Adrenergic regulation of lipolysis in human fat cells during exercise

The adrenergic regulation of lipolysis was studied, before and after 30 min of submaximal exercise, in isolated adipocytes removed from the abdominal and gluteal regions of healthy non-obese men and women. Noradrenaline-induced lipolysis was significantly enhanced in gluteal adipocytes from men but not in women after exercise. However, the pure beta-adrenergic responsiveness was equally increased in gluteal adipocytes of both sexes after exercise, as judged by the effect of isoprenaline. Furthermore, the alpha 2-adrenergic anti-lipolytic responsiveness was more apparent after exercise in females than in males thereby counter-balancing the increase in the beta-adrenergic effect in the gluteal region in the former. The increased beta-adrenergic responsiveness induced by exercise in gluteal adipocytes of males could be mimicked by agents acting at the levels of adenylate cyclase, coupling proteins, phosphodiesterase, and protein kinase and seems to be due to an adaptive enhancement at the hormone-sensitive-lipase level. There was no change in the stoichiometric properties of beta-adrenoceptors of gluteal adipocytes after exercise. Abdominal adipocytes of both sexes were four to five times more responsive to noradrenaline than gluteal ones. However, exercise induced no further enhancement of the catecholamine-stimulated lipolysis rate in fat cells from this site. Thus, the influence of exercise on catecholamine-stimulated lipolysis is regional and sex dependent. Men, but not women, have a greater ability to adapt lipolysis to increasing energy demands during exercise that are due to an acute increase in the effectiveness of the hormone-sensitive lipase complex.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-adrenoceptor expression in human fat cells from different regions.

The expression of beta-adrenoceptors (BAR) was investigated in abdominal and gluteal fat cells of 32 nonobese men and women using radioligand binding and RNA excess solution hybridization. In both sexes the number of BAR binding sites was about twice as high in abdominal as in gluteal fat cells (P less than 0.01). Northern blot analysis of total RNA from adipose tissue showed hybridization of the BAR1 probe to an mRNA species of about 2.5 kb and of the BAR2 probe to an mRNA species of approximately 2.2 kb. The steady-state mRNA levels of BAR 1 and BAR 2 were also about twice as high in abdominal as in gluteal adipocytes of men and women (P less than 0.01). In abdominal fat cells the mRNA levels were approximately 45 and 30 molecules/cell for BAR1 and BAR2, respectively. There were no regional or sex variations in BAR 1 and BAR 2 mRNA stability. The apparent half-life of mRNA for both receptor subtypes was approximately 6 h in both regions. The mRNA levels for beta actin did not differ between the two regions in either sex. Thus, differences in expression of the genes encoding for BAR 1 and BAR 2 can explain why abdominal fat cells have more BAR than gluteal fat cells. This variation in gene expression may be a molecular mechanism underlying the well known regional differences in catecholamine-induced lipolysis activity between central and peripheral adipose tissue.     

Lipolytic catecholamine resistance due to decreased beta 2-adrenoceptor expression in fat cells.

The existence of lipolytic beta-adrenoceptor (BAR) resistance was investigated in vivo and in isolated abdominal subcutaneous adipocytes in 65 healthy and drug-free subjects. The concentration of isoprenaline (nonselective BAR agonist) causing half-maximum lipolysis effect (ED50) varied bimodally and 10(6)-fold between individuals but was almost constant in the same subject when measured two times at rest or before and 30 min after exercise. The subjects were categorized as having either high or low isoprenaline sensitivity. The former group had a 50% reduced in vivo lipolytic response to exercise and mental stress, despite a 50% increased plasma noradrenaline response (P < 0.01) and a 350% increased plasma adrenaline response (P < 0.02). In fat cells the lipolytic ED50 values for noradrenaline and terbutaline (BAR2 agonist) were 10 times lower (P < 0.001) in low-sensitive subjects, but the maximum lipolytic actions of these agents (and of isoprenaline) were similar in both groups. The action on lipolysis of dobutamine (BAR1 agonist), forskolin (stimulating adenylate cyclase), dibutyryl cyclic AMP (activating protein kinase), clonidine (alpha 2-adrenergic agonist), or phenyl isopropyladenosine (adenosine receptor agonist) were almost identical in high- and low-sensitivity subjects. ED50 for isoprenaline correlated with ED50 for terbutaline (r = 0.75), but not with ED50 for dobutamine. In high-sensitivity subjects the number of BAR2 was almost three-fold increased (P < 0.002) and the steady-state adipocyte mRNA level for BAR2 was sixfold increased (P < 0.005). BAR2 affinity as well as BAR1 number, affinity and mRNA expression were similar in both groups. In 11 cholecystectomy patients (otherwise healthy) lipolytic ED50 for beta agonists correlated in omental and subcutaneous fat cells (r = 0.85 for isoprenaline; r = 0.95 for terbutaline). In conclusion, lipolytic resistance to catecholamines is present in vivo in apparently healthy subjects due to reduced expression of BAR2 in adipocytes.     

Importance of beta-adrenoceptor function in fat cells for lipid mobilization

The role of peripheral catecholamine sensitivity in lipid mobilization was investigated in 78 healthy non-obese subjects by comparing beta-adrenergic regulation of lipolysis in isolated adipocytes with circulating catecholamines and glycerol (lipolysis index). Small intra-individual variations (5-7%) in adipocyte lipolytic beta-adrenoceptor sensitivity (ED50) for isoprenaline were found. However, large inter-individual variations (almost 10(5)-fold) in isoprenaline ED50 were observed in abdominal or gluteal adipocytes, which correlated (r = 0.52) negatively with the resting plasma noradrenaline levels. A correlation was also observed between circulating noradrenaline and adipocyte ED50 for noradrenaline (r = -0.38). In subjects with high (ED50 less than 10(-11) mol l-1) as compared to low isoprenaline sensitivity (ED50 greater than 10(-10) mol l-1) physical exercise induced a two times greater increase in plasma glycerol (P less than 0.01), in spite of a 50% less marked increase of plasma noradrenaline (P less than 0.01). Findings with beta-adrenoceptor mRNA and with total beta-adrenoceptor number or affinity for agonist did not show any strong correlation with the resting plasma noradrenaline level (r less than 0.25). In conclusion, inter-individual variations in beta-adrenoceptor sensitivity and its relation to circulating noradrenaline can be ascribed to specific modulations of either BAR-subtypes or in the postreceptor activation of lipolysis. These variations in adipocyte beta-adrenoceptor sensitivity may participate in the regulation of peripheral nervous activity and play a putative role in lipolysis during exercise when subjects with high beta-adrenoceptor sensitivity increased their ability to mobilize lipids despite a reduced noradrenaline response.     

Differences in Lipolysis between Human Subcutaneous and Omental Adipose Tissues

Hydrolysis of triglycerides to fatty acids and glycerol in fat cells (lipolysis) is of importance for the control of lipid and carbohydrate metabolism. This process is regulated by several hormones and parahormones acting on cyclic AMP formation or breakdown, which in turn influences the activity of hormone sensitive lipase. The latter enzyme stimulates hydrolysis of triglycerides in fat cells. It is well established through in vivo and in vitro investigations that there are regional variations in the lipolytic activity of human adipose tissue. The rate of lipolysis is low in the subcutaneous femoral/gluteal region, intermediate in the subcutaneous abdominal region and high in the visceral (i.e. omental) region. In non-obese subjects the differences between the subcutaneous and visceral fat depots may be explained by site variations in the function of receptors for insulin, catecholamines and adenosine. The lipolytic beta₁ and beta₂ adrenoceptors, as well as the newly discovered beta₃, are most active in the visceral fat cells. The antilipolytic insulin receptors, alpha₂ adrenoceptors and adenosine receptors are most active in the subcutaneous fat cells. In subjects with upper-body obesity the regional variations in the action of catecholamines on lipolysis are further enhanced. Decreased action of beta₂-adrenergic receptors and increased activity of alpha₂-adrenergic adrenoceptors in combination with defects in hormone sensitive lipase function inhibits the lipolytic effect of catecholamines in subcutaneous fat cells whereas increased activity of beta₃-adrenergic receptors and decreased activity of alpha₂ adrenoceptors augment the lipolytic response in visceral fat cells. These abnormalities in catecholamine function promote release of free fatty acids from the visceral fat cells to the liver through the portal system and might cause several of the metabolic complications to upper-body obesity.     

Heterogeneous distribution of beta and alpha-2 adrenoceptor binding sites in human fat cells from various fat deposits: functional consequences

Investigations have been carried out to explain the heterogeneity of response to catecholamines of human fat cells from various deposits. Adipocytes from two subcutaneous sites (abdominal and femoral) were studied concomitantly in women while omental fat cells were taken from another group of patients undergoing abdominal surgery. Alpha-2 and beta sites were identified in fat-cell membranes with [3H]yohimbine and [3H]dihydroalprenolol, respectively. Lipolytic responses were tested with isoproterenol (beta agonist), clonidine (alpha-2 agonist) and epinephrine. There are clear differences in the relative number of beta and alpha-2 sites according to the origin of the fat deposit; beta sites are less numerous than alpha-2 sites in subcutaneous fat cells of both regions (alpha-2:beta sites are in a ratio of 3 +/- 0.4:2 +/- 0.4). However, in membranes of omental fat cells, beta sites are at least as numerous as alpha-2 sites (ratio 0.9 +/- 0.2). Epinephrine always has a higher affinity for alpha-2 sites than for beta sites in the subcutaneous and omental deposits. In lipolysis studies, epinephrine, in the absence of adenosine in the incubation medium, initiated an anti-lipolytic effect in femoral fat cells and promoted inhibition of lipolysis at lower concentrations in abdominal subcutaneous fat cells, the effect being reversed at higher doses; epinephrine, however, was always lipolytic in omental adipocytes. There was no striking differences in the sensitivity to isoproterenol in the various deposits. Clonidine had a higher affinity for alpha-2 sites in femoral fat cells and was equipotent in the omental and abdominal ones. Thus, the differences in the lipolytic responses to epinephrine in adipocytes from different sites are linked to a variable alpha-2 inhibiting effect (and alpha-2 site number) rather than to a modified beta driven increase in lipolysis initiated by the physiological amine.     

beta-adrenoceptor-stimulated lipolysis of subcutaneous abdominal adipocytes as a determinant of fat oxidation in obese men

BACKGROUND: To verify whether an impaired lipolytic capacity of subcutaneous adipocytes may contribute to low rate of fat oxidation. DESIGN: Relationships between adipose tissue lipolysis of subcutaneous (subc) abdominal and femoral isolated adipocytes and respiratory quotient (RQ) were investigated in 20 obese men (age: 44 +/- 5 years; means +/- SD) studied in a fasting state. RESULTS: Maximal isoproterenol-induced lipolysis was greater in subcutaneous abdominal than in femoral fat cells even if glycerol release was corrected for variation in cell surface area (P < 0.01). On the other hand, no regional variation was observed in the adipose cell lipolytic responses to postadrenoceptor agents such as dibutyryl-cyclic AMP, forskolin and theophylline. Maximal isoproterenol-induced lipolysis of subc abdominal, but not of femoral adipocytes, was inversely related to RQ (r = - 0.61; P < 0. 01) and positively associated to fat oxidation (r = 0.57; P < 0.01). These relationships were independent of possible confounding factors such as fat mass, fat-free mass, waist girth and subc abdominal adipose tissue accumulation assessed by computed tomography, as maximal isoproterenol-induced lipolysis of subcutaneous abdominal adipocytes was the only variable retained as a significant predictor of RQ levels (38% of variance) and of fat oxidation (30% of variance). CONCLUSION: These results suggest that adipose tissue lipolytic activity of subc abdominal adipocytes acts as a determinant of fat oxidation in obese men.     

Increased α2- but similar β-adrenergic receptor activities in subcutaneous gluteal adipocytes from females compared with males

alpha 2 and beta-adrenergic binding and action were studied in subcutaneous adipocytes from the gluteal region in females and males. The beta-selective antagonist [3H]dihydroalprenolol and the alpha 2-selective antagonist [3H]yohimbine were used to identify the beta- and the alpha 2-receptor, respectively. The biological effects mediated by these receptors were determined by measuring the glycerol release induced by isoproterenol (beta-receptor agonist) and by clonidine (alpha 2-receptor agonist). The study consisted of health volunteers (eighteen females and fifteen males). Compared to men the alpha 2-receptor binding was increased by 73% (P less than 0.01) in adipocytes from females. From Scatchard analysis it was determined that the increased binding was due to an increased receptor number (438 v. 262 fmol mg-1 protein, P less than 0.001) with unaltered Kd (1.18 v. 1.35 nmol l-1, P greater than 0.05). This increased alpha 2-receptor binding in female and adipocytes was associated with a significantly increased sensitivity (P less than 0.05) and maximal antilipolytic effect of clonidine (P less than 0.05). The beta-receptor binding was similar in adipocytes from females and males. However, isoproterenol was significantly more lipolytic in female adipocytes (P less than 0.01). Since the combination of theophylline and adenosine deaminase also was significantly more lipolytic in female adipocytes the enhanced effect of isoproterenol then seemed to be due to mechanisms not directly related to the hormone-beta-receptor binding. Finally, the mixed beta- and alpha 2-receptor agonist, adrenaline showed biphasic effects on lipolysis, with stimulatory effect at low concentrations (less than 500 nmol l-1) and pronounced inhibitory effect at higher concentrations (greater than 1 mumol l-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in catecholamine-induced lipolysis in isolated human fat cells during the first year of life.

Catecholamine-induced lipolysis in isolated human adipocytes during the first year of life was investigated. During this period fat cell size increased markedly. Basal and catecholamine-induced glycerol release were positively correlated with age when lipolysis was expressed per cell. However, when lipolysis was expressed per unit of cell surface area (micrometer squared), this correlation was observed only for noradrenaline. Basal lipolysis and the effect of the pure beta-agonist, isoprenaline, were identical in infants and adults. From 0 to 2 mo of age noradrenaline had very little lipolytic effect. The addition of the alpha-2-adrenoceptor antagonist, yohimbine, to noradrenaline equalized lipolysis per micrometer squared in infants and adults and the alpha-2-adrenoceptor sensitivity was significantly enhanced in infants. In both groups the lipolytic adrenoceptor was of the beta-1 type. In conclusion, adipocytes from infants have a poor lipolytic response to noradrenaline partly because of the small fat cells but mainly because of an enhanced alpha-2-adrenoceptor activity.     

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.     

A pathogenic role of visceral fat beta 3-adrenoceptors in obesity.

Increased release of free fatty acids (FFA) from visceral fat cells to the portal venous system may cause several metabolic disturbances in obesity. However, this hypothesis and the underlying mechanism remain to be demonstrated. In this study catecholamine-induced lipid mobilization through lipolysis in omental adipose tissue was investigated in vitro in 25 markedly obese subjects (body mass index range 35-56 kg/m2) undergoing weight reduction surgery and in 19 nonobese subjects (body mass index range 20-28 kg/m2) undergoing cholecystectomy. Release of FFA and glycerol, induced by norepinephrine or adrenergic receptor subtype-specific agonists, were determined in isolated omental fat cells. The obese subjects had higher fat cell volume, blood pressure, plasma insulin levels, blood glucose, plasma triglycerides, and plasma cholesterol than the controls. There was evidence of upper-body fat distribution in the obese group. The rate of FFA and glycerol response to norepinephrine was increased twofold in the cells of obese subjects; no significant reutilization of FFA during catecholamine-induced lipolysis was observed in any of the groups (glycerol/FFA ratio near 1:3). There were no differences in the lipolytic sensitivity to beta 3- or beta 2-adrenoceptor specific agonists between the two groups. However, beta 3-adrenoceptor sensitivity was approximately 50 times enhanced (P = 0.0001), and the coupling efficiency of these receptors was increased from 37 to 56% (P = 0.01) in obesity. Furthermore, the obese subjects demonstrated a sixfold lower alpha 2-adrenoceptor sensitivity (P = 0.04). beta 3-Adrenoceptor sensitivity, but not alpha 2-, beta 1-, or beta 2-adrenoceptor sensitivity, correlated with norepinephrine-induced lipolysis (r = -0.67, P = 0.0001) and fat cell volume (r = -0.71, P = 0.0001). In conclusion, catecholamine-induced rate of FFA mobilization from omental fat cells is accelerated due to elevated rate of lipolysis in obesity, mainly because of an increased beta 3-adrenoceptor function, but partly also because of a decreased alpha 2-adrenoceptor function. This promotes an increased release of FFA to the portal system, which may contribute to the parallel metabolic disturbances observed in upper-body obesity.     

Alpha-adrenergic antilipolytic effect of adrenaline in human fat cells of the thigh: comparison with adrenaline responsiveness of different fat deposits

Abstract. The present results show that isolated fat cells from the subcutaneous adipose tissue of the lateral part of the thigh exhibit resistance to adrenaline. However, inability of adrenaline to induce lipolysis is not linked to a β-receptor defect since a β-adrenoceptor-stimulating agent (isoproterenol) exerts a clear lipid mobilizing effect. The blocking of α-adrenoceptors by phentolamine (an α-adrenoblocking drug) unmasks the strong lipolytic effect of adrenaline. Moreover, our investigation demonstrates the occurrence of an inhibiting effect of adrenaline on theophylline-induced lipolysis. This inhibitory effect is suppressed by phentolamine and strengthened by propranolol (β-adrenoblocking drug). Thus it seems that one of the important facts able to explain adrenaline resistance of the adipocytes from the subcutaneous adipose tissue of the thigh could be increased alpha-adrenergic responsiveness initiated by mixed agonists such as adrenaline or noradrenaline.
Moreover, our data demonstrate that the differences in the lipolytic responses to adrenaline between isolated fat cells taken from different sites could be linked to a variable α-adrenergic-inhibiting effect rather than a modified β-adrenergic effect. In conclusion, the balance between the two receptor site activities could be different according to the anatomical localization of the fat deposits, thus explaining the differences in adrenaline responsiveness reported in this paper.     

Effects of local alpha2-adrenergic receptor blockade on adipose tissue lipolysis during prolonged systemic adrenaline infusion in normal man

During prolonged adrenaline infusion, lipolysis peaks within 30 min and thereafter tends to decline, and we hypothesized that the stimulation of local adipose tissue alpha2-adrenergic receptors accounts for this decline. The lipolytic effect of a prolonged intravenous adrenaline infusion combined with local infusion of the alpha2-blocker phentolamine in superficial and deep abdominal subcutaneous adipose tissue and in preperitoneal adipose tissue was studied in seven healthy subjects. The interstitial glycerol concentration in the three adipose tissue depots was measured by the microdialysis method. Regional adipose tissue blood flow was measured by the (133)Xe clearance technique. Regional glycerol output (lipolytic rate) was calculated from these measurements and simultaneous measurements of arterial glycerol concentrations. Adrenaline infusion increased lipolysis in all three depots (data previously published). Phentolamine infusion did not augment lipolysis in the subcutaneous depots while it increased the lipolytic rate in the preperitoneal depot. It is concluded that alpha2-adrenergic receptors do not have a significant effect on subcutaneous adipose tissue lipolysis during high circulating adrenaline concentrations, and the decrease in lipolysis in subcutaneous adipose tissue under prolonged adrenaline stimulation is thus not attributed to alpha2-adrenergic receptor inhibition of lipolysis. However, in the preperitoneal adipose tissue depot, alpha2-adrenergic receptor tone plays a role for the lipolytic rate obtained during prolonged adrenaline stimulation.     

Genetic variance and lipolysis regulation: implications for obesity.

Catecholamines are the major lipolytic hormones in human fat cells, and lipolytic catecholamine resistance is described in obesity. Studies on twins and in rare genetic disorders suggest a strong heredity component of catecholamine-induced lipolysis. Polymorphisms in catecholamine receptor signalling pathways have been described, several of which associate with obesity. Many polymorphisms in adrenoceptor genes are functional in transfected cell lines. The importance of polymorphisms in catecholamine signalling pathways for lipolysis regulation is discussed. A Trp64Arg polymorphism in the beta3-receptor, which associates with obesity, is accompanied by changes in lipolytic sensitivity of the receptor in human fat cells. Similarly, a Gln16Glu and an Arg164Ile variation in the beta2-adrenoceptor cause marked variations in the lipolytic sensitivity of this receptor in human adipocytes. Furthermore, beta2-adrenoceptor gene polymorphisms associate with obesity. A dinucleotide (CA) intron repeat in hormone-sensitive lipase gene is linked to obesity and markedly decreases the ability of catecholamines to activate the lipase and thereby lipolysis in human fat cells. However, an Arg389Gly polymorphism in the beta1-adrenoceptor, which alters receptor function in transfected cell lines, has no effect on lipolysis in human fat cells and is not associated with obesity. Thus, polymorphism in human genes that are involved in catecholamine signal transduction have effects on fat cell lipolysis and also relate to obesity. The lipolysis effects of these polymorphisms cannot always be predicted from gene transfer experiments on artificial cell lines. It is possible that genetic variance in catecholamine signalling pathways, through alterations in adipocyte lipolysis, may promote obesity.     

Increased insulin resistance and fat cell lipolysis in obese but not lean women with a high waist/hip ratio

Increased lipolysis in abdominal adipocytes has been suggested to be of importance for the insulin resistance typical for abdominal obesity. In order to differentiate between fat distribution, measured as waist/hip ratio (WHR), and amount of body fat, glucose disposal during a euglycaemic clamp as well as lipolysis in isolated cells from abdominal and gluteo-femoral regions were studied in 20 obese and 20 lean postmenopausal women with a high (n = 10) and low (n = 10) WHR, respectively. The lipolytic response was increased in cells from obese women irrespective of region. Furthermore, lipolysis was enhanced in abdominal compared with the gluteo-femoral cells in obese women with a high WHR. Fasting blood glucose and insulin were increased in both groups of obese women while the degree of insulin resistance was most pronounced in the obese women with a high WHR. It is concluded that increased body fat is associated with both insulin resistance and increased lipolysis, and that this relationship is stronger in the presence of a high WHR. A high WHR may increase the expression of obesity as a risk for insulin resistance and this may be mediated through an increased lipolytic rate.     

Regional differences and effect of weight reduction on human fat cell metabolism

Abstract. The metabolism of adipocytes from severely obese patients was investigated before and after weight was reduced by jejuno-ileal by-pass. After weight reduction lipolysis and glucose incorporation into triglycerides were decreased as was the cell size. The effect of submaximal concentrations of insulin on glucose incorporation increased with weight reduction implying increased cellular insulin sensitivity.
The rate of glucose incorporation and basal lipolysis in the adipocytes correlated directly with the fasting plasma insulin level before weight reduction. After weight reduction there was a positive correlation between the decrease in glucose metabolism and the reduction in the plasma insulin level. These data support the concept that plasma insulin may be important for the long-term regulation of glucose metabolism and lipolysis in fat cells.
In other patients with normal body weight, studies on regional differences in adipocyte metabolism showed that fat cells from the subcutaneous abdominal region responded better to both noradrenaline and insulin than femoral fat cells. The differences between these sites were less pronounced during incubation with isopropylnoradrenaline, suggesting there was increased α-receptor activity in the femoral region.
Adipocytes in the abdominal subcutaneous region are thus metabolically much more active than those in the femoral region. This might explain why several blood parameters such as arterial free fatty acid and glycerol levels correlate with lipolysis of abdominal but not femoral cells and why plasma insulin and triglyceride levels correlate with abdominal but not femoral fat cell size. Also, the responsiveness of adipocytes in the abdominal region may explain why cells in this region decreased more in size than those in the femoral region during weight reduction.     

Catecholamine-induced lipolysis in adipose tissue of the elderly.

Age-dependent alterations in the effects of catecholamines on lipolysis were investigated in 25 young (21-35 yr) and 10 elderly (58-72 yr) healthy, nonobese subjects using isolated adipocytes obtained from abdominal subcutaneous tissue. Basal lipolysis was not affected by aging, while the rate of catecholamine-stimulated lipolysis was reduced by 50% in the elderly subjects (P less than 0.005). To elucidate the mechanisms behind this phenomenon lipolysis was stimulated with agents that act at well-defined steps in the lipolytic cascade, from the receptor down to the final step: the activation of the protein kinase/hormone-sensitive lipase complex. All agents stimulated lipolysis at a 50% lower rate in elderly as compared with young subjects (P less than 0.05 or less). However, half-maximum effective concentrations of the lipolytic agents were similar in both groups. The antilipolytic effects of alpha 2-adrenoceptor agonists were also the same in young and old subjects. Moreover, the stoichiometric properties of the beta- and alpha 2-receptors did not change with increasing age. In vivo studies performed on the same individuals likewise demonstrated an impaired lipolytic responsiveness, with 50% lower plasma glycerol concentrations during exercise in the elderly subjects (P less than 0.05), in spite of a normal rise in plasma norepinephrine. The plasma glycerol levels correlated strongly to the glycerol release caused by catecholamine-stimulated lipolysis in vitro in both young and elderly subjects (r = 0.8-0.9, P less than 0.001). In conclusion, a decreased activation of the hormone-sensitive lipase complex appears to be the mechanism underlying a blunted lipolytic response of fat cells to catecholamine stimulation in elderly subjects. This finding may, explain the age-dependent decreased lipolytic response to exercise in vivo.     

Genetic variance and lipolysis regulation: implications for obesity

Catecholamines are the major lipolytic hormones in human fat cells, and lipolytic catecholamine resistance is described in obesity. Studies on twins and in rare genetic disorders suggest a strong heredity component of catecholamine-induced lipolysis. Polymorphisms in catecholamine receptor signalling pathways have been described, several of which associate with obesity. Many polymorphisms in adrenoceptor genes are functional in transfected cell lines. The importance of polymorphisms in catecholamine signalling pathways for lipolysis regulation is discussed. A Trp64Arg polymorphism in the β₂-receptor, which associates with obesity, is accompanied by changes in lipolytic sensitivity of the receptor in human fat cells. Similarly, a Gln 16Glu and an Arg 16411e variation in the β₂-adrenoceptor cause marked variations in the lipolytic sensitivity of this receptor in human adipocytes. Furthermore, β₂-adrenoceptor gene polymorphisms associate with obesity. A dinucleotide (CA) intron repeat in hormone-sensitive lipase gene is linked to obesity and markedly decreases the ability of catecholamines to activate the lipase and thereby lipolysis in human fat cells. However, an Arg 389Gly polymorphism in the β₂-adrenoceptor, which alters receptor function in transfected cell lines, has no effect on lipolysis in human fat cells and is not associated with obesity. Thus, polymorphism in human genes that are involved in catecholamine signal transduction have effects on fat cell lipolysis and also relate to obesity. The lipolysis effects of these polymorphisms cannot always be predicted from gene transfer experiments on artificial cell lines. It is possible that genetic variance in catecholamine signalling pathways, through alterations in adipocyte lipolysis, may promote obesity.     

Regulation of lipolysis during the neonatal period. Importance of thyrotropin.

We investigated the lipolytic effect of several hormones on isolated human adipocytes obtained at different donor ages. In neonates, noradrenaline and adrenaline had an insignificant lipolytic effect (70% over basal). In this age group only thyrotropin (TSH) had a significant effect in physiological concentrations, and the maximal lipolytic effect (700% over basal) was the same as that of isoprenaline. The lipolytic effect of TSH was the same in premature 4-10-wk-old infants with a gestational age of 27-33 wk as in neonates, but fat cells from infants 4-10 wk old, born at term, showed a significantly lower effect. In children and adults, the lipolytic effect of TSH gradually decreased further and was present only in unphysiological concentrations. The catecholamine-induced lipolysis was pronounced and was similar in children and adults (350% over basal). TSH is the dominating lipolytic hormone in vitro during the neonatal period. Thus, the peak elevation of circulating TSH, which is seen immediately after birth, may be essential to lipolysis during this part of life.     

Dual action of octopamine on glucose transport into adipocytes: inhibition via beta3-adrenoceptor activation and stimulation via oxidation by amine oxidases

Octopamine, which is closely related to norepinephrine, acts as a neurotransmitter in invertebrates and is a trace amine with undefined properties in vertebrates. The octopaminergic receptors identified in insects are targets of various pesticides but are absent in vertebrates. We have established that octopamine stimulates fat cell lipolysis in mammals via activation of beta3-adrenoceptors (ARs), whereas this amine has been described elsewhere as an alpha2-AR agonist and as a substrate for monoamine oxidase (MAO) or semicarbazide-sensitive amine oxidase (SSAO). Because we have recently reported that amine oxidase substrates promote glucose transport in rat and human adipocytes, the in vitro octopamine effects on lipolysis and glucose uptake were reassessed by using adipocytes from beta3-AR-deficient mice. The lipolytic effect and the counter-regulation of insulin action on glucose transport provoked by 0.1 to 1 mM octopamine or by 1 microM beta3-AR agonists found in control animals disappeared in adipocytes from beta3-AR-deficient mice. This revealed an insulin-like effect of octopamine on glucose uptake, which was dependent on its oxidation by MAO or SSAO, as was the case for tyramine and benzylamine, devoid of beta3-adrenergic agonism. Similarly, octopamine promoted glucose transport in human adipocytes and exhibited a weaker lipolytic stimulation than in rodent adipocytes. These findings indicate that, besides its lipolytic activity, octopamine exerts, at millimolar dose, dual effect on glucose transport in adipocytes: counteracting insulin action via beta3-AR activation and stimulating basal transport via its oxidation by MAO or SSAO.