Regulation of subcutaneous adipose tissue blood flow during exercise in humans

Regulation of subcutaneous adipose tissue blood flow (ATBF) remains poorly elucidated in humans, especially during exercise. In the present study we tested the role of adenosine in the regulation of ATBF adjacent to active and inactive thigh muscles during intermittent isometric knee-extension exercise (1 s contraction followed by 2 s rest with workloads of 50, 100, and 150 N) in six healthy young women. ATBF was measured using positron emission tomography (PET) without and with unspecific adenosine receptor inhibitor theophylline infused intravenously. Adipose regions were localized from fused PET and magnetic resonance images. Blood flow in subcutaneous adipose tissue adjacent to active muscle increased from rest (1.0 ± 0.3 ml·100 g(-1)·min(-1)) to exercise (P < 0.001) and along with increasing exercise intensity (50 N = 4.1 ± 1.4, 100 N = 5.4 ± 1.8, and 150 N = 6.9 ± 3.0 ml·100 g(-1)·min(-1), P = 0.03 for the increase). In contrast, ATBF adjacent to inactive muscle remained at resting levels with all intensities (～1.0 ± 0.5 ml·100 g(-1)·min(-1)). During exercise theophylline prevented the increase in ATBF adjacent to active muscle especially during the highest exercise intensity (50 N = 4.3 ± 1.8 ml·100 g(-1)·min(-1), 100 N = 4.0 ± 1.5 ml·100 g(-1)·min(-1), and 150 N = 4.9 ± 1.8 ml·100 g(-1)·min(-1), P = 0.06 for an overall effect) but had no effect on blood flow adjacent to inactive muscle or adipose blood flow in resting contralateral leg. In conclusion, we report in the present study that 1) blood flow in subcutaneous adipose tissue of the leg is increased from rest to exercise in an exercise intensity-dependent manner, but only in the vicinity of working muscle, and 2) adenosine receptor antagonism attenuates this blood flow enhancement at the highest exercise intensities.     

Catecholamine effects on lipolysis and blood flow in human abdominal and femoral adipose tissue

With the use ofthe microdialysis method, the present study, performed on young,healthy, nonobese subjects of both genders, compares the effects oflocally infused catecholamines on glycerol concentration and blood flowin abdominal (Abd) and femoral (Fem) adipose tissue. Physiologicalactivation of the sympathetic nervous system through active tilt wasalso investigated. In both genders, extracellular glycerolconcentration was higher in Fem than in Abd adipose tissue. Local bloodflow was lower in Fem than in Abd adipose tissue. Isoproterenolperfusion increased extracellular glycerol levels, but no differenceswere found by gender or fat-deposit site. Isoproterenolinduced a greater increase in local blood flow in Fem adipose tissue inboth genders. Epinephrine and norepinephrine perfusion increasedextracellular glycerol and reduced blood flow. No major differenceswere found according to gender and fat-deposit site. Active tiltincreased plasma glycerol, free fatty acid, norepinephrine levels, andextracellular glycerol concentration to the same extent whatever thegender and fat deposit. Thus, Fem adipose tissue is characterized by ahigher extracellular glycerol concentration and a lower blood flow thanis Abd tissue in men and women. In these tissues, in situ lipolysis andlocal blood flow were similar in response to adrenergic stimulation.

     

Heterogeneity of human adipose blood flow

Background

The long time pharmacokinetics of highly lipid soluble compounds is dominated by blood-adipose tissue exchange and depends on the magnitude and heterogeneity of adipose blood flow. Because the adipose tissue is an infinite sink at short times (hours), the kinetics must be followed for days in order to determine if the adipose perfusion is heterogeneous. The purpose of this paper is to quantitate human adipose blood flow heterogeneity and determine its importance for human pharmacokinetics.

Methods

The heterogeneity was determined using a physiologically based pharmacokinetic model (PBPK) to describe the 6 day volatile anesthetic data previously published by Yasuda et. al. The analysis uses the freely available software PKQuest and incorporates perfusion-ventilation mismatch and time dependent parameters that varied from the anesthetized to the ambulatory period. This heterogeneous adipose perfusion PBPK model was then tested by applying it to the previously published cannabidiol data of Ohlsson et. al. and the cannabinol data of Johansson et. al.

Results

The volatile anesthetic kinetics at early times have only a weak dependence on adipose blood flow while at long times the pharmacokinetics are dominated by the adipose flow and are independent of muscle blood flow. At least 2 adipose compartments with different perfusion rates (0.074 and 0.014 l/kg/min) were needed to describe the anesthetic data. This heterogeneous adipose PBPK model also provided a good fit to the cannabinol data.

Conclusion

Human adipose blood flow is markedly heterogeneous, varying by at least 5 fold. This heterogeneity significantly influences the long time pharmacokinetics of the volatile anesthetics and tetrahydrocannabinol. In contrast, using this same PBPK model it can be shown that the long time pharmacokinetics of the persistent lipophilic compounds (dioxins, PCBs) do not depend on adipose blood flow. The ability of the same PBPK model to describe both the anesthetic and cannabinol kinetics provides direct qualitative evidence that their kinetics are flow limited and that there is no significant adipose tissue diffusion limitation.     

Continuous estimation of adipose tissue blood flow in rats by 133Xe elimination.

A method is described which permits continuous estimation of adipose tissue blood flow (ATBF) in anesthetized female rats. The method is basesd on continuous monitoring of the elimination of 133Xe after labeling of the animal by intraperitoneal injection. From 2 to 6 h after the beginning of the elimination period close to 100% of the measured activity is shown to be located in adipose tissue, mainly in the parametrial fat. About 18% of the elimination is by way of intertissue diffusion, 82% of the perfusing blood. Changes in ATBF can readily be detected. The coefficient of variation for ATBF determinations is 9-11%. Changes in ATBF can be determined with great accuracy. Average ATBF per g tissue for fed and 48-h fasted rats were 0.105 and 0.122 ml-g-1-min-1, respectively. Total ATBF was lower in fasted than in fed rats (1.05 vs. 1.43 ml-min-1 for parametrial plus retroperitoneal fat). Intravenous administration of glucose (250 mg/h) decreased ATBF significantly in fed but not in fasted rats.     

Regulation of adipose tissue energy availability through blood flow control in the metabolic syndrome

Maintenance of blood flow rate is a critical factor for tissue oxygen and substrate supply. The potentially large mass of adipose tissue deeply influences the body distribution of blood flow. This is due to increased peripheral resistance in obesity and the role of this tissue as the ultimate destination of unused excess of dietary energy. However, adipose tissue cannot grow indefinitely, and the tissue must defend itself against the avalanche of nutrients provoking inordinate growth and inflammation. In the obese, large adipose tissue masses show lower blood flow, limiting the access of excess circulating substrates. Blood flow restriction is achieved by vasoconstriction, despite increased production of nitric oxide, the vasodilatation effects of which are overridden by catecholamines (and probably also by angiotensin II and endothelin). Decreased blood flow reduces the availability of oxygen, provoking massive glycolysis (hyperglycemic conditions), which results in the production of lactate, exported to the liver for processing. However, this produces local acidosis, which elicits the rapid dissociation of oxyhemoglobin, freeing bursts of oxygen in localized zones of the tissue. The excess of oxygen (and of nitric oxide) induces the production of reactive oxygen species, which deeply affect the endothelial, blood, and adipose cells, inducing oxidative and nitrosative damage and eliciting an increased immune response, which translates into inflammation. The result of the defense mechanism for adipose tissue, localized vasoconstriction, may thus help develop a more generalized pathologic response within the metabolic syndrome parameters, extending its effects to the whole body.     

The response of blood flow to altered perfusion pressure in canine adipose tissue.

It is concluded that subcutaneous adipose tissue autoregulates its blood flow only weakly or not at all in the range of perfusion pressures employed in our studies. Instead, these experiments demonstrate that when perfusion pressure is altered in the fat pad, vascular resistance must change in an opposite direction since there is little tendency for the flow to return to control values. Therefore, the vascular bed is responding passively. Furthermore, there was little evidence of autoregulation in denervated tissues indicating that the extrinsic neural control does not mask an underlying ability to modulate flow.     

Nutritional regulation of adipose tissue apolipoprotein E expression

Apolipoprotein E (apoE) is a multifunctional protein that is highly expressed in human and murine adipose tissue. Endogenous adipocyte apoE expression influences adipocyte triglyceride turnover and modulates the expression of genes involved in lipid synthesis and oxidation. We now demonstrate the regulation of adipose tissue apoE expression by nutritional status in lean and obese mice. Obesity induced by high-fat diet, or by hyperphagia in ob/ob mice, produces significant reduction of adipose tissue apoE expression at the protein and messenger RNA level. Fasting in C57BL/6J mice for 24 h significantly increased apoE protein and messenger RNA levels. In ob/ob mice, transplantation of adipose tissue from lean littermate controls to restore circulating leptin levels produced significant weight loss over 12 wk and also produced an increase in adipose tissue apoE expression. The increase in adipose tissue apoE expression in this model, however, did not require leptin. Adipose tissue apoE was also significantly increased in ob/ob mice after a 48-h fast or after 7 days of caloric restriction. In summary, obesity suppresses adipose tissue apoE expression, whereas fasting or weight loss increases it. From our previous observations, these changes in adipose tissue apoE expression will have significant impact on adipose tissue lipid flux and lipoprotein metabolism. Furthermore, these results suggest adipose tissue apoE participates in defending adipose tissue and organismal energy homeostasis in response to nutritional perturbation.     

Blood flow in subcutaneous adipose tissue depends on skin-fold thickness.

Blood flow in subcutaneous adipose tissue is reduced in obese compared to lean subjects. Limitations in vascular supply might interfere with adipose tissue function as a metabolic and endocrine organ. We tested the hypothesis that nutritive blood flow and tissue metabolism depends on subcutaneous adipose tissue thickness even in normal-weight subjects. Sixteen young, healthy, normal-weight subjects (8 men, 8 women) were included in the study. Abdominal subcutaneous adipose thickness was assessed by skin-fold measurements. The microdialysis technique was applied for monitoring basal adipose tissue blood flow (ethanol dilution technique) and metabolism. An increase in skin-fold thickness from 15 to 45 mm and from 8 to 37 mm was associated with a linear increase in basal ethanol ratio from 0.19 to 0.63 and 0.25 to 0.75 and linear decreases in dialysate glucose concentrations from 1.95 to 0.24 mM and 1.68 to 0.29 mM, and 152 to 42 microM and 172 to 49 microM for glycerol concentrations in men and women, respectively (p < 0.05). Isoproterenol-stimulated blood flow also inversely correlated to skin-fold thickness (p < 0.05). We conclude that increased adipose tissue thickness is associated with reduced tissue perfusion and metabolism, even in lean subjects. Skin-fold thickness is an important confounding variable in metabolic studies, particularly in microdialysis experiments.     

The regulation of acyl-CoA dehydrogenases in adipose tissue by rosiglitazone

The acyl-CoA dehydrogenases (ACADs), which catalyze the rate-limiting step in the mitochondrial beta-oxidation spiral, were investigated in white adipose tissue (WAT) of C57Bl/6 mice treated with 10 mg/kg/day rosiglitazone. Rosiglitazone was also administered to PPAR-alpha knockout mice. ACAD abundance and activity were determined using western blotting and an ACAD enzyme activity assay. Rosiglitazone increased ACAD activity in both epididymal and inguinal WAT but not in brown adipose tissue, liver, or muscle. Given the known function of PPAR-alpha in regulating the expression of ACAD genes in liver, it was hypothesized that PPAR-alpha may be involved in upregulating the ACADs during rosiglitazone-mediated adipose tissue remodeling. However, the effect of rosiglitazone on adipose tissue ACAD activity was the same in wild-type and PPAR-alpha knockout mice. In conclusion, rosiglitazone increases expression and activity of ACAD enzymes in WAT independently of PPAR-alpha.     

Post-translational regulation of lipoprotein lipase activity in adipose tissue.

Changes in adipose-tissue lipoprotein lipase activity that are independent of protein synthesis were investigated in an incubation system in vitro. Under appropriate conditions at 25 degrees C a progressive increase in the enzyme activity occurs that is energy-dependent. Part of the enzyme is rapidly inactivated when the tissue is incubated with adrenaline or adrenaline plus theophylline. The mechanism of this inactivation appears to be distinct from, and to follow, the activation of the enzyme. A hypothesis is presented to account for the results in terms of an activation of the enzyme during obligatory post-translational processing and a catecholamine-regulated inactivation of the enzyme as an alternative to secretion from the adipocyte.     

Depot-specific regulation of autotaxin with obesity in human adipose tissue

Autotaxin (ATX) is a lysophospholipase D involved in synthesis of a bioactive mediator: lysophosphatidic. ATX is abundantly produced by adipocytes and exerts a negative action on adipose tissue expansion. In both mice and humans, ATX expression increases with obesity in association with insulin resistance. In the present study, fat depot-specific regulation of ATX was explored in human. ATX mRNA expression was quantified in visceral and subcutaneous adipose tissue in obese (BMI?>?40?kg/m²; n?=?27) and non-obese patients (BMI?<?25?kg/m²; n?=?10). Whatever the weight status of the patients is, ATX expression was always higher (1.3- to 6-fold) in subcutaneous than in visceral fat. Nevertheless, visceral fat ATX was significantly higher (42?%) in obese than in non-obese patients, whereas subcutaneous fat ATX remained unchanged. In obese patients, visceral fat ATX expression was positively correlated with diastolic arterial blood pressure (r?=?0.67; P?=?0.001). This correlation was not observed with subcutaneous fat ATX. Visceral fat ATX was mainly correlated with leptin (r?=?0.60; P?=?0.001), inducible nitric oxide synthase (r?=?0.58; P?=?0,007), and apelin receptor (r?=?0.50; P?=?0.007). These correlations were not observed with subcutaneous fat ATX. These results reveal that obesity-associated upregulation of human adipose tissue ATX is specific to the visceral fat depot.