[Fat mass expansion, fatty acids and adipokines: metabolic markers and risk factors for cardiovascular pathologies]. / Expansion de la masse grasse, acides gras et adipokines : des marqueurs métaboliques et des facteurs de risque de pathologies cardiovasculaires.

Obesity is described as an independent risk factor for cardiovascular disease. Fat mass expansion is often associated with occurrence of a pro-inflammatory state, which will interfere with cell metabolism in various tissues and alter noticeably insulin-signaling processes. This low-grade, systemic inflammatory response that characterizes obesity will develop towards dysfunctions which will include insulin-resistance, type 2 diabetes, dyslipidemia, hypertension and coronary and vascular pathologies and even toward some cancers. Metabolic and endocrine functions will be briefly considered as well as events related to fat mass expansion such as hypertrophy-related disturbances in adipocyte function and adipose tissue infiltration by immune cells (i.e., macrophages and lymphocytes which could secrete cytokines and chemokines). In addition to the well known function of storage and release on non esterified fatty acids (NEFAs), the adipocytes synthesize and secrete circulating hormones (called adipokines such as leptin, adiponectin and apelin) which are acting as signaling molecules and which are mediators/modulators of the inflammatory processes. The interest of adipose tissue productions as plasma metabolic markers and the dialogue and interactions between adipose tissue productions (i.e., NEFAs, adipokines and cytokines) and other target tissues will be considered. The objective of this paper is to describe adipose tissue dysfunctions observed in obesity and to delineate putative relationships, which could exist between adipose tissue dysfunctions and other tissues. The idea is to describe how adipose tissue dysfunction is involved in the development of type 2 diabetes and cardiovascular diseases.

Neurohumoral and metabolic response to exercise in water.

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.

Adrenaline but not noradrenaline is a determinant of exercise-induced lipid mobilization in human subcutaneous adipose tissue.

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.

Remodeling phenotype of human subcutaneous adipose tissue macrophages.

BACKGROUND: Adipose tissue macrophages (ATMs) have become a focus of attention recently because they have been shown to accumulate with an increase in fat mass and to be involved in the genesis of insulin resistance in obese mice. However, the phenotype and functions of human ATMs are still to be defined. METHODS AND RESULTS: The present study, performed on human subcutaneous AT, showed that ATMs from lean to overweight individuals are composed of distinct macrophage subsets based on the expression of several cell surface markers: CD45, CD14, CD31, CD44, HLA-DR, CD206, and CD16, as assessed by flow cytometry. ATMs isolated by an immunoselection protocol showed a mixed expression of proinflammatory (tumor necrosis factor-alpha, interleukin-6 [IL-6], IL-23, monocyte chemoattractant protein-1, IL-8, cyclooxygenase-2) and antiinflammatory (IL-10, transforming growth factor-beta, alternative macrophage activation-associated cc chemokine-1, cyclooxygenase-1) factors. Fat mass enlargement is associated with accumulation of the CD206+/CD16- macrophage subset that exhibits an M2 remodeling phenotype characterized by decreased expression of proinflammatory IL-8 and cyclooxygenase-2 and increased expression of lymphatic vessel endothelial hyaluronan receptor-1. ATMs specifically produced and released matrix metalloproteinase-9 compared with adipocytes and capillary endothelial cells, and secretion of matrix metalloproteinase-9 from human AT in vivo, assessed by arteriovenous difference measurement, was correlated with body mass index. Finally, ATMs exerted a marked proangiogenic effect on AT-derived endothelial and progenitor cells. CONCLUSIONS: The present results showed that the ATMs that accumulate with fat mass development exhibit a particular M2 remodeling phenotype. ATMs may be active players in the process of AT development through the extension of the capillary network and in the genesis of obesity-associated cardiovascular pathologies.

Advances in adipose tissue metabolism.

This review will focus on the recent findings in adipose tissue metabolism with special attention to human adipocyte biology and physiology. There are major advances stemming from the concomitant results obtained from studies on mature human adipocytes, human preadipocytes differentiated in vitro and murine adipose cell lines. Physiological developments have been based on the expanded utilization of various kinds of murine transgenic models and physiological techniques such as microdialysis, open-flow microperfusion, arteriovenous techniques and the utilization of deuterium- or tritium-labelled metabolites that have provided a number of physiological advances in the understanding of human adipose tissue physiology. Gene expression profiling studies and nutrigenomics are emerging methods that herald interesting approaches for the future. An overview of recent discoveries in the mechanisms involved in the control of free fatty acid uptake, triacylglycerol synthesis and fat deposition will be discussed, as well as recent advances in the mechanisms involved in the lipolytic pathways, the role of lipases and perilipins. In addition, the in vivo validation of catecholamine action and the discovery of the lipolytic effects of natriuretic peptides will also be covered.

Impact of visceral adipose tissue on liver metabolism and insulin resistance. Part II: Visceral adipose tissue production and liver metabolism.

Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low levels of high-density lipoprotein cholesterol that contribute to the development of type-2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver. The secreted products interact with hepatocytes and various immune cells in the liver. Altered liver metabolism and determinants of insulin resistance associated with visceral adipose tissue distribution are discussed, as well as, determinants of an insulin-resistant state promoted by the increased free fatty acids and cytokines delivered by visceral adipose tissue to the liver.

Impact of visceral adipose tissue on liver metabolism. Part I: heterogeneity of adipose tissue and functional properties of visceral adipose tissue.

Excess visceral adipose tissue is associated with anomalies of blood glucose homoeostasis, elevation of plasma triglycerides and low high-density lipoprotein cholesterol that contribute to the later appearance of type 2 diabetes and cardiovascular syndromes. Visceral adipose tissue releases a large amount of free fatty acids and hormones/cytokines in the portal vein that are delivered to the liver, and interact with hepatocytes and various immune cells in the liver. The functional characteristics of visceral adipose tissue will be compared with subcutaneous adipose tissue to clarify the major mechanisms affecting free fatty acid metabolism and cytokine production.

Use of the microdialysis technique to assess lipolytic responsiveness of femoral adipose tissue after 12 sessions of mechanical massage technique.

BACKGROUND: Adipocytes in femoral areas are known to be metabolically 'silent'. Changes related to fat cell hypertrophy may be involved in the formation of cellulite. A mechanical massage technique, with circulatory and dermotrophic properties, has been shown to have an impact on clinical evaluations (i.e. changes in morphometric measurements) in cellulite areas. Whether this technique affected lipolytic responsiveness in subcutaneous adipose tissue of cellulite areas was not known. OBJECTIVE: Using a microdialysis technique in subcutaneous adipose tissue, a study was carried out to test the in situ incidence of a mechanical massage technique in terms of adipose tissue responsiveness to a lipolytic challenge. MATERIALS AND METHODS: Nine healthy women volunteers with cellulite (grade > or = 2) were included and treated with 12 sessions of mechanical massage technique (Endermologie). Microdialysis has been carried out in the femoral adipose tissue in order to assess lipolytic responsiveness via glycerol determination following perfusion of a lipolytic agent (0.1, 1 and 10 microm isoproterenol). Clinical evaluations (measurements of waist, thighs and skin fold) were carried out in parallel. All evaluations were performed before and after treatment. RESULTS: The studied intervention lowered resting dialysate glycerol levels in femoral adipose tissue. The lipid-mobilizing effect of isoproterenol was enhanced after 1 month of treatment. In addition, a clear decrease of morphometric measurements (mean decrease on thighs perimeter: 3.1 to 3.3 cm, P < 0.01) was observed. CONCLUSION: These results suggest an increase in the lipolytic responsiveness of femoral adipose tissue in women with cellulite having undergone 12 sessions of mechanical massage.

Role of vascular alpha-2 adrenoceptors in regulating lipid mobilization from human adipose tissue.

The role of alpha-2 adrenoceptors in lipid mobilization and blood flow was investigated in situ using microdialysis of subcutaneous adipose tissue in nonobese healthy subjects. The alpha-2 agonist clonidine caused dose-dependent biphasic response with increased glycerol levels at low clonidine concentrations and decreased glycerol levels at concentrations > 10(-7) mol/liter. Similar results were observed with epinephrine plus propranolol. Clonidine action was unaffected in the presence of labetalol (beta-/alpha-1 antagonist) but completely blunted by the presence of yohimbine (alpha-2 antagonist). The pseudolipolytic effect of clonidine was significantly more pronounced in gluteal as compared with abdominal adipose tissue. When clonidine was added together with the vasodilating agents nitroprusside or hydralazine, the pseudolipolytic effect was abolished and a dose-dependent decrease in dialysate glycerol was observed at all clonidine concentrations (10(-10)-10(-4) mol/liter). When ethanol was added to the perfusate to monitor blood flow, the escape of alcohol from the dialysate was accelerated by 30% with hydralazine or nitroprusside (P < 0.01) and 30% retarded (P < 0.05) by clonidine (10(-10) mol/liter). Thus, the results demonstrate an important role of blood flow for regulating lipid mobilization from adipose tissue in vivo. Alpha-2 adrenoceptor activation causes marked retention of lipids in adipose tissue due to vasoconstriction in combination with antilipoiysis.

Neuropeptide Y and peptide YY inhibit lipolysis in human and dog fat cells through a pertussis toxin-sensitive G protein.

Neuropeptide Y (NPY) and peptide YY (PYY) are regulatory peptides that have considerable sequence homology with pancreatic polypeptide. Because (a) NPY has been shown to be colocalized with noradrenaline in peripheral as well as central catecholaminergic neurons, and (b) alpha 2-adrenergic receptors of adipocytes play a major role in the regulation of lipolysis, we investigated the effect of NPY and PYY on isolated fat cells. In human fat cells NPY and PYY promoted a dose-dependent inhibition of lipolysis elicited by 2 micrograms/ml adenosine deaminase (removal of adenosine) whatever the lipolytic index used (glycerol or nonesterified fatty acids). In dog fat cells NPY and PYY inhibited adenosine deaminase-, isoproterenol- and forskolin-induced lipolysis. In humans and dogs the effects of NPY or PYY were abolished by treatment of cells with Bordetella pertussis toxin, clearly indicating the involvement of a Gi protein in the antilipolytic effects. This study indicates that, in addition to alpha 2-adrenergic agonists, NPY and PYY are also involved in the regulation of lipolysis in human and dog adipose tissue as powerful antilipolytic agents. Further studies are needed to characterize the pharmacological nature of the receptor mediating the inhibitory effect of NPY and PYY in fat cells.

Alpha2-adrenergic receptor-mediated release of lysophosphatidic acid by adipocytes. A paracrine signal for preadipocyte growth.

In the search for the existence of adrenergic regulation of the autocrine/paracrine function of the white adipose tissue, it was observed that conditioned media from isolated adipocytes or dialysates obtained by in situ microdialysis of human subcutaneous adipose tissue increased spreading and proliferation of 3T3F442A preadipocytes. These effects were amplified when an alpha2-adrenergic agonist was present during the obtention of conditioned media and microdialysates. This alpha2-adrenergic-dependent trophic activity was completely abolished by pretreatment of the conditioned media or microdialysates with the lysophospholipase, phospholipase B. Among the different lysophospholipids tested only lysophosphatidic acid (LPA) was able to induce spreading and proliferation of 3T3F442A preadipocytes. Moreover, previous chronic treatment of 3T3F442A preadipocytes with LPA which led to a specific desensitization of LPA responsiveness, abolished the alpha2-adrenergic-dependent trophic activities of the conditioned media and microdialysates. Finally, alpha2-adrenergic stimulation led to a rapid, sustained, and pertussis toxin-dependent release of [32P]LPA from [32P]-labeled adipocytes. Based upon these results it was proposed that in vitro and in situ stimulation of adipocyte alpha2-adrenergic receptors provokes the extracellular release of LPA leading, in turn, to regulation of preadipocyte growth.

Phosphodiesterase-5A and neutral endopeptidase activities in human adipocytes do not control atrial natriuretic peptide-mediated lipolysis.

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.

Effects of CB1 antagonist on the control of metabolic functions in obese type 2 diabetic patients.

Clinical reports (RIO trials) have shown that chronic administration of a CB-cannabinoid receptor antagonist (rimonabant) provides improvements of disturbed metabolic parameters observed in overweight and obese patients with type 2 diabetes. The production of endocannabinoid and the expression of CB1-cannabinoid receptors are largely distributed in the different organs aside from the brain. It is now clearly established that endocannabinoids act both through orexigenic effects and peripheral metabolic effects in various tissues involved in the control of metabolism and energy expenditure (i.e. adipose tissue, liver, gastrointestinal tract, skeletal muscle and pancreas). This review will consider: i) the disturbances of glucose and lipid metabolisms in obese type 2 diabetics; ii) an overview of the pharmacological properties of rimonabant and iii) the various mechanisms involved in tissues and organs to explain the therapeutic efficacy of rimonabant. A special attention will be paid to its utilization in obese type 2 diabetics. The emerging concept of endocannabinoids acting as metabolic regulators is the more likely explanation of the success of rimonabant treatments in phase III studies.

Integrated physiology and pathophysiology of CB1-mediated effects of the endocannabinoid system.

The discovery of the endocannabinoid system (ECS) has raised a large interest in the scientific community providing us with a strikingly long list of apparently independent multi organ effects. As a result, in most reviews on this issue the main function of the ECS is considered as modulatory. Unfortunately, this vision does not add much to our understanding of the specific biological function of the ECS. Thus, modulatory is what in general all biological systems are or should be. In this review we will show that the apparent inconsistent puzzle of the very different tissue specific effects of endocannabinoids (ECs) can be reconstructed in one unitary picture. This picture clearly shows that all the different CB1-mediated effects of ECs sub-serve one major physiological function: to facilitate and increase energy storage. We will also analyze the implications of this unitary vision of the ECS in different contexts. First, in the context of the systems that regulate energy balance, introducing a new systematization based on two homeostatic systems: an endostatic and an exostatic system. Second, in the context of evolution, showing how the function of the ECS has shifted from essential to survival to almost pathological in current times. Finally, in a pathophysiological context, introducing the new concept of "proactive evolution diseases", which can explain the current obesity epidemic and the role the ECS plays in it.

cAMP-dependent protein kinase activation mediated by beta 3-adrenergic receptors parallels lipolysis in rat adipocytes.

Catecholamine-induced lipolysis is chiefly mediated through the recently characterized beta 3-adrenergic receptor (AR) in rat adipocytes. Discrepancies between the ability of beta 3-AR agonists to stimulate adenylyl cyclase and the resulting lipolysis were recently reported. cAMP-dependent protein kinase (A-kinase) activation induced by these agonists was compared to lipolysis. Agonist potencies were similar for A-kinase activity ratios and lipolysis. The same A-kinase activity ratio to lipolysis relationship was found for the beta 3-AR agonists tested.

Pharmacological prospects for alpha 2-adrenoceptor antagonist therapy.

The discovery of various alpha 2-adrenoceptor subtypes in numerous tissues and studies of alpha 2-adrenoceptor-mediated mechanisms has generated considerable interest in their physiological functions. It has also increased possibilities for the design of new pharmacological tools and for the study of the pharmacological impact of new drugs. Alpha 2-adrenoceptors are located pre- and postsynaptically both in the central noradrenergic pathways and on the autonomic nerve endings. It is difficult to dissociate alpha 2-adrenoceptor-mediated autoregulation, involving presynaptic receptors, from actions dependent on post- and extrajunctional alpha 2-adrenoceptor activation. A lot of alpha 2-adrenoceptors are subject to permanent tonic activation by the sympathetic nervous system. Max Lafontan and colleagues review the major actions of alpha 2-adrenoceptors and consider the sites of impact of alpha 2-antagonists that could initiate further research for putative applications of these drugs. Many of the possible targets for alpha 2-adrenoceptor antagonists have not yet been explored clinically.

Adipocyte produces matrix metalloproteinases 2 and 9: involvement in adipose differentiation.

Adipocyte hypertrophy and hyperplasia together with angiogenesis contribute to the growth of the fat mass. Because changes in the extracellular matrix (ECM) components are often associated with such cellular remodeling, we studied the adipocyte expression of the matrix metalloproteinases (MMPs) 2 and 9, two key enzymes involved in the modulation of ECM. The present study provides the first evidence that human adipose tissue produces and secretes MMP-2 and -9 as shown by gelatin zymography analysis performed on media conditioned by human subcutaneous adipose tissue and human preadipocytes in primary cultures and by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on transcripts from mature human adipocytes. The further characterization performed on the murine 3T3F442A preadipocyte cell line demonstrates that MMP expression, assessed by RT-PCR and Western blot analysis, as well as activity, assessed by gelatin zymography analysis, increased during the adipocyte differentiation, whereas the expression of tissue inhibitor metalloproteinases 1 and 2 were abolished or not affected, respectively. Finally, preadipocyte treatment with MMP inhibitors such as batimastat and captopril, as well as neutralizing antibodies, markedly decreased adipocyte differentiation as demonstrated by the inhibition in the appearance of lipogenic (triglycerides) and lipolytic (glycerol release and hormone-sensitive lipase expression) markers. These data suggest that MMP-2 and -9 could be important key regulators of adipocyte differentiation. Thus, the adipocyte-derived MMPs might represent a new target for the inhibition of adipose tissue growth.

Drop in the "atypical" beta-adrenergic response and modification of the beta/alpha 2-adrenoceptor balance in fat cells from aging rabbits.

Previous studies have shown a strong reduction of catecholamine-induced lipolysis in perirenal white fat cells in aging rabbits. The molecular basis of this observation was explored on scapular and perirenal adipocytes from 45 and 300- to 500-day-old rabbits. ACTH and forskolin were used to define the maximal lipolytic potencies of the adipocytes. beta-Adrenergic responsiveness was explored with isoproterenol and specific agonists of the "atypical" beta-adrenoceptor (beta-AR) (BRL37344 and (+/-)CGP12177); beta 1/beta 2-ARs were identified with [125I]cyanopindolol. alpha 2-adrenergic responses were evaluated with the full alpha 2-agonist, UK14304. The alpha 2 AR number was determined with the alpha 2-antagonist radioligand [3H]RX821002. Whatever the fat deposit, the relative order of lipolytic potency of the beta-agonists was: isoproterenol greater than BRL37344 greater than (+/-)CGP12177. As previously reported for catecholamines, the maximal lipolytic response initiated by isoproternol decreased with aging; the stronger reduction was observed in perirenal adipocytes compared to subscapular adipocytes. The most striking observation concerns the parallel and complete disappearance of the lipolytic responses induced by the atypical beta-agonists (BRL37344 and (+/-)CGP12177) and the preservation of a residual action of isoproterenol (30% of that described in young animals) which was attributed to the stimulation of beta 1/beta 2-ARs. The number of beta 1/beta 2-AR binding sites was practically equivalent whatever the fat deposite and the age of the animals. alpha 2-Adrenergic responsiveness and alpha 2-adrenergic receptor number were increased with aging in the various deposits but the stronger changes were observed in the perirenal adipocytes where epineprine initiated a biphasic effect on lipolysis (antilipolytic and then lipolytic). To conclude, the reduction of catecholamine-induced lipolysis observed in the rabbit fat cells with aging can be explained by changes in the atypical beta-AR/alpha 2-AR balance. First, a loss of responsiveness to the atypical beta-adrenergic agents was observed (it is impossible for the moment to distinguish between the loss of atypical beta-AR binding sites and their putative uncoupling from the adenylate cyclase system) whereas beta 1/beta 2-AR-mediated responses were maintained. Second, an increment of alpha 2-adrenergic responsiveness and of the alpha 2-AR binding sites accompanied aging and fattening. In the absence of, or after a strong reduction of the atypical beta-AR component of the lipolytic response in fat cells of aged rabbits, epinephrine exerts a biphasic effect on lipolysis, demonstrating the changes occurring in the atypical beta-AR/alpha 2-AR balance.(ABSTRACT TRUNCATED AT 400 WORDS)

Hamster adipocyte alpha 2-adrenoceptor changes during fat mass modifications are not directly dependent on adipose tissue norepinephrine content.

It is questioned whether alterations of the sympathetic nervous system can explain the specific increment of the adipocyte alpha 2-adrenoceptor observed during white adipose tissue (WAT) enlargement and fat cell size increment. The impact of a 6-hydroxydopamine-induced sympathectomy, validated by determination of the WAT norepinephrine content, was tested on isolated white fat cell alpha 2-adrenoceptor function and binding [( 3H]RX 821002 and [3H]UK 14304 binding). Chemical sympathectomy of standard adult hamsters, neither alters the alpha 2-adrenergic-dependent antilipolysis nor the adipocyte alpha 2-adrenergic binding. A slight hypersensitivity of the beta 1-adrenergic lipolytic response was observed, without modification in beta-adrenergic binding [( 125I]cyanopindolol binding). Compared with controls, caloric restriction (10 days) of adult hamsters induced a large decrease in adipocyte alpha 2-adrenoceptor (P less than 0.001) with a parallel decrement in the mean fat cell size (P less than 0.001) and alpha 2-adrenergic responsiveness while there was no significant variation of the WAT norepinephrine content (on a per pad basis). 6-Hydroxydopamine treatment of the restricted animals (from day 6 to day 9) induced a higher preservation of adipocyte alpha 2-adrenoceptor density (P less than 0.001), no change in alpha 2-adrenergic responsiveness, and higher preservation of mean fat cell size (P less than 0.05) than in the restricted only animals. No significant modification in the beta-adrenergic binding was observed whatever the conditions. It was concluded that the specific increment in the adipocyte alpha 2-adrenoceptor during fat mass enlargement was not directly dependent on sympathetic nervous system alterations. Nevertheless, the sympathetic-dependent mobilization of the fat stores, after induction of caloric restriction, can indirectly modulate the alpha 2-adrenoceptor density in the adipocyte by promoting changes in white fat cell size.

Photoperiodic control of adipocyte alpha 2-adrenoceptors in Syrian hamsters: role of testosterone.

The impact of photoperiodic manipulations and testosterone treatments on the adipocyte alpha 2-adrenergic (alpha 2-AR), beta-adrenergic (beta-AR), and A1-adenosine (A1-R) responsiveness, was explored in male Syrian hamsters (Mesocricetus auratus). Moreover, binding studies were performed with appropriate alpha 2-AR, beta-AR, and A1-R radioligands to study receptor changes. Animals were kept for 12 weeks in long day photoperiod (LD: 16 h light (L)-8 h dark (D)), in short day photoperiod (SD: 6L-18D), or in short photoperiod with testosterone treatments (1 mg/animal/day sc) 10 days before sacrifice (SD+T). The antilipolytic effect of the full alpha 2-AR agonist UK14304 and the specific binding of the alpha 2-AR radioligands [3H] RX821002 (antagonist) and [3H]UK14304 were significantly reduced in SD hamsters compared with LD hamsters. The alpha 2-site number and alpha 2-AR responsiveness were completely restored in SD+T hamsters. Whatever the experimental conditions the adipocyte beta-AR receptivity (lipolytic response of isoproterenol and [125I]cyanopindolol binding), and the A1-R receptivity (antilipolytic response initiated by (-)phenylisopropyladenosine and [3H]dipropyl-8-cyclopentylxanthine and [3H]phenylisopropyladenosine binding) remained unchanged. Moreover, the kidney and brain alpha 2-AR densities identified with [3H]RX821002 were not significantly different in LD, SD or SD+T hamsters. These results were obtained without any modification of animal weight, white adipose tissue weight, or white fat cell size. We conclude that, in the Syrian hamster, the expression of the adipocyte alpha 2-AR is under the control of the photoperiod by a testosterone-dependent mechanism probably mediated through the hypothalamic-pituitary axis, without any alteration of the animal fat stores.