Catecholamine-induced Lipolysis Research Articles

Regional and gender variations in adipose tissue lipolysis in response to weight loss

Catecholamine-induced lipolysis was investigated in 32 obese subjects (14 men and 18 premenopausal women), aged 36–50 years, whose body mass index ranged from 30 to 42 kg/m2. Isolated subcutaneous (subc) abdominal and femoral adipocytes were studied before and after a 15-week weight reducing program, during which mean body weight loss averaged 9 vs. 10 kg in women and men, respectively (P < 0.0001). Participants were re-examined when they were weight-stable. Fat cell weight decreased by about 15–20% in both depots (P values ranging from 0.01 to 0.05). Epinephrine (mixed α2-/β-adrenoceptor (AR) agonist) induced antilipolysis at low concentrations and a net lipolytic response at higher doses, irrespective of subjects' fatness and anatomic location of fat. Basal lipolysis, maximal lipolytic responses to isoprenaline (β-AR agonist), dobutamine and procaterol (β1- and β2-AR agonists, respectively) as well as maximal antilipolytic effects of epinephrine or UK-14304 (α2-AR agonist) were similar before and after weight reduction. However, both β- and β2-AR lipolytic sensitivities and the β-AR density were increased in both genders after weight reduction, this effect being more marked in subc abdominal than in femoral adipocytes (P values ranging from 0.001 to 0.05). The α2-AR antilipolytic sensitivity was reduced in adipose cells from both regions in women, but only in subc abdominal adipocytes in men (P < 0.05), although the α2-AR density remained unchanged after weight reduction.▪In conclusion, a moderate weight loss leads to a higher adipose cell lipolytic efficiency which is associated with changes at receptor levels (mainly an increased β2- and a decreased α2-AR sensitivities), in both genders.—Mauriège, P., P. Imbeault, D. Langin, M. Lacaille, N. Alméras, A. Tremblay, and J. P. Després. Regional and gender variations in adipose tissue lipolysis in response to weight loss. J. Lipid Res. 1999. 40: 1559–1571.

Direct effects of ephedrine isomers on human β-adrenergic receptor subtypes

Ephedrine and its alkaloids are used for the treatment of asthma, nasal congestion, and obesity. Ephedrine, with two chiral centers, exists as four isomers that exhibit direct and indirect effects on both α- and β-adrenergic receptors (AR). Our main goal was to study the direct effects of the ephedrine isomers on human β 1-, β 2-, and β 3-AR expressed in Chinese hamster ovary cells. Previous work indicated that the ephedrine isomers are inactive as agonists and that 1 R,2 S-ephedrine is more potent than the 1 S,2 R-isomer as an antagonist of catecholamine-induced lipolysis in rat adipose tissue (Lee et al., J Pharmacol Exp Ther 190: 249–259, 1974). Stimulation of adenylyl cyclase, associated with cyclic AMP accumulations, was measured by a luciferase reporter gene assay. On human β 1-AR, the rank order of potency ( ec 50 values, maximal response relative to isoproterenol = 100%) was 1 R,2 S-ephedrine (0.5 μM, 68%) > 1 S,2 R-ephedrine (72 μM, 66%) > 1 S,2 S- pseudoephedrine (309 μM, 53%) = 1 R,2 R- pseudoephedrine (1122 μM, 53%). On human β 2-AR, the rank order of potency was 1 R,2 S-ephedrine (0.36 μM, 78%) > 1 R,2 R- pseudoephedrine (7 μM, 50%) ≥ 1 S,2 S- pseudoephedrine (10 μM, 47%) > 1 S,2 R-ephedrine (106 μM, 22%). Only 1 R,2 S-ephedrine showed significant agonist activity on human β 3-AR with an ec 50 = 45 μM and a maximal response of 31%. Our studies demonstrated that (a) stereoselective and rank order differences exist among the direct effects of ephedrine isomers; (b) 1 R,2 S-ephedrine is the most potent of the four ephedrine isomers on all three human β-AR; and (c) 1 R,2 S- ephedrine was nearly equipotent as a β 1-/β 2-AR agonist and the only isomer possessing weak partial agonist activity on β 3-AR.

Catecholamine-induced lipolysis in obesity.

Catecholamines are the only hormones with pronounced lipolytic action in man. A number of in vivo and in vitro studies suggest that there is lipolytic resistance to catecholamines in subcutaneous adipose tissue, which is the major fat depot in obese subjects. This is due to multiple alterations in catecholamine signal transduction, involving decreased expression and function of beta2-adrenoceptors, increased function of alpha2-adrenoceptors and decreased ability of cyclic monophosphate (AMP) to stimulate hormone sensitive lipase. A sedentary life-style, which usually characterizes obesity, may contribute to the catecholamine resistance. However, hereditary/genetic factors may also be involved. Recently, decreased expression and function of hormone sensitive lipase has been found in subcutaneous adipocytes of non-obese subjects with heredity for obesity. In addition, polymorphisms in the genes for beta2-adrenoceptors, beta3-adrenoceptors and hormone sensitive lipase, associate with obesity. On the other hand, catecholamine-induced lipolysis in visceral adipose tissue is increased in obesity due to increased function of beta3-adrenoceptors (major finding), decreased function of alpha2-adrenoceptors and increased ability of cyclic AMP to stimulate lipolysis. When the findings in different adipose regions are considered together, it appears that there is a redistribution of lipolysis and thereby fatty acid mobilization in obesity, favouring the visceral fat depot. This leads to an increase in the circulating fatty acid levels in the portal vein, which connects visceral fat with the liver. As a consequence, the liver function may be altered leading to hyperinsulinemia, hyperglycemia and dyslipidemia, which usually accompany the obese state.

Magnesium and cardiovascular disease.

Magnesium and cardiovascular disease.

Phosphorylation and Activation of Hormone-Sensitive Adipocyte Phosphodiesterase Type 3B

Phosphodiesterases (PDEs) include a large group of structurally related enzymes that belong to at least seven related gene families (PDEs 1–7) that differ in their primary structure, affinity for cAMP and cGMP, response to specific effectors, sensitivity to specific inhibitors, and regulatory mechanism. One characteristic of PDE3s involves their phosphorylation and activation in response to insulin as well as to agents that increase cAMP in adipocytes, hepatocytes, and platelets and in response to insulin-like growth factor 1 in pancreatic β cells. In adipocytes, activation of the membrane-associated PDE3B is the major mechanism whereby insulin antagonizes catecholamine-induced lipolysis. PDE3B activation results in increased degradation of cAMP and, thereby, a lowering of the activity of cAMP-dependent protein kinase (PKA). The reduced activity of PKA leads to a net dephosphorylation and decreased activity of hormone-sensitive lipase and reduced hydrolysis of triglycerides. Activation of the rat adipocyte PDE3B by insulin is associated with phosphorylation of serine-302. The mechanism whereby insulin stimulation leads to phosphorylation/activation of PDE3B is only partly understood. In rat adipocytes, lipolytic hormones and other agents that increase cAMP, including isoproterenol, also induce rapid phosphorylation, presumably catalyzed by PKA, of serine-302 of PDE3B. The phosphorylation is associated with activation of the enzyme, most likely representing “feedback” regulation of cAMP, presumably allowing close coupling of the regulation of steady-state concentrations of both cAMP and PKA and, thereby, control of lipolysis. In the review we describe methods and strategies used in the authors’ laboratories to study phosphorylation and activation of PDE3B in adipocytes andin vitro.

Short-term metabolic and haemodynamic effects of GR79236 in normal and fructose-fed rats

The adenosine (A1) receptor agonist, GR79236 ( N-[(1 S, trans)-2-hydroxycyclopentyl]adenosine), inhibits catecholamine-induced lipolysis in vitro, but the short-term metabolic and haemodynamic effects have not been previously reported in the fructose fed model of insulin resistance, dyslipidaemia and hypertension. This study reports the effects of GR79236 (1 mg/kg/day for 8 days) on nonesterified free fatty acid and triglyceride metabolism, oral and i.v. glucose tolerance, blood pressure and heart rate, and insulin sensitivity, in normal rats and rats fed a fructose-enriched diet. In normal rats, GR79236 significantly reduced fasting glucose (25%), free fatty acid (50%) and triglyceride (55%) concentrations, and improved glucose tolerance (AUC[glu] 21.2±1.3 vs. 16.5±1.1 mmol h/l, p<0.05). Fructose feeding induced a state of insulin resistance and dyslipidaemia, as shown by an increase in steady-state plasma glucose levels (7.1 vs. 6.1 mmol/l), impaired i.v. glucose tolerance and a 3-fold rise in fasting triglyceride levels; fructose-fed rats also developed a significant increase in blood pressure. GR79236 ameliorated the effects of fructose feeding on fatty acid and triglyceride levels, and blood pressure, and improved i.v. glucose tolerance in fructose-fed rats. The hypotriglyceridaemic effect was due to a reduction in triglyceride secretion rate (17.3±1.7 vs. 30.2±1.1). Thus, in normal rats and in a dietary-induced rodent model of insulin resistance, dyslipidaemia and hypertension, GR79236 has lipid-lowering and glucose-lowering activity, as well as haemodynamic effects, which are potentially useful for treating both the metabolic and haemodynamic features of insulin resistance and NIDDM in humans.

Variation in adrenergic regulation of lipolysis between omental and subcutaneous adipocytes from obese and non-obese men

Regional variations in adipocyte lipolysis between subcutaneous and visceral fat may be important for obesity complications. In the present study, we compared adrenergic regulation of lipolysis in omental and subcutaneous adipocytes from obese (n = 15) and non-obese (n = 14) male subjects. Waist-to-hip ratio, blood pressure, plasma insulin, and plasma triglycerides were increased in obesity. No regional differences in adrenoceptor lipolytic function were observed in non-obese subjects with the exception of a slight increase in noradrenaline sensitivity in omental adipocytes (P < 0.05), because of increased beta(1)-adrenoceptor sensitivity (P < 0.05). In the obese subjects, the rate of noradrenaline-induced glycerol release was 2-fold higher (P < 0.005) and the noradrenaline sensitivity was 3-fold higher (P < 0.05) in omental versus subcutaneous adipocytes. These findings were mainly due to a 50-fold increase in omental beta(3)-adrenoceptor sensitivity (P < 0.002) and to a smaller 6-fold increase in omental beta(1)-adrenoceptor sensitivity (P < 0.02), accompanied by increased beta(3)- as well as beta(1)-adrenoceptor lipolytic rates at approximately 50% receptor subtype occupancy by the agonist (P < 0.05). In conclusion, minor regional differences in adipocyte lipolytic response to catecholamines are present in non-obese males. In contrast, catecholamine-induced lipolysis is markedly increased in omental as compared to subcutaneous adipocytes in obese males, mainly due to an increase in beta(3)-adrenoceptor function of visceral fat cells, in combination with a smaller increase in beta(1)-adrenoceptor function.

Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance?

The polycystic ovary syndrome (PCOS) is the most common hyperandrogenic disorder among women and is characterized by metabolic and cardiovascular aberrations similar to those seen in the so-called insulin resistance syndrome. The regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 10 nonobese women with PCOS and in 11 age- and body mass index-matched healthy women. Eight PCOS women were reinvestigated after 3 months of treatment with combined oral contraceptives containing ethinyl estradiol and norethisterone, which normalized hyperandrogenicity. The PCOS women showed a marked resistance to the lipolytic effect of noradrenaline due to defects at two different levels in the lipolytic cascade: first, a 7-fold reduction in sensitivity to the beta 2-selective agonist terbutaline (P < 0.005), which could be ascribed to a 50% lower beta 2-adrenoceptor density (P < 0.02) as determined with radioligand binding; there was no difference with regard to dobutamine (beta 1) or clonidine (alpha 2-sensitivity) or beta 1-adrenoceptor density; second, the maximum lipolytic response was also 35% lower (P < 0.02) in the PCOS women compared to that in the healthy women. This was seen with all beta-adrenergic agonists and the postreceptor-acting agents forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating protein kinase). Neither beta 2-adrenoceptor sensitivity or density nor the reduced lipolytic responsiveness was restored by 3 months of oral contraceptives treatment. The results indicate the existence of a marked impairment of catecholamine-induced lipolysis in nonobese PCOS women displaying early features of the insulin resistance syndrome due to multiple lipolysis defects as a lower beta 2-adrenoceptor density and reduced function of the protein kinase, hormone-sensitive lipase complex. These lipolysis defects are identical to those observed in the insulin resistance (metabolic) syndrome and could be a primary pathogenic mechanism for the development of these disorders.

Catecholamine-induced adipocyte lipolysis in human hyperthyroidism.

Increased lipid mobilization in thyrotoxicosis is attributed to amplification of catecholamine action in fat cells by thyroid hormones. We investigated the adrenergic regulation of lipolysis in isolated sc abdominal fat cells obtained from 14 patients with thyrotoxicosis and 18 control subjects. Ten of the hyperthyroid subjects were also reinvestigated after antithyroid treatment. The thyrotoxic state was associated with a 3-fold increase in maximum norepinephrine-induced lipolysis (P < 0.005), unaltered sensitivity to dobutamine (selective beta 1-adrenoceptor agonist) and clonidine (selective alpha 2-adrenoceptor agonist), but 15 times enhanced sensitivity to terbutaline (selective beta 2-adrenoceptor agonist; P < 0.01). Moreover, thyrotoxicosis was accompanied by a 3-fold increase in beta 2-adrenoceptor number (P < 0.005), but unchanged beta 1-adrenoceptor levels. Further, the lipolytic effects of dibutyryl cAMP (activating protein kinase A and thereby hormone-sensitive lipase) and forskolin (activating adenylate cyclase) were about 60% enhanced (P < 0.005). No change in the maximum activity of the hormone-sensitive lipase could be demonstrated in the hyperthyroid state compared to that in the euthyroid state. The observed abnormalities in lipolysis and beta 2-adrenoceptor number were normalized after antithyroid treatment. It is concluded that in human hyperthyroidism, the interactions between thyroid hormone and catecholamines in adipocytes involve abnormalities at both receptor and postreceptor levels. The former mechanism seems to be a selective increase in the expression of the beta 2-adrenoceptors. The latter mechanism involves increased ability of cAMP to activate hormone-sensitive lipase, but not a change in maximum enzyme capacity.

Catecholamine-Induced Adipocyte Lipolysis in Human Hyperthyroidism

Catecholamine-Induced Adipocyte Lipolysis in Human Hyperthyroidism

Specific inhibition of the cGMP-inhibited cAMP phosphodiesterase blocks the insulin-like antilipolytic effect of growth hormone in rat adipocytes.

Growth hormone (GH) exerts acute insulin-like effects, such as increased lipogenesis and inhibition of catecholamine-induced lipolysis, in rat adipocytes that have not been exposed to GH during the preceding three hours. We found that OPC3911, a highly specific inhibitor of the cGMP-inhibited cAMP phosphodiesterase, completely blocked the antilipolytic but not the lipogenic effect of GH. This indicates that the antilipolytic effect of GH is mediated through activation of this phosphodiesterase leading to reduction of cAMP levels in the same manner as has been shown for insulin.

Microdialysis for the Assessment of Catecholamine-Induced Lipolysis in Adipose and Skeletal Muscle Tissue

Publisher Summary In recent times in situ techniques for studies of regional adipose tissue lipolysis have been developed, such as the arteriovenous-metabolite difference technique over a subcutaneous fat depot and the microdialysis technique. Microdialysis also has been introduced for studies of skeletal muscle tissue as well as several other tissues in the body. The major regulatory hormones for human adipose tissue lipolysis are insulin and catecholamines, which act on hormone-sensitive lipase. Binding sites for all adrenoceptor subtypes have been found in fat cells. It has to be pointed out that, with microdialysis, only one of the end-products of lipolysis, glycerol, can be monitored. Free fatty acids (FFAs) are hydrophobic and not dialyzable with the presently used membranes. As glycerol is not reutilized by adipose tissue, it is considered an index of lipolysis. The evaluation of blood flow variations in conjunction to in situ glycerol measurements is an important aspect. This is because the interstitial concentration of a metabolite can be determined both by its production and uptake in the tissue and by the transportation away or delivery to the tissue by the capillary bloodstream. The content of the dialysis sample reflects the net sum of these events. Tissue blood flow can be estimated either by Xenon-133 washout or by addition of a flow marker (for example, ethanol) to the microdialysis perfusate solvent. The microdialysis technique can be used in various types of lipolysis studies such as mechanistic in situ studies, systemic hormonal challenge, combinations of mechanistic in situ studies and systemic hormonal challenge, hormonal interactions, and in investigations of various tissues.

Growth hormone treatment of hypophysectomized rats increases catecholamine-induced lipolysis and the number of beta-adrenergic receptors in adipocytes: no differences in the effects of growth hormone on different fat depots.

Growth hormone (GH) has a lipolytic effect in adipose tissue but this effect may differ in adipose tissue from various fat depots. This latter possibility was investigated in the present study, in which the effects of GH in vivo on catecholamine-induced lipolysis and the number of beta-adrenergic receptors in isolated adipocytes from different fat depots of hypophysectomized rats were investigated. Female and male Sprague-Dawley rats were hypophysectomized or sham-operated at 45 days of age. One week after the operation, hormonal replacement therapy with L-thyroxine and hydrocortisone acetate was given. In addition, groups of rats were treated with GH (1.33 mg/kg per day, given as two daily subcutaneous injections). After 1 week of hormonal treatment, adipocytes were isolated from the parametrial, epididymal and inguinal fat pads, and glycerol release after catecholamine-stimulation and 125I-cyanopindolol binding were measured. Hypophysectomy resulted in a marked decrease in the lipolytic response to catecholamines. GH treatment significantly increased catecholamine-induced lipolysis with similar effects in adipocytes from parametrial or epididymal and inguinal fat depots in both female and male rats. There were no differences between norepinephrine compared with isoproterenol-induced responses. 125I-cyanopindolol binding was reduced after hypophysectomy and normalized by GH treatment, without differences between parametrial and inguinal adipose tissue regions. We conclude that the lipolytic effects of GH in the rat may partly be mediated by a stimulatory effect on beta-adrenergic receptors in adipocytes. In addition, GH exerted similar effect on catecholamine induced lipolysis and beta-adrenergic receptors in adipocytes from parametrial, epididymal and inguinal fat depots.

Expression of beta3-adrenoceptors with low lipolytic action in human subcutaneous white adipocytes.

Beta3-Adrenoceptors are involved in the control of catecholamine-induced lipolysis in rodent adipose tissues. The expression and function of human beta3-adrenoceptors were investigated in subcutaneous white adipocytes of young healthy women. In these cells, beta3-adrenoceptor mRNAs represent 20% of total amount of beta-adrenoceptor transcripts and less than half of beta1-adrenoceptor transcripts. Among beta3-agonists known to stimulate beta3-adrenoceptor-mediated lipolysis in rodent fat cells, only CGP12177 was able to mediate such activity in human fat cells. In in vitro lipolysis experiments and in situ microdialysis studies, CGP12177 had a 4- to 5-times lower lipolytic efficacy than isoprenaline, a nonselective beta-adrenoceptor agonist. CGP12177-induced lipolysis was antagonized in vitro by bupranolol, a beta-adrenergic antagonist potent on rodent beta3-adrenoceptors but not by nadolol, a beta1- and beta2-adrenoceptor antagonist. The in vitro blockade of isoprenaline-stimulated lipolysis by nadolol showed that the agonist acted solely via beta1- and beta2-adrenoceptors. Isoprenaline and CGP12177 were able to increase the nutritive blood flow suggesting an interaction of these molecules with receptors present in adipose tissue vessels. In conclusion, beta3-adrenoceptors are expressed in human subcutaneous white adipocytes but do not significantly contribute to isoprenaline-induced lipolysis.

Molecular mechanisms underlying regional variations of catecholamine-induced lipolysis in rat adipocytes

The mechanisms underlying catecholamine control of lipolysis were studied in rat white adipocytes from epididymal, retroperitoneal, and subcutaneous fat depots. Sensitivity of subcutaneous adipocytes to selective beta 3-adrenoceptor agonists was lower than that of internal adipocytes. beta 3-Adrenoceptor mRNA levels were lower in subcutaneous adipocytes. A decreased beta 1/beta 2-adrenoceptor-mediated lipolysis was also observed in these adipocytes, and the number of beta 1/beta 2-adrenoceptors was lower than in the internal adipocytes. The number of alpha 2-adrenoceptors was higher in subcutaneous adipocytes without a marked difference in alpha 2-adrenoceptor-mediated antilipolysis between the depots. Subcutaneous adipocytes were also characterized by a lower maximal lipolytic response to drugs acting at different levels of the lipolytic cascade, suggesting differences at the postreceptor level. Lower hormone-sensitive lipase activity and mRNA levels in subcutaneous adipocytes were in agreement with the lipolysis data. These results suggest that the pattern of expression of the genes of the lipolytic pathway varies with the anatomic location of the fat depot.

Evidence for the key role of the adipocyte cGMP-inhibited cAMP phosphodiesterase in the antilipolytic action of insulin

Enhancement of cAMP degradation by increased cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) activity is thought to be an important component of the mechanism whereby insulin counteracts catecholamine-induced lipolysis in adipocytes. In this study the selective cGI-PDE inhibitor OPC3911 was used to evaluate this role of cGI-PDE activation in intact rat adipocytes with special reference to changes in cAMP levels measured as cAMP-dependent protein kinase (cAMP-PK) activity ratios. OPC3911 completely blocked (IC 50 = 0.3 μM) the maximal inhibitory effect of insulin on noradrenaline-induced lipolysis and the net dephosphorylation of hormone-sensitive lipase and other intracellular target proteins for insulin action, whereas insulin-induced lipogenesis was not changed. The effect of OPC3911 on cAMP-PK activity ratios at different levels of lipolysis achieved by noradrenaline stimulation revealed that the reduction of cAMP-PK caused by 1 nM insulin was completely blocked by 3 μM OPC3911. The effect of OPC3911 was not due to an excessive increase in cellular cAMP resulting in ‘supramaximal’ lipolysis unresponsive to insulin. These data demonstrate that reduction in cAMP levels by the activation of cGI-PDE may be sufficient to account for the antilipolytic action of insulin.

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.

Catecholaminergic innervation of white adipose tissue in Siberian hamsters.

When Siberian hamsters are transferred from long summerlike days (LDs) to short winterlike days (SDs) they decrease their body weight, primarily as body fat. These SD-induced decreases in lipid stores are not uniform. Internally located white adipose tissue (WAT) pads are depleted preferentially of lipid, whereas the more externally located subcutaneous WAT pads are relatively spared. These data suggest a possible differential sympathetic neural control over catecholamine-induced lipolysis and that lipolytic rates are greater for internal vs. external WAT pads. Moreover, if these differential rates of lipolysis are due to differential sympathetic nervous system (SNS) drives on the pads, then fat pad-specific catecholaminergic innervation may exist. Therefore, we tested whether inguinal WAT (IWAT; an external pad) and epididymal WAT (EWAT; an internal pad) were innervated differentially. In addition, we tested whether norepinephrine (NE) turnover (TO) reflected the presumed greater SNS drive on EWAT vs. IWAT after SD exposure. Injections of fluorescent tract tracers [Fluoro-Gold or indocarbocyanine perchlorate (DiI)] demonstrated projections from the SNS ganglia T13-L3 to both fat pads. Retrograde labeling revealed a relatively separate pattern of distribution of labeled neurons in the ganglia projecting to each pad. In vivo anterograde transport of DiI resulted in labeling in both IWAT and EWAT that included staining around individual adipocytes and occasionally retrogradely labeled cells. The proportionately greater decrease in EWAT compared with IWAT mass after 5 wk of SD exposure was reflected in greater EWAT NE TO than found in their LD counterparts for this pad.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of Non-Esterified Fatty Acids and Triacylglycerol in Experimental Animals by the Adenosine Analogue GR79236

1. This is the first description of the metabolic activity of a novel adenosine A1-receptor agonist, GR79236. GR79236 inhibited catecholamine-induced lipolysis in human, rat and dog isolated adipocytes. 2. Oral administration of GR79236 (0.1-10 mg/kg) to fed rats induced minimal changes in the plasma concentration of non-esterified fatty acids and in the blood concentrations of glucose and lactate. 3. Intravenous infusion of GR79236 to fasted pithed rats, or oral administration of GR79236 to fasted conscious rats and dogs, produced time- and dose-dependent decreases in the plasma non-esterified fatty acid concentration. In the fasted rats, doses of GR79236 that lowered plasma levels of non-esterified fatty acids also produced hypotriglyceridaemia and anti-ketotic effects. 4. Only in the pithed rats were acute effects on the plasma glucose and lactate concentrations observed. Hypoglycaemia and hyperlactataemia occurred over the dose range studied (1 x 10(-11)-1 x 10(-8) mol min-1 kg-1). 5. This profile of activity suggests that compounds such as GR79236 might be agents which can be used to define the role of excessive lipolysis in experimental (and human) pathophysiology.

The Rationale of Magnesium Supplementation in Acute Myocardial Infarction

Magnesium is the second most abundant intracellular cation in the human body, next to potassium, and is involved in more than 300 different enzymatic reactions, including glucose use; the synthesis of fat, protein, and nucleic acids; the metabolism of adenosine triphosphate; muscle contraction; and some membrane transport systems. 1,2 Over recent years, evidence has accumulated that patients with acute myocardial infarction (AMI) are magnesium deficient 3,4 and develop an increased hypomagnesemia during the acute phase of the infarct. 5-8 Hypomagnesemia might be due to migration from extracellular to intracellular space, 9 which is caused by catecholamine-induced lipolysis forming in soluble magnesium soaps, as demonstrated in animal experiments. 6,10,11 Furthermore, experiments in animals and humans have shown that the acute as well as the chronic reduction in extracellular magnesium levels are harmful to the myocardium in the setting of acute ischemia. 12-14 While the metabolism of magnesium in AMI and the incidence