Subcutaneous abdominal adipose tissue lipolysis during exercise determined by arteriovenous measurements in older women

OBJECTIVES: To characterize the lipolytic response in the subcutaneous abdominal adipose tissue in older women to endurance exercise. DESIGN: Cross-sectional exercise study.SETTING: Exercise laboratory, Copenhagen, Denmark. PARTICIPANTS: Seven healthy, older women (mean age +/- standard error = 75 +/- 2 years); weight: 67.8 +/- 4.9 kg; body fat: 40 +/- 3; maximal oxygen uptake (VO2max): 1.43 +/- 0.07 L.min 1). MEASUREMENTS: Body composition (dual energy x-ray absorptiometry (DEXA)), maximal oxygen uptake (VO2max, maximal cycling test), lipolytic response to exercise (arterial and adipose tissue venous catheterization at rest and during 60 minutes of continuous cycling at a load corresponding to 60 of VO2max), adipose tissue blood flow (ATBF) (133Xenon (133Xe) washout), oxygen consumption and respiratory exchange ratio during exercise (indirect calorimetry), whole blood glycerol, plasma nonesterified fatty acids (NEFA), lactate, glucose, epinephrine, norepinephrine, insulin, serum growth hormone, and hematocrit. RESULTS: Glycerol and NEFA mobilization rates increased by 250 and 180, respectively, from rest to exercise. This was achieved primarily by an increase in veno-arterial differences, because ATBF did not increase significantly. NEFA:glycerol mobilization ratio was about two at rest and remained at that level during exercise, indicating significant local reesterification in both conditions. After an initial decrease, arterial plasma NEFA concentration increased significantly, by 26, indicating that NEFA delivery exceeded muscle uptake. CONCLUSIONS: Older women are capable of prompt and substantial increase in subcutaneous abdominal adipose tissue glycerol and NEFA mobilization rates in response to moderate acute endurance exercise. The lipolytic response matches skeletal muscle NEFA uptake, and decreased ability to mobilize fat during exercise is therefore not likely to cause increased fat mass with advancing age.     

Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human subcutaneous abdominal adipose tissue assessed with microdialysis

Thyroid hormones play a major role in lipid metabolism. However, whether they directly affect lipolysis locally in the adipose tissue remains unknown. Therefore, we measured abdominal sc adipose tissue norepinephrine (NE), basal, and isoprenaline-stimulated lipolysis in 12 hypothyroid patients (HYPO), six hyperthyroid patients (HYPER), and 12 healthy controls by in vivo microdialysis. Adipose tissue NE was decreased in HYPO and increased in HYPER compared with controls (90.4 +/- 2.9 and 458.0 +/- 69.1 vs. 294.9 +/- 19.5 pmol/liter, P < 0.01). Similarly, basal lipolysis, assessed by glycerol assay, was lower in HYPO and higher in HYPER than in controls (88.2 +/- 9.9 and 566.0 +/- 42.0 vs. 214.3 +/- 5.1 micromol/liter P < 0.01). The relative magnitude of isoprenaline-induced glycerol increase was smaller in HYPO (39 +/- 19.4%, P < 0.05 vs. basal) and higher in HYPER (277 +/- 30.4%, P < 0.01) than in controls (117 +/- 5.6%, P < 0.01). The corresponding changes in NE after isoprenaline stimulation were as follows: 120 +/- 9.2% (P < 0.05), 503 +/- 113% (P < 0.01), and 267 +/- 17.2 (P < 0.01). In summary, by affecting local NE levels and adrenergic postreceptor signaling, thyroid hormones may influence the lipolysis rate in the abdominal sc adipose tissue.     

Effects of microdialysis catheter insertion into the subcutaneous adipose tissue assessed by the SCGM1 system

To monitor glucose in patients with diabetes continuously a microdialysis-based glucose sensor system (SCGM1 System, Roche Diagnostics GmbH, Mannheim, Germany) is under clinical development. This system allows monitoring of glucose levels in the subcutaneous interstitial fluid of patients with diabetes for a maximum duration of up to 120 h. The aim of the study was to determine the effect of microdialysis catheter insertion on the stability of the SCGM1 System glucose sensor signal. At four study sites, 47 experiments with the prototype of the novel SCGM1 System were performed in 42 patients with type 1 diabetes; two additional experiments were performed in two healthy volunteers. The microdialysis catheter was inserted in the subcutaneous adipose tissue of the patients in order to measure the glucose concentration in the interstitial fluid continuously. The catheter was perfused with a pump rate of 0.3 microL/min. For method comparison capillary blood glucose measurements were performed as reference values. In addition, the skinfold thickness was measured. Out of the total of 49 experiments 34 were usable. The average monitoring time in these experiments was 106.0 +/- 14.3 h (mean +/- SD). However, for this study the data from the first study day were evaluated in more detail. The analysis showed that during the first 12 h after catheter insertion the sensor signal increased 20% in comparison with the capillary blood glucose values (normalized calibration factor). This leads to a lower normalized calibration factor compared with the following study days. It remains stable in the time thereafter. The skinfold thickness showed no significant effect on the sensor signal. The observed increase in sensor signal in the first hours after insertion of the microdialysis catheter was probably due to a local trauma, which can induce an inflammation reaction. Thereafter, the signal registered by the SCGM1 System was stable and free of drift to the end of the experiment.     

Regulation of lipolysis by human adipose tissue in hyperthyroidism.

The effects of noradrenaline (NA) and isopropyl-noradrenaline (ISNA) on glycerol release and cAMP levels in sc adipose tissue were studied in vitro in 27 patients with hyperthyroidism. In 11 patients, the studies were repeated after 6--12 months of treatment for hyperthyroidism. A third group comprised 21 euthyroid patients otherwise healthy except for morbid obesity. The lipolytic response to ISNA, observed in untreated thyrotoxic patients, was found to be reduced by 30% when the patients were reexamined after treatment for thyrotoxicosis. This reduction was attributable to a decrease in the cAMP level. This was observed whether adipose tissue was incubated in the presence or absence of a phosphodiesterase inhibitor, theophylline. Both NA and ISNA induced 50% more rapid glycerol release and 4 times higher cAMP levels in adipose tissue of the thyrotoxic subjects than in the obese euthyroid patients. A positive correlation between tissue cAMP and glycerol release, on one hand, and mean fat cell size, on the other hand, was observed in treated thyrotoxic patients and obese euthyroid patients but was not recorded in the untreated hyperthyroid patients. The basal rate of lipolysis was not altered in thyrotoxicosis. The results suggest that the enhanced lipolytic response to catecholamines in adipose tissue of hyperthyroid patients is due to increased beta-adrenergic responsiveness. In addition, a disruption in subsequent stages of the regulatory pathway at the level of protein kinase or hormone-sensitive lipase also seems possible.     

Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo

Apelin is a peptide present in different cell types and secreted by adipocytes in humans and rodents. Apelin exerts its effects through a G-protein-coupled receptor called APJ. During the past years, a role of apelin/APJ in energy metabolism has emerged. Apelin was shown to stimulate glucose uptake in skeletal muscle through an AMP-activated protein kinase (AMPK)-dependent pathway in mice. So far, no metabolic effects of apelin have been reported on human adipose tissue (AT). Thus, the effect of apelin on AMPK in AT was measured as well as AMPK-mediated effects such as inhibition of lipolysis and stimulation of glucose uptake. AMPK and acetyl-CoA carboxylase phosphorylation were measured by western blot to reflect the AMPK activity. Lipolysis and glucose uptake were measured, ex vivo, in response to apelin on isolated adipocytes and explants from AT of the subcutaneous region of healthy subjects (body mass index: 25.6 ± 0.8 kg/m(2), n = 30 in total). APJ mRNA and protein are present in human AT and isolated adipocytes. Apelin stimulated AMPK phosphorylation at Thr-172 in a dose-dependent manner in human AT, which was associated with increased glucose uptake since C compound (20 μM), an AMPK inhibitor, completely prevented apelin-induced glucose uptake. However, in isolated adipocytes or AT explants, apelin had no significant effect on basal and isoprenaline-stimulated lipolysis. Thus, these results reveal, for the first time, that apelin is able to act on human AT in order to stimulate AMPK and glucose uptake.     

Changes in abdominal adipose tissue depots assessed by MRI correlate with hepatic histologic improvement in non-alcoholic steatohepatitis

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Effect of beta-adrenergic stimulation on whole-body and abdominal subcutaneous adipose tissue lipolysis in lean and obese men

Aims/hypothesis Obesity is characterised by increased triacylglycerol storage in adipose tissue. There is in vitro evidence for a blunted beta-adrenergically mediated lipolytic response in abdominal subcutaneous adipose tissue (SAT) of obese individuals and evidence for this at the whole-body level in vivo. We hypothesised that the beta-adrenergically mediated effect on lipolysis in abdominal SAT is also impaired in vivo in obese humans. Methods We investigated whole-body and abdominal SAT glycerol metabolism in vivo during 3 h and 6 h [²H₅]glycerol infusions. Arterio–venous concentration differences were measured in 13 lean and ten obese men after an overnight fast and during intravenous infusion of the non-selective beta-adrenergic agonist isoprenaline [20 ng (kg fat free mass)⁻¹ min⁻¹]. Results Lean and obese participants showed comparable fasting glycerol uptake by SAT (9.7 ± 3.4 vs 9.3 ± 2.5% of total release, p = 0.92). Furthermore, obese participants showed an increased whole-body beta-adrenergically mediated lipolytic response versus lean participants. However, their fasting lipolysis was blunted [glycerol rate of appearance: 7.3 ± 0.6 vs 13.1 ± 0.9 μmol (kg fat mass)⁻¹ min⁻¹, p < 0.01], as was the beta-adrenergically mediated lipolytic response per unit SAT [Δ total glycerol release: 140 ± 71 vs 394 ± 112 nmol (100 g tissue)⁻¹ min⁻¹, p < 0.05] compared with lean participants. Net triacylglycerol flux tended to increase in obese compared with lean participants during beta-adrenergic stimulation [Δ net triacylglycerol flux: 75 ± 32 vs 16 ± 11 nmol (100 g tissue)⁻¹ min⁻¹, p = 0.06]. Conclusions/interpretation We demonstrated in vivo that beta-adrenergically mediated lipolytic response is impaired systematically and in abdominal SAT of obese versus lean men. This may be important in the development or maintenance of increased triacylglycerol stores and obesity.     

Physiological concentrations of tissue factor pathway inhibitor do not inhibit prothrombinase

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type serine proteinase inhibitor that directly inhibits factor Xa and, in a factor Xa dependent manner, inhibits the factor VIIa/tissue factor catalytic complex. The inhibitory effect of TFPI in prothrombin activation assays using purified components of the prothrombinase complex was examined. When factor Xa is added to mixtures containing TFPI, prothrombin, calcium ions, and nonactivated platelets or factor V and phospholipids, TFPI significantly reduces subsequent thrombin generation, and the inhibitory effect is enhanced by heparin. If factor Xa is preincubated with calcium ions and thrombin-activated platelets or factor Va and phospholipids to permit formation of prothrombinase before the addition of prothrombin and physiologic concentrations of TFPI (< 8 nmol/L), minimal inhibition of thrombin generation occurs, even in the presence of heparin. Thus, contrary to results in amidolytic assays with chromogenic substrates, prothrombinase is resistant to inhibition by TFPI in the presence of its physiological substrate, prothrombin. Higher concentrations of TFPI (approximately 100 nmol/L), similar to those used in animal studies testing for therapeutic actions of TFPI, do effectively block prothrombinase activity.     

Regulation of lipolysis and leptin biosynthesis in rodent adipose tissue by growth hormone

The present study examined the effects of growth hormone (GH) on lipolysis and leptin release by cultured adipose tissue from rats and mice incubated for 24 hours in primary culture. A stimulation of leptin release by GH in rat adipose tissue was found in the presence of 25 nmol/L dexamethasone, and this was accompanied by a 28% increase in leptin mRNA content. GH stimulated lipolysis in rat adipose tissue in the presence of 0.1 nmol/L CL 316,243. In contrast, basal lipolysis in mouse adipose tissue was stimulated by GH, but this was not accompanied by an increase in leptin release. However, in the presence of insulin plus triiodothyronine (T3), the stimulation of lipolysis by GH was abolished and GH increased leptin release. These results indicate that GH can stimulate leptin release by both mouse and rat adipose tissue in the absence of a stimulation of lipolysis. In contrast, under conditions in which lipolysis is stimulated by GH, there is no effect on leptin release.     

Modulation of adipose tissue lipolysis and body weight by high-density lipoproteins in mice

Background:

Obesity is associated with reduced levels of circulating high-density lipoproteins (HDLs) and its major protein, apolipoprotein (apo) A-I. As a result of the role of HDL and apoA-I in cellular lipid transport, low HDL and apoA-I may contribute directly to establishing or maintaining the obese condition.

Methods:

To test this, male C57BL/6 wild-type (WT), apoA-I deficient (apoA-I^−/−) and apoA-I transgenic (apoA-I^tg/tg) mice were fed obesogenic diets (ODs) and monitored for several clinical parameters. We also performed cell culture studies.

Results:

ApoA-I^−/− mice gained significantly more body weight and body fat than WT mice over 20 weeks despite their reduced food intake. During a caloric restriction regime imposed on OD-fed mice, apoA-I deficiency significantly inhibited the loss of body fat as compared with WT mice. Reduced body fat loss with caloric restriction in apoA-I^−/− mice was associated with blunted stimulated adipose tissue lipolysis as verified by decreased levels of phosphorylated hormone-sensitive lipase (p-HSL) and lipolytic enzyme mRNA. In contrast to apoA-I^−/− mice, apoA-I^tg/tg mice gained relatively less weight than WT mice, consistent with other reports. ApoA-I^tg/tg mice showed increased adipose tissue lipolysis, verified by increased levels of p-HSL and lipolytic enzyme mRNA. In cell culture studies, HDL and apoA-I specifically increased catecholamine-induced lipolysis possibly through modulating the adipocyte plasma membrane cholesterol content.

Conclusions:

Thus, apoA-I and HDL contribute to modulating body fat content by controlling the extent of lipolysis. ApoA-I and HDL are key components of lipid metabolism in adipose tissue and constitute new therapeutic targets in obesity.     

Stimulation of human omental adipose tissue lipolysis by growth hormone plus dexamethasone

Growth hormone [GH] administration results in a reduction in adiposity of humans that is attributed to stimulation of lipolysis. We examined the effect of direct addition of human GH, in both the absence and presence of dexamethasone [Dex], as well as that of interferon beta on lipolysis by omental adipose tissue explants from obese women incubated for 48h in primary culture. There was a significant stimulation of lipolysis by GH in the presence of Dex but not by Dex or GH alone. There was also a significant further stimulation by GH in the presence of Dex of hormone-sensitive lipase, perilipin, lipoprotein lipase and beta1 adrenergic receptor mRNA. We conclude that the direct lipolytic effect of GH is accompanied by an increase in HSL mRNA in the presence of DEX, but GH also increased the mRNAs for other proteins that could explain all or part of its lipolytic action.     

Metformin inhibits catecholamine-stimulated lipolysis in obese, hyperinsulinemic, hypertensive subjects in subcutaneous adipose tissue: an in situ microdialysis study.

AIMS: Metformin has been reported to decrease the plasma concentrations of non-esterified fatty acids in Type 2 diabetic subjects. This study investigated the effects of metformin on basal and catecholamine-stimulated lipolysis in abdominal subcutaneous adipose tissue of obese, hyperinsulinaemic, hypertensive subjects. METHODS: Fourteen subjects with severe obesity (12 female, twomale, age 35.4 +/- 4 years, body mass index 48.2 +/- 2 kg/m2, body fat mass 63.3 +/- 5 kg) were recruited. Glycerol and lactate concentrations were determined in the presence of metformin and after administration of catecholamines using microdialysis. Simultaneously, blood flow was assessed with the ethanol escape method. RESULTS: Glycerol release was lowered by metformin during the 3-h experiment (P<0.01). The lipolytic activity of catecholamines was suppressed when adipose tissue was pre-treated with metformin (P<0.001). Lactate concentration increased after application of metformin (P<0.01) and catecholamines (P<0.001). Blood flow was decreased in the presence of adrenaline (P < 0.01), but this effect was abolished by metformin. CONCLUSIONS: The present data demonstrate the effects of metformin on lipolysis in subcutaneous adipose tissue in vivo. In the large body fat mass of obese subjects, a reduction of lipolysis in adipose tissue may contribute to a decrease of VLDL synthesis in the liver resulting in a lowered plasma triglyceride concentration.     

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.