Atrial natriuretic peptide (ANP) stimulates lipid mobilization and lipid oxidation in humans. The mechanism appears to promote lipid mobilization during exercise. We tested the hypothesis that water immersion augments exercise-induced ANP release and that the change in ANP availability is associated with increased lipid mobilization and lipid oxidation. In an open randomized and cross-over fashion we studied 17 men (age 31+/-3.6 years; body mass index 24+/-1.7 kg/m(2); body fat 17+/-6.7%) on no medication. Subjects underwent two incremental exercise tests on a bicycle ergometer. One test was conducted on land and the other test during immersion in water up to the xiphoid process. In a subset (n=7), we obtained electromyography recordings in the left leg. We monitored gas exchange, blood pressure, and heart rate. In addition, we obtained blood samples towards the end of each exercise step to determine ANP, norepinephrine, epinephrine, lactate, free fatty acids, insulin, and glucose concentrations. Heart rate, systolic blood pressure, and oxygen consumption at the anaerobic threshold and during peak exercise were similar on land and with exercise in water. The respiratory quotient was mildly reduced when subjects exercised in water. Glucose and lactate measurements were decreased whereas free fatty acid concentrations were increased with exercise in water. Water immersion attenuated epinephrine and norepinephrine and augmented ANP release during exercise. Even though water immersion blunts exercise-induced sympathoadrenal activation, lipid mobilization and lipid oxidation rate are maintained or even improved. The response may be explained by augmented ANP release.

Objectif La mobilisation des lipides a partir du tissu adipeux differe en fonction de la localisation. Cette difference persiste-t-elle lors d’une obesite massive ? Le but de l’etude est de comparer, in vitro, la lipolyse du tissu adipeux sous-cutane a celle du tissu adipeux profond. Pour cela, du tissu adipeux sous-cutane abdominal et du tissu adipeux omental ont ete preleves en per-operatoire chez 22 femmes obeses (âge : 51 ± 9 ans, IMC : 43 ± 1 kg/m2). Resultats L’effet max (en % de la basale) de l’isoprenaline est superieur dans le tissu profond par rapport au tissu sous-cutane (p = 0,02). En presence d’insuline (10-7 M), l’effet max de l’isoprenaline est diminue des 10-9 M pour le tissu profond (p Conclusion Cette etude met en evidence que, chez l’obese, la lipolyse induite par la stimulation beta-adrenergique est superieure dans le tissu adipeux profond par rapport au tissu adipeux sous-cutane et que l’effet antilipolytique de l’insuline est moindre dans le tissu adipeux profond. De plus, dans ce dernier, on observe une plus grande activite de la LHS. Ces resultats montrent la persistance d’une meilleure mobilisation des lipides dans le tissu adipeux profond chez la femme lors d’obesite morbide.

The relative contribution of noradrenaline (norepinephrine) and adrenaline (epinephrine) in the control of lipid mobilization in subcutaneous adipose tissue (SCAT) during exercise was evaluated in men treated with a somatostatin analogue, octreotide. Eight lean and eight obese young men matched for age and physical fitness performed 60 min exercise bouts at 50% of their maximal oxygen consumption on two occasions: (1) during i.v. infusion of octreotide, and (2) during placebo infusion. Lipolysis and local blood flow changes in SCAT were evaluated using in situ microdialysis. Infusion of octreotide suppressed plasma insulin and growth hormone levels at rest and during exercise. It blocked the exercise-induced increase in plasma adrenaline while that of noradrenaline was unchanged. Plasma natriuretic peptides (NPs) level was higher at rest and during exercise under octreotide infusion in lean men. Under placebo, no difference was found in the exercise-induced increase in glycerol between the probe perfused with Ringer solution alone and that with phentolamine (an alpha-adrenergic receptor antagonist) in lean subjects while a greater increase in glycerol was observed in the obese subjects. Under placebo, propranolol infusion in the probe containing phentolamine reduced by about 45% exercise-induced glycerol release; this effect was fully suppressed under octreotide infusion while noradrenaline was still elevated and exercise-induced lipid mobilization maintained in both lean and obese individuals. In conclusion, blockade of beta-adrenergic receptors during exercise performed during infusion of octreotide (blocking the exercise-induced rise in adrenaline but not that of noradrenaline) does not alter the exercise-induced lipolysis. This suggests that adrenaline is the main adrenergic agent contributing to exercise-induced lipolysis in SCAT. Moreover, it is the combined action of insulin suppression and NPs release which explains the lipolytic response which remains under octreotide after full local blockade of fat cell adrenergic receptors. For the moment, it is unknown if results apply specifically to SCAT and exercise only or if conclusions could be extended to all forms of lipolysis in humans.

Thyroid dysfunction is associated with several abnormalities in intermediary metabolism, including impairment of lipolytic response to catecholamines in subcutaneous abdominal adipose tissue (SCAAT). Atrial natriuretic peptide (ANP) is a powerful lipolytic peptide; however, the role of ANP-mediated lipolysis in thyroid disease has not been elucidated. The aim of this study was to investigate the role of thyroid hormones in the regulation of ANP-induced lipolysis as well as in the gene expression of hormone-sensitive lipase, phosphodiesterase 3B (PDE3B), uncoupling protein-2 (UCP2), natriuretic peptide receptor type A, and beta(2)-adrenergic receptor in SCAAT of hyperthyroid and hypothyroid patients. Gene expression in SCAAT was studied in 13 hypothyroid and 11 hyperthyroid age-matched women before and 2-4 mo after the normalization of their thyroid status. A microdialysis study was performed on a subset of nine hyperthyroid and 10 hypothyroid subjects. ANP- and isoprenaline-induced lipolyses were higher in hyperthyroid subjects, with no differences between the groups following treatment. Hormone-sensitive lipase gene expression was higher in hyperthyroid compared with hypothyroid subjects before treatment, whereas no difference was observed following treatment. No differences in gene expression of other genes were observed between the two groups. Following treatment, the gene expression of UCP2 decreased in hyperthyroid, whereas the expression of PDE3B decreased in hypothyroid subjects. We conclude that thyroid hormones regulate ANP- and isoprenaline-mediated lipolysis in human SCAAT in vivo. Increased lipolytic subcutaneous adipose tissue response in hyperthyroid patients may involve postreceptor signaling mechanisms.

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.

Background and purpose: Atrial natriuretic peptide (ANP) stimulates lipolysis in human adipocyte through a cGMP signalling pathway, the regulation of which is poorly known. Since phosphodiesterases (PDE) and neutral endopeptidase (NEP) play a major role in the regulation of the biological effects of natriuretic peptides in the cardiovascular and renal systems, we investigated whether these mechanisms could regulate cGMP signalling and ANP-mediated lipolysis in human adipocytes.Experimental approach: The presence of cGMP-specific PDE and NEP in differentiated pre-adipocytes and in mature adipocytes was evaluated by real-time qPCR and Western blot. The effect of non-selective and selective inhibition of these enzymes on ANP-mediated cGMP signalling and lipolysis was determined in isolated mature adipocytes.Key results: PDE-5A was expressed in both pre-adipocytes and adipocytes. PDE-5A mRNA and protein levels decreased as pre-adipocytes differentiated ( 10 days). PDE-5A is rapidly activated in response to ANP stimulation and lowers intracellular cGMP levels. Its selective inhibition by sildenafil partly prevented the decline in cGMP levels. However, no changes in baseline- and ANP-mediated lipolysis were observed under PDE-5 blockade using various inhibitors. In addition, NEP mRNA and protein levels gradually increased during the time-course of pre-adipocyte differentiation. Thiorphan, a selective NEP inhibitor, completely abolished NEP activity in human adipocyte membranes but did not modify ANP-mediated lipolysis.Conclusions and implications: Functional PDE-5A and NEP activities were present in human adipocytes, however these enzymes did not play a major role in the regulation of ANP-mediated lipolysis.

Cette revue vise à recenser les aspects cellulaires, physiologiques et physiopathologiques du contrôle de la lipolyse par le peptide atrial natriurétique dans le tissu adipeux humain. Le texte aborde également une fonction nouvellement caractérisée de ce peptide dans la régulation autocrine-paracrine des sécrétions des adipocytes et des macrophages du tissu adipeux.

Aims/hypothesis Increased adipose tissue secretion of adipokines and cytokines has been implicated in the chronic low-grade inflammation state and insulin resistance associated with obesity. We tested here whether the cardiovascular and metabolic hormone atrial natriuretic peptide (ANP) was able to modulate adipose tissue secretion of several adipokines (derived from adipocytes) and cytokines (derived from adipose tissue macrophages).Subjects and methods We used protein array to measure the secretion of adipokines and cytokines after a 24-h culture of human subcutaneous adipose tissue pieces treated or not with a physiological concentration of ANP. The effect of ANP on protein secretion was also directly studied on isolated adipocytes and macrophages. Gene expression was measured by real-time RT-quantitative PCR.Results ANP decreased the secretion of the pro-inflammatory cytokines IL-6 and TNF-alpha, of several chemokines, and of the adipokines leptin and retinol-binding protein-4 (RBP-4). The secretion of the anti-inflammatory molecules IL-10 and adiponectin remained unaffected. The cytokines were mainly expressed in macrophages that expressed all components of the ANP-dependent signalling pathway. The adipokines, leptin, adiponectin and RBP-4 were specifically expressed in mature adipocytes. ANP directly inhibited the secretion of IL-6 and monocyte chemoattractant protein-1 by macrophages. The inhibitory effects of ANP on leptin and growth-related oncogene-alpha secretions were not seen under selective hormone-sensitive lipase inhibition.Conclusions/interpretation We suggest that ANP, either by direct action on adipocytes and macrophages or through activation of adipocyte hormone-sensitive lipase, inhibits the secretion of factors involved in inflammation and insulin resistance.