Isabelle Harant

We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise–stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.

Differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been demonstrated on adipose tissue physiology. Facing to the widely recognized beneficial effects of n-3 PUFAs, the n-6 PUFA effects remain controversial. Thus, we further analyzed the linoleic acid (LA) influence on adipocyte functions. To this aim, we treated by LA supplementation at three distinct doses (1, 2.5, or 5 % of energy intake) rats with essential fatty acids deficiency (EFAD). PUFA composition was determined in blood and white adipose tissue (WAT), while lipolytic and lipogenic activities were measured in isolated adipocytes. EFAD rats exhibited reduced WAT mass and increased EFAD biomarkers. WAT mass was completely recovered after supplementation, irrespective of LA dose. However, neither body mass nor EFAD biomarkers returned to control with 1 % LA, while LA abundance doubled in adipocytes from rats supplemented with 5 % LA. Regarding lipolysis, 2.5 % LA normalized the EFAD-induced alterations. A trend to decrease the maximal stimulation of lipolysis was observed with 1 and 5 % LA. Regarding lipogenesis, the lower and higher LA doses increased basal activity and hampered insulin to further stimulate glucose incorporation into lipids whereas 2.5 % LA normalized the basal or insulin-stimulated levels. Our results show that dietary linoleate at 2.5 % restored anatomical, biochemical, and functional disturbances induced by EFAD. At higher dose, LA tended to reduce triacylglycerol breakdown, to increase triacylglycerol assembly, and to provoke insulin resistance. Therefore, LA influence on adipocyte functions does not appear to follow a typical dose–response relationship, adding further complexity to the definition of its dietary requirement.

The aim of the present study was to investigate the influence of substrate availability on fuel selection during exercise. Eight endurance-trained male cyclists performed 90-min exercise at 70 % of their maximal oxygen uptake in a cross-over design, either in rested condition (CON) or the day after 2-h exercise practised at 70 % of maximal oxygen uptake (EX). Subjects were given a sucrose load (0.75 g kg⁻¹ body weight) 45 min after the beginning of the 90-min exercise test. Lipolysis was measured in subcutaneous abdominal adipose tissue (SCAT) by microdialysis and substrate oxidation by indirect calorimetry. Lipid oxidation increased during exercise and tended to decrease during sucrose ingestion in both conditions. Lipid oxidation was higher during the whole experimental period in the EX group (p = 0.004). Interestingly, fuel selection, assessed by the change in respiratory exchange ratio (RER), was increased in the EX session (p = 0.002). This was paralleled by a higher rate of SCAT lipolysis reflected by dialysate glycerol, plasma glycerol, and fatty acids (FA) levels (p < 0.001). Of note, we observed a significant relationship between whole-body fat oxidation and dialysate glycerol in both sessions (r ² = 0.33, p = 0.02). In conclusion, this study highlights the limiting role of lipolysis and plasma FA availability to whole-body fat oxidation during exercise in endurance-trained subjects. This study shows that adipose tissue lipolysis is a determinant of fuel selection during exercise in healthy subjects.

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP–dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training–induced improvement in skeletal muscle fat oxidative capacity in humans.

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 β-adrenergic receptor (AR) antagonist]. Under placebo, exercise increased dialysate glycerol concentration (DGC) in both groups. Phentolamine (α-AR antagonist) potentiated exercise-induced lipolysis in overweight but not in lean subjects; the α₂-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 β-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 α₂-antilipolytic effect, the lipid mobilization in subcutaneous adipose tissue that persists during exercise under β-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.

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.

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 [α‐adrenergic receptor (AR) antagonist] added to a dialysis probe potentiated exercise‐induced lipolysis only in men. In a probe containing phentolamine plus propranolol (β‐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. α₂‐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 β‐ARs than on an increase in plasma atrial natriuretic peptide concentrations and the decrease in plasma insulin.

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.

T 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 μmol·L−1 isoproterenol and 10 μmol·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 V̇O2max, 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 β-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....