Showing papers by "Peter Arner published in 2009"
TL;DR: Adipocyte-derived secretion of chemerin may be involved in the negative cross talk between adipose tissue and skeletal muscle contributing to the negative relationship between obesity and insulin sensitivity.
Abstract: OBJECTIVE Chemerin is an adipokine that affects adipogenesis and glucose homeostasis in adipocytes and increases with BMI in humans. This study was aimed at investigating the regulation of chemerin release and its effects on glucose metabolism in skeletal muscle cells. RESEARCH DESIGN AND METHODS Human skeletal muscle cells were treated with chemerin to study insulin signaling, glucose uptake, and activation of stress kinases. The release of chemerin was analyzed from in vitro differentiated human adipocytes and adipose tissue explants from 27 lean and 26 obese patients. RESULTS Human adipocytes express chemerin and chemokine-like receptor 1 (CMKLR1) differentiation dependently and secrete chemerin (15 ng/ml from 10 6 cells). This process is slightly but significantly increased by tumor necrosis factor-α and markedly inhibited by >80% by peroxisome proliferator–activated receptor-γ activation. Adipose tissue explants from obese patients are characterized by significantly higher chemerin secretion compared with lean control subjects (21 and 8 ng from 10 7 cells, respectively). Chemerin release is correlated with BMI, waist-to-hip ratio, and adipocyte volume. Furthermore, higher chemerin release is associated with insulin resistance at the level of lipogenesis and insulin-induced antilipolysis in adipocytes. Chemerin induces insulin resistance in human skeletal muscle cells at the level of insulin receptor substrate 1, Akt and glycogen synthase kinase 3 phosphorylation, and glucose uptake. Furthermore, chemerin activates p38 mitogen-activated protein kinase, nuclear factor-κB, and extracellular signal–regulated kinase (ERK)-1/2. Inhibition of ERK prevents chemerin-induced insulin resistance, pointing to participation of this pathway in chemerin action. CONCLUSIONS Adipocyte-derived secretion of chemerin may be involved in the negative cross talk between adipose tissue and skeletal muscle contributing to the negative relationship between obesity and insulin sensitivity.
357 citations
TL;DR: Investigation of the roles of HSL, ATGL, and its coactivator CGI-58 in basal and forskolin-stimulated lipolysis in a human white adipocyte model, the hMADS cells suggest that ATGL/CGI-58 acts independently of H SL and precedes its action in the sequential hydrolysis of triglycerides in human hM ADS adipocytes.
191 citations
TL;DR: The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-β and HomA-IR on LF than on HF diet.
Abstract: Background:The A risk allele of rs9939609 of the fat mass- and obesity-associated gene (FTO) increases body fat mass.Objective:To examine whether FTO rs9939609 affects obese individuals' response to a high-fat, low-carbohydrate (CHO) (HF) or low-fat, high-CHO (LF), hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content.Design:In a 10-week, European, multi-centre dietary intervention study 771 obese women and men were randomized to either LF (20-25% of energy (%E) from fat, 60-65%E from CHO) or HF (40-45%E from fat, 40-45%E from CHO), hypo-energetic diet (measured resting metabolic rate multiplied by 1.3-600 kcal day(-1)). Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation as % of REE (FatOx), insulin release (HOMA-beta) and a surrogate measure of insulin resistance (HOMA-IR) were measured at baseline and after the intervention. In all, 764 individuals were genotyped for FTO rs9939609.Results:For A-allele carriers the drop-out rate was higher on HF than LF diet (in AT, P=0.002; in AT/AA combined, P=0.003). Among those individuals completing the intervention, we found no effect of FTO rs9939609 genotype on Deltaweight, DeltaFM, DeltaFFM, DeltaWC or DeltaFatOx. However, participants with TT had a smaller reduction in REE on LF than on HF diet (75 kcal/24 h; interaction: P=0.0055). These individuals also showed the greatest reduction in HOMA-beta and HOMA-IR (interaction: P=0.0083 and P=0.047).Conclusion:The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-beta and HOMA-IR on LF than on HF diet.International Journal of Obesity advance online publication, 18 August 2009; doi:10.1038/ijo.2009.159.
73 citations
TL;DR: Findings in human tissue are not in accordance with those previously described in rat epididymal fat pad, and do not justify the assumption that a decrease in the tissue level of FFA is the “trigger mechanism” for the lipolysis-promoting effect of glucose.
Abstract: . The influence of glucose on the in vitro lipolysis of human omental adipose tissue has been studied. Omental tissue obtained at surgery during general anesthesia was incubated in Krebs-Henseleit bicarbonate buffer containing 3% bovine albumin with and without added glucose (2 mg/ml). Glycerol release into the medium was considered as an index of lipolysis. Glucose enhanced the basal lipolysis and potentiated significantly the adipokinetic effects of noradrenaline, isopropylnoradrenaline and N6-2′0-dibutyryl cAMP (dibutyryl cAMP). The slope of glycerol release obtained for dibutyryl cAMP in glucose-free versus glucose-containing medium was significantly different from those obtained for noradrenaline and isopropylnoradrenaline. This difference might be explained if it is admitted that glucose stimulates lipolysis by acting on two different sites: (a) close to the triglyceride-splitting enzyme system, and (b) close to the beta-adrenergic receptor.
In a second series of experiments the effect of glucose on the level of FFA was studied in tissue and in medium with noradrenaline present. No changes in the net release of FFA were observed, whereas a slight increase in the tissue level of FFA was demonstrated. These findings in human tissue are not in accordance with those previously described in rat epididymal fat pad, and do not justify the assumption that a decrease in the tissue level of FFA is the “trigger mechanism” for the lipolysis-promoting effect of glucose.
A marked decrease in the glycerol release was noticed when 2-deoxy-d-glucose was added to medium containing noradrenaline, isopropylnoradrenaline and dibutyryl cAMP. The data are consistent with the view that glucose metabolism and the activity of triglyceride lipase are closely related.
70 citations
TL;DR: Down-regulated WAT expression of follistatin in obesity may counteract adiposity but could, by inhibiting adipogenesis, contribute to hypertrophic obesity (large fat cells) and insulin resistance.
Abstract: CONTEXT: Follistatin is a glycoprotein that binds and neutralizes biological activities of TGFbeta superfamily members including activin and myostatin. We previously identified by expression profiling that follistatin levels in white adipose tissue (WAT) were regulated by obesity. OBJECTIVE: The objective of the study was to elucidate the role of follistatin in human WAT and obesity. DESIGN: We measured secreted follistatin protein from WAT biopsies and fat cells in vitro. We also quantified follistatin mRNA expression in sc and visceral WAT and in WAT-fractionated cells and related it to obesity status, body region, and cellular origin. We investigated the effects of follistatin on adipocyte differentiation of progenitor cells in vitro. PARTICIPANTS: Women (n = 66) with a wide variation in body mass index were recruited by advertisement and from a clinic for weight-reduction therapy. RESULTS: WAT secreted follistatin in vitro. Follistatin mRNA levels in sc but not visceral WAT were decreased in obesity and restored to nonobese levels after weight reduction. Follistatin mRNA levels were high in the stroma-vascular fraction of WAT and low in adipocytes. Recombinant follistatin treatment promoted adipogenic differentiation of progenitor cells and neutralized the inhibitory action of myostatin on differentiation in vitro. Moreover, activin and myostatin signaling receptors were detected in WAT and adipocytes. CONCLUSION: Follistatin is a new adipokine important for adipogenesis. Down-regulated WAT expression of follistatin in obesity may counteract adiposity but could, by inhibiting adipogenesis, contribute to hypertrophic obesity (large fat cells) and insulin resistance.
61 citations
TL;DR: CES1 expression was linked to body fat and adipocyte fat content but not to lipolytic activity, and was associated with diet-induced weight loss.
59 citations
TL;DR: T-cell activation causes inflammation in adipose tissue but does not lead to insulin resistance in this tissue in the absence of interleukin-6, and insulin sensitivity was not impaired in adipOSE tissue of Apoe−/−×CD4dnTGFbR mice unless exogenous interleuko-6 was administered.
Abstract: Obesity is associated with chronic inflammation in adipose tissue. Proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-6 secreted by adipose tissue during the metabolic syndrome are proposed to cause local and general insulin resistance and promote development of type 2 diabetes. We have used a compound mutant mouse, Apoe(-/-)xCD4dnTGFbR, with dysregulation of T-cell activation, excessive production of proinflammatory cytokines, hyperlipidemia, and atherosclerosis, to dissect the role of inflammation in adipose tissue metabolism. These mice are lean, which avoids confounding effects of concomitant obesity. Expression and secretion of a set of proinflammatory factors including tumor necrosis factor-alpha, interferon-gamma, and monocyte chemoattractant protein-1 was increased in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice, as was the enzyme 11beta-hydroxysteroid dehydrogenase type 1, which converts cortisone to bioactive cortisol. Interleukin-6, which has an inhibitory glucocorticoid response element in its promoter, was not upregulated. In spite of intense local inflammation, insulin sensitivity was not impaired in adipose tissue of Apoe(-/-)xCD4dnTGFbR mice unless exogenous interleukin-6 was administered. In conclusion, T-cell activation causes inflammation in adipose tissue but does not lead to insulin resistance in this tissue in the absence of interleukin-6.
49 citations
TL;DR: Evidence is provided that activation of LXRs up-regulates mitochondrial beta-oxidation in both human and murine white adipocytes and that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965.
Abstract: Liver X receptors (LXRs) are nuclear receptors with established roles in cholesterol, lipid, and carbohydrate metabolism, although their function in adipocytes is not well characterized. Increased adipose tissue mass in obesity is associated with increased adipocyte lipolysis. Fatty acids (FA) generated by lipolysis can be oxidized by mitochondrial beta-oxidation, reesterified, or released from the adipocyte. The latter results in higher circulating levels of free FAs, in turn causing obesity-related metabolic complications. However, mitochondrial beta-oxidation can at least in part counteract an increased output of FA into circulation. In this study, we provide evidence that activation of LXRs up-regulates mitochondrial beta-oxidation in both human and murine white adipocytes. We also show that the expression of a kinase regulating the cellular fuel switch, pyruvate dehydrogenase kinase 4 (PDK4), is up-regulated by the LXR agonist GW3965 in both in vitro differentiated human primary adipocytes and differentiated murine 3T3-L1 cells. Moreover, activation of LXR causes PDK4-dependent phosphorylation of the pyruvate dehydrogenase complex, thereby decreasing its activity and attenuating glucose oxidation. The specificity of the GW3965 effect on oxidation was confirmed by RNA interference targeting LXRs. We propose that LXR has an important role in the regulation of substrate oxidation and the switch between lipids and carbohydrates as cellular fuel in both human and murine white adipocytes.
48 citations
TL;DR: Several gene polymorphisms associated with obesity-related phenotypes but not FTO and UCP variants may be responsible for some of the inter-individual variability in postabsorptive REE and fat-induced thermogenesis unaccounted for by FFM, FM, age and sex.
Abstract: Several obesity- and nutrient-related gene polymorphisms but not FTO and UCP variants modulate postabsorptive resting energy expenditure and fat-induced thermogenesis in obese individuals: the NUGENOB Study
40 citations
TL;DR: The findings indicate that basal lipolysis was increased in obesity, probably due to increased basal metabolic activity of triacylglycerol lipase, since the basal cAMP levels were similar in the two patient groups.
Abstract: Tissue monoacylglycerols (MG), diacylglycerols (DG), free fatty acids (FFA), and cyclic AMP (cAMP) and release of FFA and glycerol have been studied in vitro in subcutaneous adipose tissue of 6 obese and 7 normal-weight subjects. The tissue was incubated without or with 6 X 10(-5) mol/l of isoprenaline (ISNA). The DG level and the fat cell volume were strongly interrelated (r=+0.95, p less than 0.001). The concentration of DG was increased (p less than 0.05) in obesity. The changes in DG and MG were significantly interrelated (r=+0.65, p less than 0.05) during basal incubation. ISNA increased the DG concentration in a way that was correlated (r=+0.81, p less than 0.001) with the ISNA-induced glycerol release. This indicates that 1) the basal metabolic activities of MG and DG lipase are similar and 2) DG lipase is an important rate limiting factor in lipolysis. Without ISNA, tissue FFA and the release of FFA and glycerol were significantly increased in the obese patients. As a mean, MG and DG did not accumulate in the basal state in the two patient groups. The findings indicate that basal lipolysis was increased in obesity. This was probably due to increased basal metabolic activity of triacylglycerol lipase, since the basal cAMP levels were similar in the two patient groups. In the presence of ISNA, the production of FFA and the glycerol release were similar in both patient groups, as was the increase in tissue DG. Also the ISNA-induced maximal level of cAMP was similar in the two groups. With ISNA, a small increment of MG was observed in adipose tissue of the normal-weight subjects. Taking all metabolites into account, the rate of lipolysis as well as the activation of triacylglycerol lipase via cAMP in the presence of ISNA appeared to be unaltered in obesity. Separate experiments with 1-14C-glycerol provided further evidence for the existence of a MG pathway for the esterification of FFA.
39 citations
TL;DR: There was a positive correlation between the maximal increase in tissue cAMP and the rate of lipolysis in adipose tissue exposed to ISNA, both in individual experiments and in a group of 23 persons.
Abstract: Human subcutaneous adipose tissue has been incubated in vitro in the presence and absence of isoprenaline (ISNA). The tissue concentration of cyclic AMP (cAMP) and the release of glycerol into the incubation medium were measured after various incubation periods. In the presence of ISNA (6 X 10(-5) mol/l), the tissue concentration of cAMP reached a peak after around 10 min and then declined to a level significantly lower than that at the start of the incubation. In contrast, the ISNA-induced rate of lipolysis was a linear function of the incubation time. The addition of propranolol (13 mumol/l) at different times after ISNA did not influence the rate of lipolysis, although it resulted in a decrease in the tissue level of cAMP. There was a positive correlation between the maximal increase in tissue cAMP and the rate of lipolysis in adipose tissue exposed to ISNA, both in individual experiments and in a group of 23 persons. No correlation was found between the rate of lipolysis and the tissue level of cAMP in adipose tissue incubated under basal conditions. The findings are compatible with the theory that the beta-adrenergic-induced lipolysis by human adipose tissue is a function of the maximal rise in the concentration of tissue cAMP. It is concluded that this peak level of cAMP represents single compartment of the nucleotide.
TL;DR: Using beta1-, beta2-, and beta3-adenoceptor agonists, lipolysis was found to be significantly higher in omental as compared to subcutaneous differentiated preadipocytes and ANP-inducedlipolysis is not subject to primary regional variation.
Abstract: Catecholamine-induced lipolysis is elevated in omental as compared to subcutaneous adipocytes due to primary differences between the two cell types (i.e., they have different progenitor cells). Whether there is regional variation in atrial natriuretic peptide (ANP)-induced lipolysis is unknown. We studied whether beta-adrenoceptor signaling to lipolysis and ANP-induced lipolysis are involved in the primary differences in lipolysis. In vitro experiments on differentiated preadipocytes from human subcutaneous and omental adipose tissue were performed. The cells were kept in culture for a relative long duration, so any influence of local environment and circulation in the various adipose tissue depots could be excluded. Using beta1-, beta2-, and beta3-adenoceptor agonists, lipolysis was found to be significantly higher in omental as compared to subcutaneous differentiated preadipocytes. Forskolin and dibutyryl cAMP, which act at post-adrenoceptor levels, did not show any regional difference. There was no regional difference in ANP-induced lipolysis. Gene expression of beta1- and beta3-adrenoceptors was higher and beta2-adrenoceptor expression was lower in the omental cells. Omental fat cells have an increased beta-adrenoceptor-mediated lipolysis principally due to primary differences in the early event that couples beta-adrenoceptor subtypes to G-proteins. ANP-induced lipolysis is not subject to primary regional variation.
TL;DR: The first study on the local metabolic and inflammatory effect of intra-articular administered morphine or ketorolac is conducted, and for the first time, glutamate was studied in synovial tissue, and the results suggest that local release of glutamate may be important for nociception and inflammation.
TL;DR: The site variations may be involved in the development of regional forms of obesity and may raise the free fatty acid levels in the portal system and therefore impair metabolism of glucose and insulin by the liver.
Abstract: Regional differences have been found in the hormone regulation of adipose tissue lipolysis. Lipolytic activity is greater in omental than in subcutaneous adipocytes owing, in part, to a less marked insulin action and lower alpha 2-adrenoceptor antilipolytic activity in the omental region. In the subcutaneous region catecholamines are less lipolytic in gluteal/femoral than in subcutaneous abdominal adipocytes, which is partly due to enhanced alpha 2-adrenoceptor responsiveness in the gluteal/femoral cells. Insulin action also differs in the two subcutaneous adipose regions in a complex way that is influenced by the degree of obesity and nutritional factors. The regional differences in the antilipolytic effects of hormones seem to be caused by site variations in the receptors as well as in the signals from the receptors. The site variations may be involved in the development of regional forms of obesity, such as android or gynoid obesity and may raise the free fatty acid levels in the portal system and therefore impair metabolism of glucose and insulin by the liver.
TL;DR: The haemodynamic response was altered only by the non-selective alprenolol and not by the selective beta-adrenergic blocking agent (metoprolol), and the signs of hypoglycaemia were not masked.
Abstract: Insulin hypoglycaemia was induced three times in 6 insulin-dependent, hypertensive diabetics: before instituting antihypertensive long-term treatment and after obtaining a satisfactory blood pressure with either alprenolol or metoprolol given in a randomized order. The blood glucose concentration (1.6-1.9 mmol/l) at which the hypoglycaemia necessitated intravenous administration of glucose was almost identical on all three occasions. During hypoglycaemia the systolic and diastolic blood pressures increased significantly by a mean maximal rise of 27/14 mmHg on alprenolol treatment, but remained unchanged on metoprolol. The responses of adrenaline, noradrenaline, cortisol, and growth hormone did not differ significantly on the three occasions. None of the beta-adrenergic drugs counteracted the early hormone defence mechanisms in hypoglycaemia and the signs of hypoglycaemia were not masked. The haemodynamic response was altered only by the non-selective (alprenolol) and not by the selective beta-adrenergic blocking agent (metoprolol).
TL;DR: In diabetes mellitus, blood glucose homeostasis and rate of lipolysis in adipose tissue seem to be associated with the blood glucose level and the relationship is most apparent in JOD.
Abstract: The relationship between the blood glucose level and the rate of lipolysis was investigated in 19 maturity onset diabetics (MOD) and 9 juvenile onset diabetics (JOD). Subcutaneous adipose tissue was incubated with and without isoprenaline or noradrenaline. Before antidiabetic treatment the blood glucose concentration was positively correlated with basal and catecholamine-induced rates of lipolysis in MOD (R = 0.41--0.60) and in JOD (r = 0.51--0.71). The reduction in blood glucose concentration during antidiabetic treatment was positively correlated with the reduction in the rate of lipolysis in MOD (r = 0.50--0.64) and in JOD (r = 0.75--0.90). Fat cell size and blood glucose level were not correlated either in untreated or treated diabetics. In diabetes mellitus, blood glucose homeostasis and rate of lipolysis in adipose tissue seem to be associated. The relationship is most apparent in JOD.
TL;DR: It is suggested that chronic treatment with the beta 1-selective adrenergic blocker metoprolol leads to a significant increase in beta-adrenoceptor density and an increase in the lipolytic response to beta- adrenergic agonists, which may account for the increased plasma triglyceride level observed.
Abstract: The influence of beta-adrenergic blockade with metoprolol, a beta 1-selective agent, on the adrenergic regulation of lipid mobilization was explored in subcutaneous adipocytes removed from 13 patients with essential hypertension. Treatment with metoprolol, which was associated with adequate beta-adrenergic blockade and an antihypertensive effect, resulted in a significant increase (p less than 0.05) in the binding of the beta-adrenergic antagonist (-)-(3H)-dihydroalprenolol and a 50% increase (p less than 0.01) in the maximum lipolytic response to the beta-adrenergic agonist isopropylnoradrenaline. In 7 patients with normotriglyceridaemia the total plasma triglyceride level increased significantly (p less than 0.025) during metoprolol treatment, a change that was due to an increase in the very low density lipoprotein triglycerides. The findings suggest that chronic treatment with the beta 1-selective adrenergic blocker metoprolol leads to a significant increase in beta-adrenoceptor density and an increase in the lipolytic response to beta-adrenergic agonists. This latter finding may, in some measure, account for the increased plasma triglyceride level observed.
TL;DR: Eight attempts at segmental pancreatic transplantation were made in 6 diabetic patients, while the indications for transplantation differed all the patients were severely incapacitated by the disease.
Abstract: Eight attempts at segmental pancreatic transplantation were made in 6 diabetic patients. While the indications for transplantation differed all the patients were severely incapacitated by the disease. None was uremic. The body and tail of the pancreas from cadaveric donors was used, the grafts were revascularized to the recipient's iliac vessles. Six of the grafts provided control of blood glucose for 7-51 days. Five of the grafts then failed owing to rejection, and one had to be removed while still functioning, because of arterial bleeding. Important lessons have been learned concerning both surgical and immunological aspects of this form of treatment : 1) Ducto-jejunostomy should be used to provide exocrine pancreatic drainage. 2) HLA-DR typing for donor-recipient selection and thoracic-duct drainage as an adjunctive immunosuppressive measure should be used to reduce the incidence of graft rejection. 3) An elevation of the postprandial blood glucose concentration is a first sign of rejection and should cause treatment. 4) Graft rejection can be reversed by conventional steroid medication.
TL;DR: Conventional antidiabetes therapy in NIDDM mediates a suppression of adipose tissue lipolysis due to an improvement in insulin secretion in combination with a potentiation of the antilipolytic effectiveness of insulin in fat cells in the fasting state, the latter being secondary to post-binding alterations in insulin action.
Abstract: Insulin-induced antilipolysis was investigated in fat cells obtained after an overnight fast and 60 min after glucose ingestion in seven non-obese patients with non-insulin-dependent diabetes mellitus (NIDDM). The study was performed before and after long-term therapy with diet and glibenclamide. After treatment, the antilipolytic potency of insulin in fat cells was threefold enhanced (p less than 0.05) in the fasting state and remained unaltered after glucose ingestion. In untreated NIDDM oral glucose induced a significant (p less than 0.01) increase in insulin sensitivity. In consequence, in the glucose-fed state insulin sensitivity was similar before and after therapy. Adipocyte insulin receptor binding was comparable before and after therapy, both in the fasting state and following glucose intake. In untreated NIDDM, despite relative hypoinsulinemia, plasma glycerol was markedly reduced after oral glucose. After therapy, plasma glycerol was significantly reduced both in the fasting state and following glucose ingestion. At the same time, fasting and glucose-stimulated circulating insulin were significantly (p less than 0.01) increased. It is concluded that conventional antidiabetes therapy in NIDDM mediates a suppression of adipose tissue lipolysis. This seems to be due to an improvement in insulin secretion in combination with a potentiation of the antilipolytic effectiveness of insulin in fat cells in the fasting state, the latter being secondary to post-binding alterations in insulin action.
TL;DR: The present findings lend no support to the recent theory that sulfonylureas decrease the plasma levels of FFA and glycerol in man by direct action of the drug on adipose tissue by chlorpropamide.
Abstract: . Lipolysis measured as glycerol release from rat adipose tissue in vitro was inhibited by chlorpropamide. This antilipolytic effect was independent of the addition of glucose to the incubation medium. At the same time chlorpropamide decreased the re-esterification of FFA formed by lipolysis. This inhibitory effect was more pronounced in tissue incubated in medium with glucose present. Since lipolysis as well as re-esterification of FFA is accelerated by glucose, present data would indicate that chlorpropamide primarily interferes with the glucose metabolism or the stimulatory action of glucose on the two pathways of the triglyceride-FFA cycle. Chlorpropamide (1 mg/ml) had no effect on the glycerol release and lipogenesis of human omental tissue. The present findings lend no support to the recent theory that sulfonylureas decrease the plasma levels of FFA and glycerol in man by direct action of the drug on adipose tissue.