consumption or rested (Cont). The subjects were fed 30 minutes after the exercise with 300 kcal (1256 kJ) more energy in the exercise sessions than in the Cont session. Respiratory quotient and FO were calculated by indirect calorimetry. Blood samples were analyzed to measure plasma glycerol, nonesterified fatty acid, glucose, and insulin. During exercise, mean respiratory quotient was lower (P < .05) and FO was higher (P < .01) in the E35 than in the E70 session (FO [in mg min(-1)]: E35 = 290 +/- 12, E70 = 256 +/- 38, and Cont = 131 +/- 7). Conversely, FO was higher in the E70 than in both the E35 session and the Cont session during the immediate recovery as well as during the postprandial recovery period (P = .005 for all; FO from the end of the exercise to the end of the session [in grams]: E70 = 45.7 +/- 8.9, E35 = 38.2 +/- 6.8, and Cont = 36.0 +/- 4.3). Blood parameters did not differ between the 3 sessions but changed according to the absorption of the nutrients. In overweight subjects, high-intensity exercise increased FO during the postexercise period even after food intake compared with the low-intensity exercise and the control session.

Exercise-induced lipid mobilization in subcutaneous adipose tissue is mainly related to natriuretic peptides in overweight men.

Involvement of sympathetic nervous system and natriuretic peptides in the control of exercise-induced lipid mobilization was compared in overweight and lean men. Lipid mobilization was determined using local microdialysis during exercise. Subjects performed 35-min exercise bouts at 60% of their maximal oxygen consumption under placebo or after oral tertatolol [a beta-adrenergic receptor (AR) antagonist]. Under placebo, exercise increased dialysate glycerol concentration (DGC) in both groups. Phentolamine (alpha-AR antagonist) potentiated exercise-induced lipolysis in overweight but not in lean subjects; the alpha(2)-antilipolytic effect was only functional in overweight men. After tertatolol administration, the DGC increased similarly during exercise no matter which was used probe in both groups. Compared with the control probe under placebo, lipolysis was reduced in lean but not in overweight men treated with the beta-AR blocker. Tertatolol reduced plasma nonesterified fatty acids and insulin concentration in both groups at rest. Under placebo or tertatolol, the exercise-induced changes in plasma nonesterified fatty acids, glycerol, and insulin concentrations were similar in both groups. Exercise promoted a higher increase in catecholamine and ANP plasma levels after tertatolol administration. In conclusion, the major finding of our study is that in overweight men, in addition to an increased alpha(2)-antilipolytic effect, the lipid mobilization in subcutaneous adipose tissue that persists during exercise under beta-blockade is not dependent on catecholamine action. On the basis of correlation findings, it seems to be related to a concomitant exercise-induced rise in plasma ANP when exercise is performed under tertatolol intake and a decrease in plasma insulin.

Control of lipolysis by natriuretic peptides and cyclic GMP.

Human fat cell lipolysis was, until recently, thought to be mediated exclusively by a cAMP-dependent protein kinase (PKA)-regulated pathway under the control of catecholamines and insulin. We have shown that atrial- and B-type natriuretic peptides (ANP and BNP respectively) stimulate lipolysis in human fat cells through a cGMP-dependent protein kinase (PKG) signaling pathway independent of cAMP production and PKA activity. Pharmacological or physiological (exercise) increases in plasma ANP levels stimulate lipid mobilization in humans. This pathway becomes important during chronic treatment with beta-adrenoceptor antagonists, which inhibit catecholamine-induced lipolysis but enhance cardiac ANP release. These findings have metabolic implications and point to potential problems when natriuretic peptide secretion is altered or during therapeutic use of recombinant BNP.

Sex differences in lipolysis-regulating mechanisms in overweight subjects: effect of exercise intensity.

OBJECTIVE: To explore sex differences in the regulation of lipolysis during exercise, the lipid-mobilizing mechanisms in the subcutaneous adipose tissue (SCAT) of overweight men and women were studied using microdialysis. RESEARCH METHODS AND PROCEDURES: Subjects matched for age, BMI, and physical fitness performed two 30-minute exercise bouts in a randomized fashion: the first test at 30% and 50% of their individual maximal oxygen uptake (Vo(2max)) and the second test at 30% and 70% of their Vo(2max). RESULTS: In both groups, an exercise-dependent increment in extracellular glycerol concentration (EGC) was observed. Whatever the intensity, phentolamine [alpha-adrenergic receptor (AR) antagonist] added to a dialysis probe potentiated exercise-induced lipolysis only in men. In a probe containing phentolamine plus propranolol (beta-AR antagonist), no changes in EGC occurred when compared with the control probe when exercise was performed at 30% and 50% Vo(2max). A significant reduction of EGC (when compared with the control probe) was observed in women at 70% Vo(2max). At each exercise power, the plasma non-esterified fatty acid and glycerol concentrations were higher in women. Exercise-induced increase in plasma catecholamine levels was lower in women compared with men. Plasma insulin decreased and atrial natriuretic peptide increased similarly in both groups. DISCUSSION: Overweight women mobilize more lipids (assessed by glycerol) than men during exercise. alpha(2)-Anti-lipolytic effect was functional in SCAT of men only. The major finding is that during low-to-moderate exercise periods (30% and 50% Vo(2max)), lipid mobilization in SCAT relies less on catecholamine-dependent stimulation of beta-ARs than on an increase in plasma atrial natriuretic peptide concentrations and the decrease in plasma insulin.

Lipid oxidation according to intensity and exercise duration in overweight men and women.

OBJECTIVE: Our objective was to compare the effect of different exercise intensities on lipid oxidation in overweight men and women. RESEARCH METHODS AND PROCEDURES: Nine young, healthy, overweight men and women were studied (age, 31.4 +/- 2.3 and 26.7 +/- 2.1 years; BMI, 27.9 +/- 0.4 and 27.2 +/- 0.5; for men and women, respectively). On one study day, the subjects first performed 30 minutes of cycling exercise at 30% of their maximal oxygen uptake (Vo(2max); E1 session), followed by 30 minutes of exercise at 50% Vo(2max) (E2 session). On a second study day, a similar E1 session was followed by 30 minutes of exercise at 70% Vo(2max) (E3 session). From the gas exchange measurements, the respiratory exchange ratio (RER) and the fat oxidation rate (FOR) were calculated. Plasma concentrations of glycerol and non-esterified fatty acids (NEFAs) were assayed. RESULTS: RER was significantly lower for women during only the E1 session. For both sexes, RER decreased over time during the E2 and E3 sessions. During the E1 session, the FOR per kilogram of lean mass (LM) was higher among women, and it did not change over time despite an increase in plasma NEFAs. FOR per kilogram of LM was higher during the E2 exercise for both sexes. During E2 and E3 sessions, as the exercise time was prolonged, the FOR/kg LM increased simultaneously with the increase in the plasma glycerol. DISCUSSION: Lipid oxidation during exercise is optimized for moderate and lengthy exercise. The enhancement of lipid oxidation occurring over time during moderate- and high-intensity exercises could be, in part, linked to the improvement of lipid mobilization. This fact is discussed to shed light on exercise modalities as a tool for the management of overweight.

Post-exercise abdominal, subcutaneous adipose tissue lipolysis in fasting subjects is inhibited by infusion of the somatostatin analogue octreotide.

To determine whether blockade of the exercise-induced increase in growth hormone (GH) secretion may affect the regional lipolytic rate in the post-exercise recovery period, the aim of the present experiments was to study the effect of infusion of the somatostatin analogue octreotide on the s.c., abdominal adipose tissue metabolism, before, during and after exercise in healthy, fasting, young male subjects. The adipose tissue net releases of fatty acids and glycerol were measured by arterio-venous catheterizations and simultaneous measurements of adipose tissue blood flow with the local Xe-clearance method. Nine subjects were studied during 1-h basal rest, and then during continuous octreotide infusion during 1-h rest, 1-h exercise at 50% of maximal oxygen consumption and 4-h post-exercise rest. A control study on seven subjects was performed under similar conditions but without octreotide infusion. The results show that octreotide infusion during rest increased lipolysis and fatty acid release from the abdominal, s.c. adipose tissue. The exercise-induced increase in lipolysis and fatty acid release does not seem to be affected by octreotide when compared with the control study without octreotide infusion while the post-exercise increase in lipolysis is inhibited by octreotide, suggesting that the exercise-induced increase in GH secretion plays a role for the post-exercise lipolysis in s.c., abdominal adipose tissue.

Acute exposure to long-chain fatty acids impairs {alpha}2-adrenergic receptor-mediated antilipolysis in human adipose tissue.

The acute in vitro and in vivo effects of long-chain fatty acids (LCFAs) on the regulation of adrenergic lipolysis were investigated in human adipose tissue. The effect of a 2 h incubation, without or with LCFA (200 mumol/l), on basal and hormonally induced lipolysis was tested in vitro on isolated fat cells. The lipolytic response to epinephrine was enhanced by suppression of the antilipolytic alpha(2)-adrenergic effect. Then, healthy lean and obese male subjects performed a 45 min exercise bout at 50% of their heart rate reserve either after an overnight fast or 3 h after a high-fat meal (HFM: 95% fat, 5% carbohydrates). Subcutaneous adipose tissue lipolysis was measured by microdialysis in the presence or absence of an alpha-antagonist (phentolamine). In vivo, a HFM increased plasma levels of nonesterified fatty acids in lean and obese subjects. In both groups, the HFM did not alter hormonal responses to exercise. Under fasting conditions, the alpha(2)-adrenergic antilipolytic effect was more pronounced in obese than in lean subjects. The HFM totally suppressed the alpha(2)-adrenergic antilipolytic effect in lean and obese subjects during exercise. LCFAs per se, in vitro as well as in vivo, suppress alpha(2)-adrenergic-mediated antilipolysis in adipose tissue. LCFA-mediated suppression of antilipolytic pathways represents another mechanism whereby a high fat content in the diet might increase adipose tissue lipolysis.

Atrial natriuretic peptide contribution to lipid mobilization and utilization during head-down bed rest in humans.

Head-down bed rest (HDBR) increases plasma levels of atrial natriuretic peptide (ANP) and decreases norepinephrine levels. We previously demonstrated that ANP promotes lipid mobilization and utilization, an effect independent of sympathetic nervous system activation, when infused into lean healthy men at pharmacological doses. The purpose of the present study was to demonstrate that a physiological increase in ANP contributes to lipid mobilization and oxidation in healthy young men. Eight men were positioned for 4 h in a sitting (control) or in a HDBR position. Indexes of lipid mobilization and hormonal changes were measured in plasma. Extracellular glycerol, an index of lipolysis, was determined in subcutaneous adipose tissue (SCAT) with a microdialysis technique. A twofold increase in plasma ANP concentration was observed after 60 min of HDBR, and a plateau was maintained thereafter. Plasma norepinephrine decreased by 30-40% during HDBR, while plasma insulin and glucose levels did not change. The level of plasma nonesterified fatty acids was higher during HDBR. SCAT lipolysis, as reflected by interstitial glycerol, as well as interstitial cGMP, the second messenger of the ANP pathway, increased during HDBR. This was associated with an increase in blood flow observed throughout HDBR. Significant changes in respiratory exchange ratio and percent use of lipid and carbohydrate were seen only after 3 h of HDBR. Thus the proportion of lipid oxidized increased by 40% after 3 h of HDBR. The rise in plasma ANP during HDBR was associated with increased lipolysis in SCAT and whole body lipid oxidation. In this physiological setting, independent of increasing catecholamines, our study suggests that ANP contributes to lipid mobilization and oxidation in healthy young men.

Atrial natriuretic peptide stimulates lipid mobilization during repeated bouts of endurance exercise.

Atrial natriuretic peptide (ANP) controls lipolysis in human adipocytes. Lipid mobilization is increased during repeated bouts of exercise, but the underlying mechanisms involved in this process have not yet been delineated. The relative involvement of catecholamine- and ANP-dependent pathways in the control of lipid mobilization during repeated bouts of exercise was thus investigated in subcutaneous adipose tissue (SCAT) by microdialysis. The study was performed in healthy males. Subjects performed two 45-min exercise bouts (E1 and E2) at 50% of their maximal oxygen uptake separated by a 60-min rest period. Extracellular glycerol concentration (EGC), reflecting SCAT lipolysis, was measured in a control probe perfused with Ringer solution and in two other probes perfused with either Ringer plus phentolamine (alpha(1/2)-AR antagonist) or Ringer plus both phentolamine and propranolol (beta-AR antagonist). Plasma epinephrine, plasma glycerol, and EGC were 1.7-, 1.6-, and 1.2-fold higher in E2 than in E1, respectively. Phentolamine potentiated exercise-induced EGC increase during E2 only. Propranolol reduced the lipolytic rate during both E1 and E2 compared with the probe with phentolamine. Plasma ANP concentration increased more during E2 than during E1 and was correlated with the increase in EGC in the probe containing phentolamine plus propranolol. The results suggest that ANP is involved in the control of lipolysis during exercise and that it contributes to stimulation of lipolysis during repeated bouts of exercise.

An unsuspected metabolic role for atrial natriuretic peptides: the control of lipolysis, lipid mobilization, and systemic nonesterified fatty acids levels in humans.

In normal and obese humans, lipid mobilization and systemic nonesterified fatty acid levels are thought to be acutely controlled by catecholamines (ie, epinephrine and norepinephrine) and insulin. Natriuretic peptides (NPs) are known to play a key role in the regulation of salt and water balance and blood pressure homeostasis. They are involved in the pathophysiology of hypertension and heart failure. NPs have recently been found to exert potent lipolytic effects (ie, activating the breakdown of stored triacylglycerols) in isolated human fat cells and to promote lipid mobilization in vivo. Atrial natriuretic peptide increases the intracellular 3', 5'-cyclic guanosine monophosphate (cGMP) concentration which activates cGMP-dependent protein kinase leading to perilipin and hormone-sensitive lipase phosphorylation and lipolysis. NPs promote lipid mobilization when administered intravenously. NPs are also responsible for the residual lipid-mobilizing action observed under oral beta-blockade in subjects performing physical exercise. NPs are therefore novel factors which may open promising research pathways to explain the control of lipid mobilization in physiological and pathological conditions. The metabolic impact of altered production and circulation of NPs remains to be established. The potential influence of NPs on the development of lipid disorders, obesity-related cardiovascular events, and cardiac cachexia will be discussed in this review.

Training enhances ANP lipid-mobilizing action in adipose tissue of overweight men.

PURPOSE: This study was designed to evaluate whether a 4-month endurance training program could improve ANP- as well as isoproterenol-mediated (beta-adrenergic receptor agonist) in situ lipolysis and adipose tissue blood flow (ATBF) in the subcutaneous adipose tissue (SCAT) of untrained overweight subjects. METHODS: Ten overweight men aged 26.0 +/- 1.4 yr with a mean body mass index of 27.6 +/- 0.2 kg.m(-2), performed aerobic exercise 5 d.wk(-1) for 4 months. Before and after the training period, SCAT responsiveness was investigated in situ during a 60-min infusion of 1 micromol.L(-1) isoproterenol and 10 micromol.L(-1) ANP through microdialysis probes. Plasma metabolic parameters and physical fitness variables were measured as well. RESULTS: Endurance training significantly increased fat-free mass and VO2max, while reducing plasma insulin, glucose, NEFA, low density lipoprotein (LDL)-C and the respiratory exchange ratio at rest. Training significantly lowered resting dialysate glycerol levels in SCAT. The lipid-mobilizing effect of ANP was markedly enhanced (by 191%, P < 0.05) after training as was that of isoproterenol (by 145%, P < 0.05). Resting adipose tissue blood flow as well as ANP- and isoproterenol-mediated rise in ATBF was increased after training. CONCLUSION: The present study shows that endurance training improves ANP- as well as beta-adrenergic-receptor-mediated lipid mobilization and ATBF in the SCAT of overweight subjects. The recovery of a higher lipolytic efficiency in adipose tissue is an important benefit of a training program in overweight subjects.

Atrial natriuretic peptide contributes to physiological control of lipid mobilization in humans.

In humans, lipid mobilization is considered to depend mainly on sympathetic nervous system activation and catecholamine action. A contribution of ANP was hypothesized because we have previously shown that atrial natriuretic peptide (ANP) is a lipolytic agent on isolated human fat cells. Control of lipid-mobilizing mechanisms was investigated using in situ microdialysis in subcutaneous adipose tissue (SCAT) in healthy young men during two successive exercise bouts performed at 35% and 60% peak oxygen consumption (VO2max) after placebo or acute oral tertatolol (nonselective beta-antagonist) treatment. In placebo-treated subjects, infusion of propranolol in the probe (100 micromol/l) only partially reduced (40%) the increment in extracellular glycerol concentration (EGC) promoted by exercise. Moreover, oral beta-adrenergic receptor blockade did not prevent exercise-induced lipid mobilization in SCAT while exerting fat cell beta-adrenergic receptor blockade. Exercise-induced increase in plasma ANP was potently amplified by oral tertatolol. A positive correlation was found between EGC and plasma ANP levels but also between extracellular cGMP (i.e., index of ANP-mediated lipolysis) and EGC. Thus, we demonstrate that exercise-induced lipid mobilization resistant to local propranolol and lipid-mobilizing action observed under oral beta-blockade is related to the action of ANP. Oral beta-adrenergic receptor blockade, which potentiates exercise-induced ANP release by the heart, may contribute to lipid mobilization in SCAT. The potential relevance of an ANP-related lipid-mobilizing pathway is discussed.

Functional and pharmacological characterization of the natriuretic peptide-dependent lipolytic pathway in human fat cells.

A lipolytic pathway involving natriuretic peptides has recently been discovered in human fat cells. Its functional characteristics and the interactions of the atrial natriuretic peptide (ANP)-induced effects with adrenergic and insulin pathways were studied. Characterization of the action of ANP antagonists, i.e., A71915, anantin, S-28-Y (Ser-28-Tyr, a synthesized peptide), and HS-142-1 (a microbial polysaccharide), was performed. Lipolytic assays and intracellular cGMP and cAMP determinations were performed on isolated fat cells. Cell membranes were used for binding studies. At low concentrations ANP and isoproterenol [beta-adrenergic receptor (beta-AR) agonist] exerted additive lipolytic effects. The alpha(2)-AR pathway did not interfere with that of ANP. Lipolytic effects of ANP were unaltered by a 2-h pretreatment of fat cells with insulin, whereas beta-AR-induced lipolysis was reduced. Homologous desensitization occurred for ANP-dependent lipolytic pathways. Dendroapsis natriuretic peptide exhibited a similar maximal effect but a 10-fold higher lipolytic potency than ANP and mini-ANP (the shortest form of ANP). The antagonist A71915 exhibited competitive antagonistic properties with a pA(2) value of 7.51. Anantin displayed noncompetitive antagonism and exerted an inhibitory action on basal and beta-adrenergic receptor-induced lipolytic response. S-28-Y exhibited antagonist potencies toward ANP-induced lipolysis and behaved as a partial lipolytic agonist with a lower pD(2) value (7.4 +/- 0.2) than ANP (9.4 +/- 0.3). HS-142-1 exerted the weakest antagonistic effects. The results demonstrate that ANP-dependent effects do not interfere with beta- and alpha(2)-adrenergic pathways in human fat cells. They are unaffected by insulin pretreatments of fat cells but undergo desensitization. In the search of potent and specific natriuretic peptide receptor-A antagonist, in the human fat cell, A71915 was the only reliable one found.

Effects of a longitudinal training program on responses to exercise in overweight men.

OBJECTIVE: The aim of this study was to determine how training modifies metabolic responses and lipid oxidation in overweight young male subjects. RESEARCH METHODS AND PROCEDURES: Eleven overweight subjects were selected for a 4-month endurance training program. Before and after the training period, they cycled for 60 minutes at 50% of their VO(2)max after an overnight fast or 3 hours after eating a standardized meal. Various metabolic and endocrine parameters, and respiratory exchange ratio values were evaluated. RESULTS: Exercise-induced plasma norepinephrine concentration increases were similar before and after training in fasted or fed conditions. After food intake, exercise promoted a decrease in plasma glucose and a higher increase in epinephrine than in fasting conditions. The increase in epinephrine after the meal was more marked after training (264 +/- 32 vs. 195 +/- 35 pg/mL). Training lowered the resting plasma nonesterified fatty acids. During exercise, changes in glycerol were similar to those found before training. Lipid oxidation during exercise was higher in fasting than in fed conditions (15.5 +/- 1.4 vs. 22.3 +/- 1.7 g/h). Training did not significantly increase fat oxidation when exercise was performed in fed conditions, but it did in fasting conditions (18.6 +/- 1.4 vs. 27.2 +/- 1.8 g/h). DISCUSSION: Endurance training decreased plasma nonesterified fatty acids, cholesterol, and insulin concentrations. Training increased lipid oxidation during exercise, in fasting conditions, and not when exercise was performed after the meal. During exercise in overweight subjects, the fasting condition seems more suited to oxidizing fat and maintaining glucose homeostasis than a 3-hour wait after a standard meal.

Effect of macronutrient composition of the diet on the regulation of lipolysis in adipose tissue at rest and during exercise: microdialysis study.

The aim of the present study was to elucidate, using a microdialysis technique, whether modifications in the proportion of fat in the diet influence lipid mobilization from adipose tissue in situ. Nine healthy volunteers (age, 23.4 +/- 0.2 years; body mas index [BMI], 23.5 +/- 1.6 kg/m(2)) were fed, in random order, with a high-fat diet (HFD) (65% of energy content fat, 15% protein, 20% carbohydrate) or a high-carbohydrate diet (HCD) (70% carbohydrate, 15% protein, 15% fat) for 5 days, with a washout period of 10 days between the diets. Subjects were studied in the fasting state on the morning following days 4 and 5 of each diet. We measured the concentration of extracellular glycerol (EGC) in adipose tissue in response to (1) pharmacologic stimulation with isoprenaline (1 and 10 micromol/L) in situ, (2) stimulation with intravenous infusion of epinephrine (0.0375 microg/min/kg body weight), and (3) submaximal aerobic exercise (50% V*O2max, 60-minute duration). No effect of the diet composition was found in the increases of EGC in response to isoprenaline (area under the curve [AUC]: HFD, 1,534 +/- 370 micromol/90 min; HCD, 1,108 +/- 465 micromol/90 min; not significant [NS]) or epinephrine stimulations (AUC: HFD, 190 +/- 92 micromol/30 min; HCD, 251 +/- 298 micromol/30 min; NS). The exercise-induced increase in EGC was higher during the HFD (AUC: HFD, 1,641 +/- 181 micromol/60 min; HCD, 963 +/- 156 micromol/60 min; P <.05) and was associated with a higher exercise-induced response of norepinephrine (P <.05) and epinephrine (P =.056) and lower insulinemia during exercise. The results suggest that macronutrient composition of diet does not affect the beta-adrenergic responsiveness of adipose tissue to catecholamine action at rest. During exercise, the HFD promotes higher lipolysis in adipose tissue and this is associated with a higher catecholamine response and lower insulinemia.