Catecholamine-stimulated Lipolysis Research Articles

Multiple symmetric lipomatosis: a defect in adrenergic-stimulated lipolysis.

The cellularity of normal and lipomatous adipose tissue and its response to different lipolytic agents have been studied in a group of 10 patients with multiple symmetric lipomatosis (MSL). In MSL patients, fat cells from lipomatous tissue are smaller than normal, uninvolved adipocytes. Fat cells from lipomata show minimal variations in size following conspicuous increase of lipomatous masses. These findings suggest that the growth of lipomata can be attributed to the neoformation of adipocytes rather than to an enlargement in the single fat cells. The incidence of reduced glucose tolerance and of hyperlipoproteinemia is similar in MSL patients and in controls. A significant reduction in plasma free fatty acids was observed in MSL patients after a 24-h fast as well as after noradrenaline infusion. A specific insensitivity of lipomatous tissue to the lipolytic effect of noradrenaline and isoprenaline was observed in vitro, as indicated by glycerol release in the medium, whereas response to theophylline and to dibutyryl cyclic AMP was retained. The lipolytic response to catecholamines was retained. The lipolytic response to catecholamines was normal in the nonlipomatous adipose tissue of MSL patients. In basal conditions ATP concentrations were similar in normal and in lipomatous adipose tissue. However, incubation with noradrenaline induced a significant fall in intracellular ATP levels in normal tissue, whereas no variations were observed in lipomatous tissue. Theophylline, instead, induced a prompt and significant decrease in intracellular ATP levels in lipomatous tissue. These observations indicate that the block in catecholamine-stimulated lipolysis in lipomatous tissue of MSL patients can be localized at a level preceding the formation of cyclic AMP.

Selective inhibition of cholera toxin- and catecholamine-stimulated lipolysis by blocking agents.

Vibrio cholerae enterotoxin stimulates lipolysis in rat epididymal fat cell suspensions. Like hormones this toxin increases adenylate cyclase activity, raising levels of cyclic adenosine 3',5'-monophosphate (cAMP), which activates a cellular lipase. Using specific blocking agents, we studied the responses to the adrenergic lipolytic hormones epinephrine, norepinephrine, and isoproterenol, and to cholera toxin. All stimulators were used at 100 x threshold dose. Propranolol (34 muM), a beta blocking agent, inhibited epinephrine stimulation (P less than 0.001) but not that of toxin (P greater than 0.2). Choleragenoid (25 mug/ml), a natural toxoid of cholera toxin, blocked stimulation by toxin (P less than 0.001) but not that of the adrenergic agents (P greater than 0.2). A beta blocker, practolol (3 mM), inhibited stimulation by the catecholamines tested (P less than 0.005) but not that of toxin (P greater than 0.05). Higher concentrations of propranolol (340 muM) and the alpha blocking agents phenoxybenzamine (3 mM) and phentolamine (1.6 mM) inhibited all agonists (P less than 0.001). The response to theophylline was inhibited by all blockers (P less than 0.05) except propranolol at the lower concentration (34 muM). A combined beta and alpha blockade using propranolol and epinephrine together did not inhibit toxin-mediated lipolysis. It appears that stimulation by cholera toxin is independent of beta adrenergic receptors. A major inhibition of theophylline-mediated lipolysis by alpha blocking drugs indicated a nonspecific effect of these agents at the concentrations used. The uninhibited response to toxin in the presence of propranolol and epinephrine suggests a lack of relationship of the toxin receptor to either alpha or beta receptors.

Opposing metabolic effects of theophylline and dibutyryl cyclic AMP

Bothe dibutyryl cyclic AMP (DCAMP) and theophylline have been used to increase cyclic AMP (CAMP) levels in studies suggesting CAMP to be a link between catecholamines and their metbolic effects. However, DCAMP and CAMP have different effects on in vitro lipolysis. Since theophylline increases CAMP levels by inhibing its phosphodiesterase, theophylline and DCAMP could effect lipolysis differently. To provide an in vivo evaluation of the effects of DCAMP and theopylline upon lipolysis, comparison of glyccrol and free fatty acid (FFA) levels was made in puppes receiving these agents under basal conditions and during epinephine (E) stimulation.Theophylline infusions given to six puppies resulted in plasma gycerol (160 ± 36%) and mean control; mean plusmn; S.E.) and FFA (175 ± 32%) increases, while DCAMP given to five others produced falls in gycerol (–23 ± 6%) and FFA (–24 ± 9%) levels. Prolonged glycerol (245 ± 33%) and FFA (160 ± 36%) elevations were sustained in six puppies during 75-minute E infusions. Five puppies receiving similar E infusions with similar glycerol and FFA elevations had added increases in glycerol (147 ± 41%) and FFA (85 ± 19%) when theophylline was administered after 30 minutes of E. However, when DCAMP was added instead of theophylline in five other animals receiving E, glycerol (–108 ± 16%) and FFA (–82 ± 17%) levels fell.These observations demonstrate tjat DCAMP and theophylline produce opposite effects on basal and catecholamine-stimulated lipolysis in the puppy, and suggest the need for added caution in the use of these agents as tools for the study of CAMP.

Metabolic inhibitors and catecholamine-stimulated lipolysis

The effects of varying dose and time in the antagonism between oxidative phosphorylation inhibitors (rotenone, oligomycin, 2,4-DNP) and norepinephrine-stimulated lipolysis in vitro were determined. A comparison was made between the kinetics of antagonism of this group of compounds with that of some glycolysis inhibitors (mono-iodoacetic acid, sodium fluoride). The results led to the following conclusions, (a) The antagonism by oxidative phosphorylation inhibitors is a non-competitive one. In the experimental conditions used, pD' 2 values were: rotenone = 5, oligomycin = 4.8 and 2,4-DNP = 2.7. (b) Both oxidative phosphorylation and glycolysis seem to be implicated in the norepinephrine-stimulated lipolysis. However, the results gave no indicationofthe relative importance of the two metabolic pathways in the process studied.

Digitoxin and prostaglandin ei as inhibitors of catecholamine-stimulated lipolysis and their interaction with Ca 2+ in the process

The antagonistic action of digitoxin and prostaglandin E 1 on the norepinephrine-stimulated lipolysis has been studied qualitatively and quantitatively. The actions of the two drugs are somewhat similar: (a) their antagonism appears, from the log dose-effect curves, to be of a mixed type; (b) Ca 2+ concentration in the medium clearly influences their antagonistic effect. A relation between the action of these drugs on lipolysis and active ion transport or oxidative phosphorylation cannot be entirely excluded. Calcium movements appear more directly involved. The importance of Ca 2+ in the process studied is pointed out.