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Biomedical subjects

S W Coppack

Publications and source records attributed to S W Coppack.

At least 19 recordsLinked to original sources
PubMed2005

Adipose tissue changes in obesity.

This review gives a broad description of some of the changes in adipose tissue seen in obesity. There are multiple changes in adipose tissue in obesity: histological, neural and vascular, relating to lipid and carbohydrate metabolism and to adipose tissue's endocrine functions. Some may originate from a simple physical expansion of cell size and number. It is unclear which are the most important either in terms of intermediary metabolism or of contributing to the co-morbidities of obesity. Important questions for the future include the reversibility of obesity-related changes and indeed whether the changes differ between depots and species. Recent studies examining physiological regulation within adipose tissue demonstrate it to be relatively unresponsive to changes in everyday life.

Adipose Tissue↗
PubMed2004

The EGIR-RISC STUDY (The European group for the study of insulin resistance: relationship between insulin sensitivity and cardiovascular disease risk): I. Methodology and objectives.

AIMS/HYPOTHESES: Insulin resistance is thought to be a key predictor for the development of Type 2 diabetes mellitus and cardiovascular disease (CVD), a leading cause of morbidity and premature mortality in Europe. Insulin resistance is influenced by both genetic and lifestyle factors (e.g. obesity and physical inactivity). The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is using the infrastructure of an extended European collaborative research group to study insulin resistance and CVD risk in 1500 healthy people aged 30 to 60 years from 20 centres in 13 countries. METHODS: Baseline measurements of glucose tolerance and insulin sensitivity are made by the oral glucose tolerance test and the euglycaemic insulin clamp, respectively; carotid artery intima-medial thickness (by ultrasound), ankle/brachial pressure index and electrocardiography will enable evaluation of subclinical CVD at baseline and at follow-up. Classic CVD risk factors, as well as socioeconomic and lifestyle factors will be recorded at baseline; samples for measurement of biochemical and genetic markers will be collected and stored for future analyses. Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis as measured by carotid artery intima-media thickness. Development of Type 2 diabetes, dyslipidaemia, obesity, hypertension and cardiovascular events are additional endpoints. CONCLUSIONS: This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies.

Adult↗
PubMed2003

Integrative physiology of human adipose tissue.

Adipose tissue is now recognised as a highly active metabolic and endocrine organ. Great strides have been made in uncovering the multiple functions of the adipocyte in cellular and molecular detail, but it is essential to remember that adipose tissue normally operates as a structured whole. Its functions are regulated by multiple external influences such as autonomic nervous system activity, the rate of blood flow and the delivery of a complex mix of substrates and hormones in the plasma. Attempting to understand how all these factors converge and regulate adipose tissue function is a prime example of integrative physiology. Adipose tissue metabolism is extremely dynamic, and the supply of and removal of substrates in the blood is acutely regulated according to the nutritional state. Adipose tissue possesses the ability to a very large extent to modulate its own metabolic activities, including differentiation of new adipocytes and production of blood vessels as necessary to accommodate increasing fat stores. At the same time, adipocytes signal to other tissues to regulate their energy metabolism in accordance with the body's nutritional state. Ultimately adipocyte fat stores have to match the body's overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the body's energy status, and points once again to the need for an integrative view of adipose tissue function.

Adipocytes↗
PubMed2002

Effects of tumour necrosis factor-alpha in the human forearm: blood flow and endothelin-1 release.

Increased circulating concentrations of tumour necrosis factor-alpha (TNF-alpha) are seen in several pathological conditions associated with vascular disease. TNF-alpha induces the synthesis of endothelin-1 (ET-1), a potent vasoconstictor, by the endothelium. However, there is profound vasodilatation in sepsis, where circulating levels of both ET-1 and TNF-alpha are elevated. The details of the interaction between ET-1 and TNF-alpha and the predominant resulting haemodynamic effect in healthy humans are unclear. The aim of the present study was to determine the effects of intra-arterial TNF-alpha on ET-1 spillover, vascular tone and endothelial function in the healthy human forearm. Brachial arterial and deep venous blood samples, forearm plasma flow measurements and blood flow responses to acetylcholine and sodium nitroprusside were obtained in six healthy subjects before and during a 6 h infusion of TNF-alpha into the brachial artery. Forearm blood flow was significantly greater than baseline during exposure to TNF-alpha [median (lower quartile, upper quartile): baseline, 2.6 (2.1, 2.8) ml.min(-1).100 ml(-1); TNF-alpha, 4.6 (4.5, 5.1) ml.min(-1).100 ml(-1); P <0.05]. The rate of release of ET-1 was significantly greater than baseline after 30 and 260 min of TNF-alpha infusion [median (lower quartile, upper quartile): baseline, 0.8 (0.6, 1.1) pg.min(-1).100 ml(-1); 30 min, 2.4 (1.9, 3.2) pg.min(-1).100 ml(-1); 260 min, 4.1 (3.1, 4.2) pg.min(-1).100 ml(-1); P <0.05]. The vasodilatory response to acetylcholine was diminished during TNF-alpha infusion, whereas the response to sodium nitroprusside remained unchanged. We thus demonstrate for the first time that local TNF-alpha increases ET-1 spillover from the human forearm and impairs endothelium-dependent vasodilatation. In spite of this action, TNF-alpha has a vasodilatory effect, resulting in an increase in forearm blood flow.

Acetylcholine↗
PubMed2002

Norepinephrine spillover from human adipose tissue before and after a 72-hour fast.

Adipose tissue lipolysis is at least in part stimulated by the sympathetic nervous system (SNS). Although there is a generalized decrease in SNS activity with fasting, the rate of lipolysis during fasting increases. The aim of this study was to determine whether there is an association between activation of sympathetic nerves innervating adipose tissue and the increase in lipolysis seen during fasting in humans. We used the isotope dilution technique to measure regional norepinephrine spillover from abdominal sc adipose tissue from seven healthy subjects before and after a 72-h fast. Our results showed a significant increase in adipose tissue spillover of norepinephrine (mean +/- SEM, 0.40 +/- 0.09 vs. 1.08 +/- 0.18 pmol.100 g(-1).min(-1), P < 0.05) and arterial norepinephrine concentrations (0.92 +/- 0.10 vs. 1.23 +/- 0.08 nmol.liter(-1), P < 0.05) after the fast with no significant change in total body norepinephrine spillover, forearm norepinephrine spillover, epinephrine concentrations, or energy expenditure. We show for the first time, in humans, a selective regional increase in adipose tissue norepinephrine spillover in response to a 72-h fast and suggest that the SNS may play a greater role in the regulation of lipid metabolism during fasting than previously thought.

Adipose Tissue↗
PubMed2001

Nutritional regulation of lipid metabolism in human adipose tissue.

Pfeiffer and colleagues years ago pointed out that different distributions and amounts of adipose tissue are associated with abnormalities of lipolysis and lipoprotein metabolism. Adipose tissue has several crucial roles including (i) mobilization from stores of fatty acids as an energy source, (ii) catabolism of lipoproteins such as very-low-density lipoprotein and (iii) synthesis and release of hormonal signals such as leptin and interleukin-6. These adipose tissue actions are crucially regulated by nutrition. The review considers the existence of metabolic pathways and modes of regulation within adipose tissue, and how such metabolic activity can be quantitated in humans. Nutrition can influence adipose tissue at several 'levels'. Firstly the level of obesity or malnutrition has important effects on many aspects of adipose tissue metabolism. Secondly short-term overfeeding, underfeeding and exercise have major impacts on adipose tissue behaviour. Lastly, specific nutrients are capable of regulating adipose tissue metabolism. Recently there have been considerable advances in understanding adipose tissue metabolism and in particular its regulation. This review discusses the behaviour of adipose tissue under various nutritional conditions. There is then a review of recent work examining the ways in which nutritional influences act via intra-cellular mechanisms, insulin and the sympathetic innervation of adipose tissue.

Adipose Tissue↗
PubMed2001

Pro-inflammatory cytokines and adipose tissue.

Cytokines appear to be major regulators of adipose tissue metabolism. Therapeutic modulation of cytokine systems offers the possibility of major changes in adipose tissue behaviour. Cytokines within adipose tissue originate from adipocyte, preadipocyte and other cell types. mRNA expression studies show that adipocytes can synthesise both tumour necrosis factor alpha (TNF-alpha) and several interleukins (IL), notably IL-1beta and IL-6. Other adipocyte products with 'immunological' actions include complement system products and macrophage colony-stimulating factor. Cytokine secretion within adipocytes appears similar to that of other cells. There is general agreement that circulating TNF-alpha and IL-6 concentrations are mildly elevated in obesity. Most studies suggest increased TNF-alpha mRNA expression or secretion in vitro in adipose tissue from obese subjects. The factors regulating cytokine release within adipose tissue appear to include usual 'inflammatory' stimuli such as lipopolysaccaride, but also the size of the fat cells per se and catecholamines. There is conflicting data about whether insulin and cortisol regulate TNF-alpha. The effects of cytokines within adipose tissue include some actions that might be characterised as metabolic. TNF-alpha and IL-6 inhibit lipoprotein lipase, and TNF-alpha additionally stimulates hormone-sensitive lipase and induces uncoupling protein expression. TNF-alpha also down regulates insulin-stimulated glucose uptake via effects on glucose transporter 4, insulin receptor autophosphorylation and insulin receptor substrate-1. All these effects will tend to reduce lipid accumulation within adipose tissue. Other effects appear more 'trophic', and include the induction of apoptosis, regulation of cell size and induction of de-differentiation (the latter involving reduced peroxisome proliferator-activated receptor gamma). Cytokines are important stimulators and repressors of other cytokines. In addition, cytokines appear to modulate other regulatory systems. Examples of the latter include effects on leptin secretion (probably stimulation followed by inhibition) and reduction of beta3-adrenoceptor expression. There seems to be no clear agreement as to which cytokines derived from adipose tissue act as remote regulators, i.e. hormones. Leptin, which is structurally a cytokine, is also a hormone. IL-6 appears to be released systemically by adipose tissue, but TNF-alpha is probably not. Both leptin and IL-6 appear to act on the hypothalamus, IL-6 acts on the liver, while leptin may have actions on the pancreas. The importance of the immune system in whole-body energy balance provides a rationale for the links between cytokines and adipose tissue. It seems clear that TNF-alpha is a powerful autocrine and paracrine regulator of adipose tissue. Other cytokines, notably leptin, and possibly IL-6, have lesser actions on adipose tissue. These cytokines act as hormones, reporting the state of adipose tissue stores throughout the body.

Adipocytes↗
PubMed2001

Whole-body and adipose tissue glucose metabolism in response to short-term fasting in lean and obese women.

BACKGROUND: Alterations in glucose metabolism during early fasting may be an important trigger of the hormonal and metabolic responses to fasting. OBJECTIVE: The purpose of this study was to determine whether glucose metabolism in response to brief starvation differs in lean and abdominally obese women. DESIGN: We evaluated whole-body glucose metabolism by use of stable-isotope tracer methods and glucose uptake in subcutaneous abdominal adipose tissue by use of arteriovenous balance in 7 lean [58 +/- 2 kg; body mass index (BMI; in kg/m(2)): 21 +/- 5] and 6 abdominally obese (96 +/- 2 kg; BMI: 36 +/- 1) women after 14 and 22 h of fasting. RESULTS: Between 14 and 22 h of fasting, whole-body glucose production and disposal declined in both groups (P < 0.05), but the reduction was 50% greater in lean than in obese women (P < 0.05). The decline in glucose uptake at 22 h of fasting was also lower in obese (0.11 +/- 0.04 micromol*100 g(-1) x min(-1)) than in lean (0.26 +/- 0.03 micromol x 100 g(-1) x min(-1)) women (P < 0.05). Decreases in plasma insulin and leptin concentrations between 14 and 22 h of fasting were also lower in obese than in lean women (insulin: 20 +/- 3% and 32 +/- 5%; leptin: 18 +/- 3% and 37 +/- 6%; both P < 0.05). CONCLUSIONS: The normal decline in glucose production and uptake that occurs during early fasting is blunted in women with abdominal obesity. These alterations in glucose metabolism are associated with a blunted decline in circulating concentrations of both insulin and leptin, which may explain some of the differences in the metabolic response to fasting observed between lean and abdominally obese persons.

Abdomen↗
PubMed2001

Effect of short-term fasting on free and bound leptin concentrations in lean and obese women.

Plasma leptin exists in protein-bound and free forms, which may affect its hormonal bioactivity. Therefore, the relationship between bound and free leptin may be particularly important during physiological conditions that cause rapid alterations in total plasma leptin concentration, such as fasting. The purpose of this study was to evaluate the effect of short-term fasting on bound and free plasma leptin concentrations and leptin binding capacity (a measure of plasma leptin-binding protein content) in lean and obese women. Six lean (body mass index, 21 +/- 1 kg/m2) and 6 abdominally obese (BMI, 36 +/- 1 kg/m2) women were studied after 14 h and 22 h of fasting. Although total plasma leptin concentration was more than 6-fold greater in obese (45.4 +/- 7.6 microg/liter) compared with lean (7.4 +/- 1.0 microg/liter) women at 14 h of fasting (P < 0.05), the percentage of leptin in the bound form was greater in lean than obese subjects (29 +/- 2% vs. 12 +/- 3%; P < 0.05). Arterial total, free, and bound plasma leptin concentrations all declined between 14 h and 22 h of fasting in both lean and obese groups, but the relative decline of these fractions was greater in lean (36 +/- 4%, 60 +/- 9%, and 51 +/- 13%, respectively) than in obese (19 +/- 5%, 21 +/- 8%, and 12 +/- 7%, respectively) subjects (all P < 0.05). In contrast, leptin binding capacity was unchanged. The percentage of total plasma leptin present in bound form was constant between 14 h and 22 h of fasting in lean subjects and increased slightly but significantly in obese subjects. These data demonstrate that both free and bound fractions of leptin in plasma decrease quickly in response to energy restriction, but the decline is blunted in abdominally obese compared with lean women. In addition, the equilibrium between bound and free leptin fractions is maintained during brief fasting and is not regulated by leptin binding capacity.

Absorptiometry, Photon↗
PubMed2000

Central obesity, depression and the hypothalamo-pituitary-adrenal axis in men and postmenopausal women.

OBJECTIVE: We examined the relationship of adiposity to pituitary-adrenal responses to corticotrophin-releasing hormone (CRH) in men and postmenopausal women, controlling for the influence of depression. DESIGN: Studies of CRH responses, cortisol metabolite levels and depression scores in relation to adiposity in men and postmenopausal women. SUBJECTS: Thirteen men: age (median, interquartile range) 62 y (52-63), body mass index (BMI) 29.0 kg/m2 (26.3-33.1), waist circumference (waist) 105 cm (97-111), waist:hip ratio (WHR) 1.03 (0.98-1.07), subscapular to triceps skinfold thickness ratio (STR) 2.0 (1.2-2.4), total body fat (TBF) 25.4 kg (19.8-28.8); and eight women: age 54 y (53-62), BMI 30 kg/m2 (23-41), waist 86 cm (79-117), WHR 0.94 (0.87-1.10), STR 1.0 (0.85-1.07), TBF 35.0 kg (18.7-48.8). MEASUREMENTS: A standard CRH test was conducted with additional basal samples taken for leptin and interleukin 6 (IL-6). Total urine cortisol metabolites (TCM) and the ratio of urinary cortisol:cortisone (Fm/Em) metabolites were measured. Depression scores were measured by the General Health Questionnaire (GHQ-30) and Hospital Anxiety and Depression Scale (HAD) questionnaire. All subjects completed an overnight dexamethasone suppression test. RESULTS: The basal to peak percentage increments (%inc.) in adrenocorticotrophic hormone (ACTH) and cortisol in men correlated directly with STR (ACTH %inc. r=0.70, P<0.01; cortisol %inc. r=0.55, P=0.05); this relationship was independent of depression scores. In women, the ACTH area under incremental curve (AUIC) correlated negatively with STR (r=-0.81, P<0.05). In men, but not in women, there was a significant correlation between GHQ-30 score and ACTH AUIC (r=0.62, P<0.05) and cortisol AUIC (r=0.72, P<0.01). Depression scores were consistently and directly related to indices of obesity and central obesity. There were no significant relationships in either sex between urinary TCM or Fm/Em ratio and BMI, waist, WHR, TBF, STR or CRH responses. The urinary Fm/Em ratio was higher in men than in women (median 0.74 vs 0.66, P<0.05). In men, but not in women, GHQ-30 scores correlated positively with urinary TCM (r=0.57, P=0.05) and HAD-depression scores were inversely related to the urine Fm/Em ratio (r=-0.65, P<0.05). All subjects suppressed normally with dexamethasone. CONCLUSIONS: Cortisol metabolite levels were increased in depression in men, but were not related to adiposity in either sex. We demonstrate that central obesity in men, but not postmenopausal women, is associated with an enhanced pituitary-adrenal response to CRH and that this relationship is independent of depression score. International Journal of Obesity (2000) 24, 246-251

Adrenal Cortex Function Tests↗
PubMed2000

Increased response of cortisol and ACTH to corticotrophin releasing hormone in centrally obese men, but not in post-menopausal women.

There is evidence for enhanced hypothalamo-pituitary-adrenal axis (HPAA) activity in centrally obese premenopausal women. This has led to the hypothesis that increased cortisol production rates may be an aetiological factor in the genesis of central obesity. However, the relationship of obesity and body fat distribution to HPAA activity in men and postmenopausal women has not been established. We carried out CRH tests in 13 men and 8 post-menopausal women. We measured 24 h urine cortisol metabolites prior to the CRH test in each subject, as an indication of cortisol production rate. There was a significant direct relationship between central obesity as measured by the ratio of subscapular:triceps skinfold thickness (STR)--and the ACTH/cortisol response to CRH in men, but not in postmenopausal women. There was no relationship between obesity or body fat distribution and 24h urine cortisol metabolites. This study provides evidence for hyperactivity of the HPAA in centrally obese men, but not in postmenopausal women.

Adrenocorticotropic Hormone↗
PubMed2000

beta-Adrenergic regulation of proinflammatory cytokines in humans.

OBJECTIVES: To investigate the effects of beta-adrenergic stimulation on IL-6 secretion in humans, and to determine the potential contribution to this response of adipocytes and peripheral blood cells (PBC). DESIGN: Experimental study in 8 human volunteers, and in vitro studies on murine adipocyte cell-line, 3T3.L1 and 3T3.F442A, and human PBC. MEASUREMENTS: Plasma IL-6 and TNFalpha responses to isoprenaline infusion. Cytokine secretion from differentiated adipocyte cell-lines and PBC in response to isoprenaline. RESULTS: Plasma IL-6 levels increased ninefold (median) by 180 min (baseline median 0.51 [interquartile range 0.47-1.4] vs 180 mins 4.53 [2.58-5.69] pg ml(-1), P=0.01). One hour after infusion, IL-6 levels (2.9 [1.27-3.98]) were lower than at 180 min (P=0.05), but higher than baseline (P=0.01). TNFalpha levels were unchanged. Differentiated adipocytes incubated in isoprenaline (0-0.1 microM) released significantly increased amounts of IL-6 whereas no response was elicited from PBC. CONCLUSIONS: The induction of IL-6 observed in vivo may be attributed to the beta-adrenergic stimulation of IL-6 release specifically from adipocytes, as opposed to circulating blood cells.

3T3 Cells↗
PubMed2000

Thyroid and sympathetic influences on plasma leptin in hypothyroidism and hyperthyroidism.

OBJECTIVES: To determine the dependence of plasma leptin concentrations upon circulating noradrenaline (NA) and thyroid hormones (TH) in humans. DESIGN: Cross-sectional study in 40 newly diagnosed untreated patients with primary thyroid disease, and 69 lean and obese euthyroid control subjects. MEASUREMENTS: Plasma leptin, NA, free T3 (fT3) and TSH in the fasting state. Anthropometry and % body fat (electrical bioimpedance). RESULTS: Leptin levels were highest in 37 obese euthyroid and 22 hypothyroid (median [interquartiles]31.5 [19.0- 48.0], 19.2 [11.5-31.5] ng ml(-1)), and lowest in 32 lean euthyroid and 18 hyperthyroid subjects (6.6 [3.9-14.4], 8.9 [5.5-11.1]; ANOVA, P< 0.0001). Plasma NA was similar in all groups (P= n.s.). In obese controls, TSH correlated with % body fat and leptin (r= 0.67, r= 0.61; P< 0.001). Treatment of hypothyroidism (n= 10) with T4 reduced leptin from 20.8 [11.8-31.6] to 12.9[4.6-21.2] (P= 0.005) with no change in BMI. CONCLUSIONS: Thyroid status modifies leptin secretion independently of adiposity and NA. The data suggest leptin-thyroid interactions at hypothalamic and adipocyte level.

Female↗
PubMed2000

Insulin resistance, lipid and fatty acid concentrations in 867 healthy Europeans. European Group for the Study of Insulin Resistance (EGIR).

BACKGROUND: Insulin resistance, dyslipidaemia and abnormal nonesterified fatty acid (NEFA) metabolism are features of the 'metabolic syndrome', but the mechanisms of these relationships are uncertain. MATERIALS AND METHODS: We studied associations between insulin resistance and lipoprotein concentrations by retrospective analysis of euglycaemic hyperinsulinaemic clamp data from 867 normoglycaemic subjects in 21 European centres. Data on NEFA concentrations were available in a subgroup of 541 subjects from 9 clinical centres. These subjects' characteristics do not vary significantly from those of the whole cohort. RESULTS: After adjustment for the effects of age, sex, obesity and intercentre variability, regression analysis showed relationships between triglycerides and markers of insulin sensitivity. There were significant correlations between triglycerides and fasting plasma glucose (P < 0.0001), fasting plasma insulin (P < 0.0001) and mean glucose infusion rate at steady state (M-value, P < 0.0001). Indices of insulin resistance were related to NEFA concentrations. Fasting NEFA were negatively correlated with the M-value (P < 0.0001). Non-esterified fatty acids at steady state were positively correlated with fasting markers of insulin resistance: fasting plasma glucose (P < 0.05), fasting plasma insulin (P < 0.005) and negatively correlated with the M-value (P < 0.0005). There were relationships between fasting concentrations of plasma lipids and of NEFAs. Non-esterified fatty acids at steady state correlated with fasting triglycerides (P < 0.0001), but not with any of the other plasma lipoprotein concentrations. The associations of fasting triglycerides with the M-value and with NEFAs at steady state were independent of each other. All these associations were independent of obesity and geographical location CONCLUSION: The results in this large cohort of healthy European subjects suggest that triglyceride concentrations depend upon both insulin's gluco-regulation (estimated by glucose uptake) and antilipolytic insulin action (measured by NEFA levels) during an euglycaemic clamp.

Adolescent↗