Peter Engfeldt

Adrenergic regulation of lipolysis in situ at rest and during exercise.

The adrenergic regulation of lipolysis was investigated in situ at rest and during standardized bicycle exercise in nonobese healthy subjects, using microdialysis of the extracellular space in subcutaneous adipose tissue. The glycerol concentration was about two times greater in adipose tissue than in venous blood. At rest, the glycerol concentration in adipose tissue was rapidly increased by 100% (P less than 0.01) after the addition of phentolamine to the ingoing perfusate, whereas addition of propranolol did not alter the adipose tissue glycerol level. Glycerol in adipose tissue and plasma increased during exercise and decreased in the postexercise period. Propranolol in the perfusate almost completely inhibited the increase in the tissue dialysate glycerol during the exercise-postexercise period. Phentolamine, however, was completely ineffective in this respect. During exercise, the lipolytic activity was significantly more marked in abdominal than in gluteal adipose tissue; this was much more apparent in women than in men. Thus, in vivo lipolysis in subcutaneous adipose tissue is regulated by different adrenergic mechanisms at rest and during exercise. Alpha-adrenergic inhibitory effects modulate lipolysis at rest, whereas beta-adrenergic stimulatory effects modulate lipolysis during exercise. In addition, regional differences in lipolysis are present in vivo during exercise, which seem governed by factors relating to sex.

Regional differences in the control of lipolysis in human adipose tissue

Omental fat cells were 30% smaller than those in subcutaneous regions. In omental fat cells with a mean diameter of 95 mu, the basal cAMP concentration was 50% lower, but the basal rate of glycerol release was three times as rapid as in subcutaneous (epigastric) fat cells of identical size. Added at maximal effective concentration, noradrenaline increased the level of cAMP and the rate of glycerol release more markedly in the omental than in the subcutaneous adipocytes, whereas the response to isopropyl noradrenaline was similar. Before starvation the lipolytic effects of noradrenaline and isopropyl noradrenaline, respectively, were identical in the two regions of subcutaneous adipose tissue investigated (femoral and hypogastric). The findings were well related to the tissue levels of cAMP induced by the two agents. During starvation noradrenaline and isopropyl noradrenaline increased the cAMP level and the rate of lipolysis in fat cells obtained from the hypogastric region, whereas noradrenaline decreased these parameters in femoral adipocytes. Starvation was associated with a more prominent inhibitory effect of phenylephrine on basal and isopropyl-noradrenaline-induced lipolysis in femoral than in hypogastric adipose tissue. In conclusion, differences exist between different regions of adipose tissue in their lipolytic responsiveness to noradrenaline, which seems related to the balance between alpha- and beta-adrenergic receptor response.

The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation

The antilipolytic effect of insulin in vitro was investigated in conditions known to be associated with resistance to the effect of insulin on glucose metabolism. Human subcutaneous adipose tissue was obtained from 14 obese subjects before and during starvation for 7 days, 12 untreated non-insulin dependent diabetics (NIDDM), 6 untreated insulin dependent diabetics (IDDM), and 10 nonobese control subjects. The tissue was incubated with and without insulin in concentration ranging from 1-10,000 microunits/ml. Responsiveness (maximum effect) and sensitivity to insulin were determined under basal induction conditions, since insulin had a bimodal effect on noradrenaline stimulated lipolysis. Under normal conditions both insulin sensitivity and insulin responsiveness were positively correlated with the basal rate of lipolysis. In obesity, IDDM and NIDDM there were no change in insulin sensitivity or in insulin responsiveness. When the obese subjects were divided into one hyperinsulinemic group (6 individuals) and one group with normal fasting serum insulin levels (7 individuals) a similar antilipolytic effect of insulin was observed in the two groups. During starvation there was a 20-fold increase in insulin sensitivity (p less than 0.01) but no change in insulin responsiveness in femoral fat and only a decrease in responsiveness (p less than 0.01) in abdominal fat. The present data supports the view that antilipolysis in human fat cells is not involved in the insulin resistance seen in obesity, starvation, diabetes and hyperinsulinemia.

Influence of fasting on lipolytic response to adrenergic agonists and on adrenergic receptors in subcutaneous adipocytes

Abstract. The influence of 1 weeks total fasting on the lipolytic effect of adrenergic agonists and on the binding of adrenergic antagonists was examined in isolated adipocytes of subcutaneous specimens removed from the hypogastric and the femoral sites in seventeen obese women. In the femoral adipocytes the lipolytic sensitivity to isopropyl noradrenaline decreased 30‐fold (P<0·01) during fasting. The specific binding of the radioligands (–)‐[3H]‐dihydroalprenolol and (–)‐[125I]‐cyanopindolol decreased significantly during fasting, essentially owing to a reduction in the receptor density. In adipocytes from the hypogastric region no such changes were found. For both tissue regions fasting induced a right‐ward shift in the dose–response curve for the inhibitory effect of the α2 agonist, clonidine, on theophylline‐induced lipolysis, corresponding to a 10‐fold decrease in sensitivity. There was also a significant decrease of about 20% in the α2‐adrenoceptor density, as estimated with the radioligand [3H]‐yohimbine. The results suggest that the regulation of the lipid mobilization in man by the sympathetic nervous system during fasting occurs not only through an increase in the level of circulating noradrenaline but also through changes in the adrenergic receptor density of the adipocytes.

Relationship between lipolysis, cyclic AMP, and fat-cell size in human adipose tissue during fasting and in diabetes mellitus☆

The in vitro relationship between fat-cell size, glycerol release, and peak concentration of cyclic AMP was investigated in human adipose tissue obtained from 25 obese nondiabetic patients before and after a 7-day fast and from 23 patients with untreated diabetes mellitus. In the obese nondiabetic patients there was a linear correlation between fat-cell size and cyclic AMP concentration, and fat-cell size and the rate of lipolysis. This was found both in nonfasting and fasting nondiabetic patients. However, in diabetes mellitus, there was only a relationship between cell size and cyclic AMP concentration. The alpha-adrenergic and beta-adrenergic activity in human adipose tissue was assessed by comparing the effect of isoprenaline and noradrenaline on the cyclic AMP concentration. The activity of both receptors was found to be increased in fasting obese patients and in diabetics. In both conditions the alpha-adrenergic response to catecholamines predominated in small fat cells, whereas in large ones the beta response predominated. The results suggest that during fasting and in diabetes mellitus there is a correlation between fat-cell size and the responsiveness of the adrenergic receptors. Thus, catecholamines may be involved in regulating the fat-cell volume. The view is expressed that the abnormal catecholamine-induced lipolysis is solely due to changes at the level of the adrenergic receptors during fasting, whereas in diabetes mellitus the sequentional activation of lipolysis is disturbed at deeper sites as well.

Adrenoceptor occupancy in isolated human fat cells and its relationship with lipolysis rate

The relationship between lipolysis and adrenoceptor occupancy was determined in isolated human fat cells, which possess both lipolytic beta-adrenoceptors and antilipolytic alpha 2-adrenoceptors. The beta-adrenoceptor agonist, isoprenaline, and the alpha 2-adrenoceptor agonist, clonidine, had lower affinities to compete with antagonist radioligands (Ki) than to affect the rate of lipolysis (Ka). At 1 min of incubation human fat cells bound isoprenaline and clonidine with high affinity to beta- and alpha 2-adrenoceptors, respectively, but this high-affinity binding rapidly converted to a low-affinity state. The relationship between lipolysis and adrenoceptor occupancy was also assessed after long-lasting receptor inactivation. The inactivation of a small receptor fraction shifted the dose-response curves for isoprenaline and clonidine to the right but did not alter the maximum effect of the agonists (responsiveness). These results suggest that alpha 2- and beta-adrenoceptors are coupled to lipolysis according to similar models. There is a non-linear relationship between receptor and effector for both receptors, which can be explained by the co-existence of spare receptors and a transient high-affinity state of the receptors for agonists.

Abnormal Action of Catecholamines on Lipolysis in Adipocytes of Type I Diabetic Patients Treated With Insulin

Catecholamine-induced lipolysis was investigated in adipocytes obtained before and after 30 min of exercise from 10 insulin-treated type I (insulin-dependent) diabetic men and 10 male matched control subjects. The α2-adrenoceptor-mediated antilipolytic effect of catecholamines was normal, but the β-adrenoceptor-mediated lipolytic sensitivity was increased 10-fold (P < .01) in diabetic subjects before and after exercise. The latter correlated inversely (r > .7) with the circulating norepinephrine level, which was significantly reduced in diabetic subjects. Basal lipolysis and lipolysis activated at different steps distal to the β-receptor were similar in the two groups. There was no major change in the total number of β- and α-adrenoceptors in the diabetic patients. However, the proportion of high-affinity β-adrenoceptors was significantly increased in these patients compared with control subjects. In the diabetic patients, ∼50% of the β-adrenoceptors were in a high-affinity state, compared to ∼30% in the control subjects (P < .025). In diabetic subjects there was an enhanced plasma glycerol response to exercise, despite a blunted plasma norepinephrine response. The data suggest enhanced sensitivity of catecholamine-induced lipolysis in type I diabetes due to an increase in the number of high-affinity (i.e., coupled) β-adrenoceptors in fat cells. This mechanism may be due to low levels of circulating norepinephrine and may also explain the exaggerated lipolytic response to exercise in the diabetic state.

Pharmacokinetics and Pharmacodynamics of Trandolapril After Repeated Administration of 2 mg to Young and Elderly Patients with Mild-to-Moderate Hypertension

Summary The new angiotensin-converting enzyme (ACE) inhibitor trandolapril 2 mg was administered daily for 10 consecutive days to young (mean age ± SEM 44.1 ± 2.3 years: n = 10) and elderly (mean age ± SEM 69.3 ± 0.9 years: n = 14) patients with mild-to-moderate hypertension. All groups had similar baseline blood pressures: mean 164/100 mm Hg. Maximal plasma ACE inhibition on day 10 and residual inhibition 24 h after the last dose was the same, irrespective of age: young, 85.2 and 57.4%; elderly, 89.1 and 59.8%, respectively. There was no difference between the results on day 1 for the young and elderly groups. The absorption of trandolapril was rapid (<1 h in all groups). The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were slightly higher in the older group, but the elimination half-life (t1/2) was the same, with no accumulation after repeat dosing. A steady-state plasma concentration of the active metabolite of trandolapril. trandolaprilat, was reached after 4 days in the two groups. with similar accumulation rations (young. 1.48: elderly, 1.49). At steady state, the Cmax and AUC 0–24 h for trandolaprilat were similar in the two groups: young, 7.49 ± 0.98 ng/ml and 82.27 ± 6.95 ng/ml/h: elderly, 8.35 ± 0.67 ng/ml/h and 96.75 ± 5.67 ng/ml/h. Maximal reductions in systolic/diastolic blood pressures (at 6 h postdose) were - 14.6%/-16.1% in young patients and - 14.6%/-17.5% for the elderly. Significant blood pressure reduction persisted for 48 h after the last dose. Tolerance was good. and no adverse events were reported. On the basis of the pharmacokinetic and pharmaodynamic data. we conclude that there is no need to modify the dose of trandolapril in elderly hypertensive (>65 years) patients.

In vivo subcutaneous adipose tissue glucose kinetics after glucose ingestion in obesity and fasting

The kinetic pattern of subcutaneous adipose tissue extracellular glucose following glucose ingestion was investigated in vivo with a microdialysis technique in normal-weight (n = 21) and obese subjects (n = 18) before and after a 7-day fast (n = 9). A dialysis probe (4 x 0.5 mm) was implanted subcutaneously, and was continuously perfused (5 microliters/min). The tissue dialysate glucose concentration was determined in 15-min samples before and during a period of 180 min after a 75-g oral glucose load. A comparison was made between the tissue dialysate concentrations and the venous blood glucose levels. In all study groups the increase in subcutaneous tissue dialysate glucose following glucose ingestion paralleled that in blood, with a time-lag of up to 15 min. In the normal-weight subjects the maximum relative increase in abdominal adipose tissue dialysate glucose was 25% higher (p less than 0.005) than the corresponding blood glucose level, and the total relative glucose level (area under curve, AUC) in abdominal fat was 20% (p less than 0.01) higher than in blood. In contrast, the kinetics of gluteal subcutaneous tissue dialysate and blood glucose levels were similar. In the obese patients before the fasting period the maximum relative glucose level in abdominal fat was almost twice as high as in blood (p less than 0.005), and the total glucose level (AUC) was 50% higher than the blood glucose AUC (p less than 0.005). After the fast, on the other hand, almost identical relative dynamics of abdominal subcutaneous tissue and blood glucose levels were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Validity of two questions on alcohol use in a health survey questionnaire

The aim of this study was to investigate whether consumers of high and low levels of alcohol could be identified by two questions about alcohol use in a postal questionnaire survey. A sample of 2,300 persons aged 18 - 64 years from Stockholm county were sent a masked postal questionnaire comprising 30 questions about their health and functioning. Two questions concerned their alcohol consumption. One year later the subjects underwent a psychiatric health examination, which included an assessment of their alcohol use. The two questions about alcohol consumption identified high alcohol consumers with a relatively high sensitivity and specificity, of 64% and 87%, respectively, and thus are useful for identifying high alcohol consumers in health surveys using questionnaires.