Are increased plasma non-esterified fatty acid concentrations a risk marker for coronary heart disease and other chronic diseases?
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Biomarkers↗
Biomedical subjects
P Arner
Publications and source records attributed to P Arner.
Interstitial glycerol concentration in human skeletal muscle and adipose tissue is close to the concentration in blood.
1. The suggestion that the interstitial glycerol concentration in both adipose tissue and skeletal muscle is around 3 mmol/I (Maggs DG, Jacob R, Rife F, et al. J Clin Invest 1995; 96: 370-7), rather than close to the blood concentration as previously supposed, was tested by independent methods. 2. Free glycerol was infused, as part of a triacylglycerol emulsion, into six normal subjects and the arteriovenous difference for glycerol across the forearm was measured. In addition the relative interstitial glycerol concentration in subcutaneous adipose tissue was assessed simultaneously in four of the subjects by microdialysis. 3. During glycerol infusion the arterialized glycerol concentration rose from 52 +/- 5 mumol/I to 250-300 mumol/I (P < 0.001) in a square wave fashion. The net arteriovenous difference for glycerol across the forearm changed from negative (output) to positive (uptake) (P < 0.01). In subcutaneous adipose tissue the interstitial glycerol concentration rose during glycerol infusion (P < 0.001). 4. These observations are most easily explained by the movement of glycerol from plasma to interstitial fluid down a concentration gradient. We conclude that the interstitial glycerol concentration in skeletal muscle and adipose tissue is closer to the arterial concentration than to 3 mmol/I.
Adipose Tissue↗
Agonist and antagonist properties of beta 3-adrenoceptors in human omental and mouse 3T3-L1 adipocytes.
The pharmacological properties of the native human beta 3-adrenoceptor are poorly defined. In the present study, the agonist and antagonist properties of beta 3-adrenoceptors in human omental and mouse 3T3-L1 adipocytes were compared by measuring lipolysis in the absence or presence of adrenoceptor blockers. Methodological experiments revealed that all three beta-adrenoceptors were functionally expressed in both types of adipocytes. This makes the human and the mouse cells directly comparable in pharmacological studies. CGP 12177 was a selective partial beta 3-adrenoceptor agonist in both cell types with a pD(2) of about 7.5. The order of potency of classical non-selective adrenoceptor agonists, when determined during blockade of beta 1-, beta 2- and alpha 2-adrenoceptors, was isoprenaline>noradrenaline>adrenaline in both human and 3T3-L1 adipocytes. This is different from the order of potency of the same agonists at the beta 1- or beta 2-adrenoceptors. The sensitivity of the beta 3-adrenoceptor to these catecholamines, expressed as pD(2) values, were virtually identical in both adipocyte types. Isoprenaline, noradrenaline, and adrenaline were almost full agonists in both cell types (intrinsic activity from 74% or 95%) during combined beta 1, beta 2- and alpha 2-adrenoceptor blockade. Antagonist potencies (expressed as pA(2) and using CGP 12177 as agonist) at the alpha 3-adrenoceptor were similar in both adipocyte types: bupranolol>propranolol>metoprolol. The corresponding pA(2) values for bupranolol, propanolol and metoprolol were about 7, 6 and 5, respectively in both species. In conclusion, the pharmacological properties of classical catecholamines, beta-adrenoceptor blockers and CGP 12177 are almost identical at the beta 3-adrenoceptors of human omental adipocytes and 3T3-L1 adipocytes.
Adipose Tissue↗
Microdialysis of adipose tissue during surgery: effect of local alpha- and beta-adrenoceptor blockade on blood flow and lipolysis.
The adrenergic regulation of adipose tissue lipolysis and blood flow was investigated in nonobese patients (10 men and 23 women) undergoing cholecystectomy. Two microdialysis probes were inserted into the scadipose tissue and microdialyzed in the absence or presence of 10(-4) mol/L of either nonselective beta-adrenoceptor blocker propranolol or nonselective alpha-adrenoceptor blocker phentolamine. The catecholamines increased rapidly after intubation and subsequent surgery and extubation (P = 0.0001; F = 11-13). In the middle of surgery, the elevations of the noradrenaline and adrenaline levels were almost 3 times the basal value. At the end of surgery, they dropped in parallel, but increased again, only to reach their absolute maximum in connection with extubation (10- and 3-fold elevation, respectively). Plasma glycerol and free fatty acids started to increase about 30 min after plasma catecholamines. These increases in catecholamines were paralleled by an increase in the dialysate glycerol level (lipolysis index). Propranolol inhibited by two thirds (P = 0.003) and phentolamine further stimulated by 25% (P = 0.04) the increase in glycerol in the tissue dialysate induced by the operation. There was a transient decrease in tissue blood flow (ethanol escape from the microdialysis probe; P < 0.001) at the beginning of the surgical procedure. This was not affected by propranolol or phentolamine. In conclusion, during anesthesia and surgical trauma, endogenous catecholamines modulate adipose tissue lipolysis via alpha- and beta-adrenoceptors. However, the vasoconstriction induced by these procedures seems to be independent of the adrenergic system.
Adipose Tissue↗
Effects of several putative beta 3-adrenoceptor agonists on lipolysis in human omental adipocytes.
BACKGROUND: Atypical beta 3-adrenoceptor agonists have attained an increasing interest as potential drugs against obesity and diabetes. However, their pharmacological actions on the native, human beta 3-adrenoceptor are not well defined. DESIGN: In the present study, the lipolytic effects of several putative beta 3-adrenoceptor agonists were investigated in human omental adipocytes. RESULTS: CL 316 243 and CGP 12177 had selective partial beta 3-agonist effects (pD2 about 4 and 8, respectively); the latter drug is a beta 1-/beta 2-adrenoceptor blocker in addition to its beta 3-adrenoceptor agonist activity. BRL 37344 and SM 11044 were also partial agonists, but with significant beta 1- and/or beta 2-adrenoceptor agonist properties. Bucindolol, ZD 2079, ICI D7114 and SR 58611A were ineffective as lipolytic drugs. In addition, ICI D7114 was a non-selective beta 1-/beta 2-/beta 3-adrenoceptor antagonist in human adipocytes. CONCLUSION: None of the beta 3-adrenoceptor agonists tested is an ideal drug for therapeutic use in man (i.e. regarded as a selective and full agonist with high receptor potency). Only CL 316 243 may have a potential therapeutic role, although the potency is very low. CGP 12177 is useful as a reference substance for human in vitro studies.
Adipocytes↗
Regulation of lipolysis in fat cells of obese women during long-term hypocaloric diet.
OBJECTIVE: To investigate the influence of four weeks treatment with a strictly defined very low calorie diet (VLCD) on the regulation of adipocyte matabolism in vitro in subcutaneous fat cells of obese subjects. DESIGN: Prospective study. SUBJECTS: Nine obese, but otherwise healthy and drug-free women aged 26-48 years with BMI 36.4-51.9 kg/m2 were investigated before and during the fourth week on a calorie restricted diet. MEASUREMENTS: A subcutaneous adipose tissue biopsy was obtained from the abdominal area. Isolated fat cells were prepared and incubated in vitro with different agents acting on lipolysis at defined steps in the lipolytic cascade. Glycerol (lipolytic index), hormone-sensitive lipase activity and incorporation of glucose into lipids were measured. RESULTS: VLCD caused a two-fold rise in basal lipolysis (p < 0.005). In spite of this, the maximal lipolytic response of noradrenaline, isoprenaline (non-selective beta-adrenoceptor agonist), dobutamine (beta 1-adrenoceptor agonist), terbutaline (beta 2-adrenoceptor agonist), CGP 12177 (beta 3-adrenoceptor agonist), forskolin (stimulating adenylyl cyclase), dibuturyl cyclic AMP and 8-bromo cyclic AMP (cyclic AMP analogues resistant or sensitive to phosphodiesterase, respectively) were maintained. No differences were found in the hormone-sensitive lipase activity before or during VLCD. The specific alpha 2-adrenoceptor agonist UK 14304 was equally effective in inducing antilipolysis both before and during calorie restriction. However, during VLCD, the sensitivity and maximal antilipolytic effect of insulin were significantly reduced (p < 0.05) and the ability of insulin to stimulate lipogenesis was almost completely blunted. CONCLUSIONS: Four weeks of VLCD induced elevated basal lipolysis, a resistance to the ability of insulin to induce antilipolysis and lipogenesis in subcutaneous fat cells, but preserved lipolytic catecholamine action. These are factors that together promote fat mobilization and thereby weight reduction during long-term calorie restriction.
8-Bromo Cyclic Adenosine Monophosphate↗
Application of in situ microdialysis to measure metabolic and vascular responses in adipose tissue.
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Adipose Tissue↗
Obesity and insulin resistance in Swedish subjects.
Insulin resistance and secretory defects seem to be present in Swedish obese elderly, NIDDM subjects. A defect in insulin secretion seems to dominate in lean elderly male Swedish subjects with NIDDM. Furthermore, TNF alpha expression and secretion are increased in adipose tissue from obese subjects and correlates with insulin resistance roughly measured as elevated fasting plasma insulin in spite of normal fasting blood glucose.
Adipose Tissue↗
The beta 3-adrenergic receptor--a cause and cure of obesity?
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Adipose Tissue↗
Overexpression of the obese (ob) gene in adipose tissue of human obese subjects.
Obesity is accompanied by complications such as hypertension, non-insulin-dependent diabetes mellitus and atherosclerosis, which in turn cause ischaemic heart disease, stroke and premature death. The underlying mechanisms behind imbalance in energy intake and energy expenditure that lead to obesity are still controversial. In most populations, obesity is more common among women than men and is a multifactorial phenotype, which may result from a complex network of genetic and nongenetic factors. The relative importance of genetic factors for obesity is under debate. Genome searches using polymorphic markers in inbred mice with phenotypes that result in extreme obesity and studies of human candidate genes are being performed in an attempt to identify genes that contribute to obesity. There is evidence that body weight is physiologically regulated and it has been postulated that the storage of fat may provide signals to the brain that the body is obese, which in turn may make the subject eat less and burn more fuel. One of the molecules that may be involved in such signalling is the obese (ob) gene product. Mutations in ob result in profound obesity and type II diabetes in mice. The mouse ob gene and its human homologue have been cloned and sequenced. The gene is expressed in adipose tissue and the product has features of a secreted protein. We have investigated human ob expression in subcutaneous and omental adipose tissue obtained from non-obese and massively obese subjects using in situ hybridization histochemistry and report on overexpression in obese people.
Adipose Tissue↗
Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity.
1. The regulation of lipolysis was studied in 14 upper-body obese women aged 26-55 years. Isolated subcutaneous adipocytes from the abdominal region were examined before and after an 8 to 12-week-long weight reduction programme, during which the mean body mass index (kg/m2) of the group was reduced from 36.4 +/- 0.9 to 30.3 +/- 1.0. 2. Fat cell volume was reduced from 891 +/- 39 to 655 +/- 45 pl. The sensitivity to noradrenaline stimulation of lipolysis in vitro increased fivefold after weight reduction. A corresponding increase in sensitivity was found with the beta 2-selective adrenoceptor agonist terbutaline. However, the number of beta 2-adrenoceptor binding sites as assessed by radioligand binding with 125I-labelled cyanopindolol was not changed. No changes were observed when dobutamine (a beta 1-selective adrenoceptor agonist) and clonidine (an alpha 2-adrenoceptor agonist) were used. 3. The basal lipolysis rates decreased by about 50% after weight reduction and the maximum enzyme activity of hormone-sensitive lipase was also reduced by almost 50%. 4. Plasma concentrations of insulin, noradrenaline and total testosterone decreased and sex hormone-binding globulin increased after weight reduction. Calculated apparent free testosterone levels decreased by more than 40% after weight reduction. 5. In conclusion, weight reduction leads to increased efficiency of adipocyte lipolysis with decreased resting lipolysis rate but increased sensitivity to stimulation by catecholamines, which may be attributed to a decreased activity of hormone-sensitive lipase and an increased sensitivity of beta 2-adrenoceptors. Changes in circulating levels of catecholamines, insulin and testosterone may play a role in these modifications of adipocyte function.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipocytes↗
Cholinoceptor-mediated effects on glycerol output from human adipose tissue using in situ microdialysis.
1. Possible cholinoceptor-mediated effects on lipolysis were investigated in vivo in human subcutaneous adipose tissue of non-obese, non-smoking, healthy subjects, by use of microdialysis. Cholinomimetic and sympathomimetic agents were added to the in going dialysate solvent. 2. Addition of nicotine to the perfusion solvent caused a concentration-dependent reversible increase in the levels of glycerol in the dialysate (lipolysis index). The opposite effect (also concentration-dependent and reversible) was caused by the addition of carbachol. The maximum effects were 100% stimulation and 50% inhibition, respectively, by nicotine and carbachol. Neither nicotine nor carbachol stimulated nutritive blood flow in adipose tissue (as measured with an ethanol escape technique). 3. The nicotine effect in situ was concentration-dependently counteracted by the nicotinic cholinoceptor antagonist, mecamylamine. Likewise, the carbachol effect was concentration-dependently counteracted by the muscarinic cholinoceptor antagonist, atropine. 4. When adipose tissue was pretreated with phentolamine plus propranolol in order to obtain a complete alpha and beta-adrenoceptor blockade, the subsequent addition of nicotine or carbachol still induced an increase and decrease in dialysate glycerol levels (lipolytic or antilipolytic effects), respectively. When adipose tissue was pretreated with mecamylamine or atropine, the subsequent addition of acetylcholine caused a reversible decrease and increase, respectively, of the dialysate glycerol levels. 5. Nicotine and carbachol had no effects on glycerol release from human isolated subcutaneous fat cells that were incubated in vivo. 6. In conclusion, the data demonstrate a dual effect of the cholinoceptor system on glycerol output inhuman adipose tissue: stimulation through nicotinic receptors and inhibition through muscarinic receptors. These effects, which are not observed in vitro, are independent of the adrenergic system and the local blood flow and seem not to be mediated by a direct action on the fat cell.
Adipose Tissue↗
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.
Adipose Tissue↗
Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia.
The pathophysiology of familial combined hyperlipidemia (FCHL) is unknown, but altered lipid turnover in peripheral tissues as well as hepatic overproduction of apolipoprotein B have been suggested as possible causes. In the present study, we explored whether a change in triglyceride breakdown by lipolysis in fat cells is present in FCHL. Lipolysis activation by catecholamines was examined in isolated subcutaneous adipocytes from 10 patients with FCHL and 22 healthy control subjects. Lipolysis rate was linear for at least 3 h in both groups. However, a marked (approximately 65%) decrease in the lipolytic response to noradrenaline was found in FCHL. This was also true when lipolysis was maximally stimulated at the receptor level with isoprenaline (nonselective beta-adrenergic agonist), at the adenylyl cyclase level with forskolin, or at the level of the protein kinase hormone-sensitive lipase complex with dibutyryl cAMP. The maximum enzymatic activity of hormone-sensitive lipase was decreased by approximately 40% in FCHL. On the other hand, the lipolytic sensitivity of alpha 2-, beta 1-, and beta 2-adrenoceptors was normal in this condition, as was the number and affinity of beta 1- and beta 2-adrenoceptors. Variations in the maximum lipolysis rate correlated significantly with the variations in hormone-sensitive lipase activity in the whole material, and with the serum values for triglycerides, HDL cholesterol and apoB lipoprotein within the control group, but the serum triglyceride values in FCHL were higher than this correlation predicted. In conclusion, the data demonstrate a marked resistance to the lipolytic effect of catecholamines in fat cells from patients with FCHL, in spite of normal adrenoceptor function. The lipolytic defect appears predominantly to be due to a defect in hormone-sensitive lipase, and may be of importance in the pathophysiology of FCHL.
Adipocytes↗
Demonstration of an in vivo functional beta 3-adrenoceptor in man.
Although it is well established in several mammalian species that beta 3-adrenoceptors play a major role in regulating lipolysis and thermogenesis in adipose tissue, the functional existence and role of this receptor subtype in man has been controversial. We investigated whether the beta 3-adrenoceptor functionally co-exists with beta 1- and beta 2-adrenoceptors in vivo in human adipose tissue. Subcutaneous abdominal adipose tissue of healthy non-obese subjects was microdialyzed with equimolar concentrations of dobutamine (selective beta 1-adrenoceptor agonist), terbutaline (selective beta 2-adrenoceptor agonist), or CGP 12177 (selective beta 3-adrenoceptor agonist). All three agents caused a rapid, sustained, concentration-dependent and significant elevation of the glycerol level in the microdialysate (lipolysis index). However, only terbutaline stimulated the nutritive blood flow in adipose tissue, as measured by an ethanol escape technique. Dobutamine and CGP 12177 was equally effective in elevating the glycerol level (maximum effect 150% above baseline). Terbutaline was significantly more effective than the other two beta-agonists (maximum effect 200% above baseline). When adipose tissue was pretreated with the beta 1/beta 2-selective adrenoceptor blocker propranolol the glycerol increasing effect of dobutamine or terbutaline was inhibited by 80-85% but the glycerol response to CGP 12177 was not influenced. It is concluded that a functional beta 3-adrenoceptor is present in vivo in man. It co-exists with beta 1- and beta 2-adrenoceptors in adipose tissue and may therefore play a role in lipolysis regulation. It appears, however, that the beta 2-adrenoceptor is the most important beta-adrenoceptor subtype for the mobilization of lipids from abdominal subcutaneous adipose tissue because of its concomitant stimulatory effect on lipolysis and blood flow.
Adipose Tissue↗
Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance.
Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown. In this study we examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18 control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha protein concentrations in plasma and in conditioned medium of explanted adipose tissue were measured by ELISA. Furthermore, the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were also analyzed in nine premenopausal obese women, before and after a controlled weight-reduction program. These studies demonstrated that obese individuals express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls (P < 0.001). Similar increases were also observed in adipose production of TNF-alpha protein but circulating TNF-alpha levels were extremely low or undetectable. A strong positive correlation was observed between TNF-alpha mRNA expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance. Finally, body weight reduction in obese subjects which resulted in improved insulin sensitivity was also associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat tissue. These results suggest a role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance.
Adipose Tissue↗
Effect of glucocorticosteroid treatment on glucocorticoid receptor expression in human adipocytes.
The influence of glucocorticoid excess on expression of the glucocorticoid receptor (GR) and beta-adrenoceptor subtype was studied in isolated adipocytes obtained by sc fat biopsies from 17 healthy individuals. The biopsies were taken before and after 7 days of treatment with 25 mg prednisolone, given orally. GR and beta 1- and beta 2-adrenoceptor messenger ribonucleic acid (mRNA) levels were measured with a solution hybridization assay, and the number of beta 1- and beta 2-adrenoceptor binding sites was determined in radioligand binding experiments. GR protein levels were determined by Western blot analysis using an anti-GR antibody. Both GR protein and GR mRNA levels decreased significantly (P < 0.05) by about 50% after treatment, whereas no significant changes were demonstrated in either beta 1- or beta 2-adrenoceptor mRNA levels. The number of beta 2-adrenoceptor-binding sites, however, increased by 70% after treatment (P < 0.05), whereas the number of beta 1-adrenoceptor binding sites was not affected. The affinity of each receptor subtype was not significantly altered by steroid treatment. In conclusion, an in vivo glucocorticoid excess decreases GR mRNA as well as GR protein levels and selectively increases beta 2-adrenoceptor density in sc fat cells of healthy individuals. This indicates that glucocorticoids modulate human adipose metabolism by altering the expression of regulatory proteins at various mRNA and post-mRNA levels.
Adipocytes↗
Role of phosphodiesterase III in the antilipolytic effect of insulin in vivo.
The effect of three types of phosphodiesterase (PDE) inhibitors on in vivo antilipolysis was investigated in healthy subjects using a 2-h euglycemic, hyperinsulinemic (40 mU.m-2.min) clamp together with microdialysis of abdominal subcutaneous adipose tissue. During hyperinsulinemia (approximately 330 pmol/l), the circulating glycerol concentration was reduced to approximately 50% of the basal level of 53.2 +/- 3.6 mumol/l, indicating an antilipolytic effect. The decrease in adipose tissue dialysate glycerol, which mirrors the change in interstitial glycerol concentration, was about 40% during hyperinsulinemia when Ringer's solution alone was perfused. Local perfusion with a selective PDE IV inhibitor, rolipram (10(-4) mol/l), did not influence the insulin-induced decrease in dialysate glycerol (F = 0.8 vs. perfusion with Ringer's solution by two-factor analysis of variance [ANOVA]), although rolipram increased the dialysate glycerol level by 144 +/- 7% of the baseline value. However, local perfusion with a selective PDE III inhibitor, amrinone (10(-3) mol/l), or a nonselective PDE inhibitor, theophylline (10(-2) mol/l), abolished the ability of insulin to lower dialysate glycerol (F = 16.5, P < 0.01 and F = 8.5, P < 0.01, respectively, as compared with perfusion with Ringer's solution). The findings could not be explained by changes in the local blood flow (as measured by a microdialysis--ethanol escape technique), which was not affected by hyperinsulinemia in the presence or the absence of PDE inhibitors in the dialysis solvent. We conclude that PDEs play an important role in mediating the antilipolytic effect of insulin in vivo and that PDE III is the dominant isoenzyme modulating this effect.
3',5'-Cyclic-AMP Phosphodiesterases↗