Simon W. Coppack

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 bodys nutritional state. Ultimately adipocyte fat stores have to match the bodys overall surplus or deficit of energy. This implies the existence of one (or more) signal(s) to the adipose tissue that reflects the bodys energy status, and points once again to the need for an integrative view of adipose tissue function.

Endothelial Dysfunction: Cause of the Insulin Resistance Syndrome

Insulin resistance has been proposed as the metabolic basis of atherogenesis. This hypothesis is based on the concept of the “insulin resistance syndrome,” according to which insulin resistance is viewed as the primary abnormality that gives rise to dyslipidemia, essential hypertension, impaired glucose tolerance, and NIDDM. However, this hypothesis takes no account of the wellestablished and central role of vascular endothelium in the atherogenic process. Although endothelial injury is an early and prominent feature of atherogenesis, relatively little attention has been given to its metabolic consequences. In subjects with NIDDM, we have shown that endothelial dysfunction is associated with insulin resistance, raising the question of whether this relationship could be causal. In this article, we review the factors that are considered to be responsible for the development of endothelial dysfunction during atherogenesis, together with the metabolic consequences of endothelial dysfunction. While dysfunction of the endothelium in large and medium-sized arteries plays a central role in atherogenesis, we argue that dysfunction of peripheral vascular endothelium, at arteriolar and capillary level, plays the primary role in the pathogenesis of both insulin resistance and the associated features of the insulin resistance syndrome. We propose that the insulin resistance syndrome, together with many aspects of atherogenesis, can be viewed as the diverse consequences of endothelial dysfunction in different vascular beds. This new and testable hypothesis accounts for both the endothelial and metabolic abnormalities associated with atherogenesis.

Insulin-Mediated Upregulation of the Renin Angiotensin System in Human Subcutaneous Adipocytes Is Reduced by Rosiglitazone

Background—Obesity-associated hypertension is likely to be due to multiple mechanisms. Identification of the renin-angiotensin system (RAS) within adipose tissue does, however, suggest a potential causal role for it in obesity-associated hypertension. Obese patients are often hyperinsulinemic, but mechanisms underlying insulin upregulation of the RAS in adipose tissue are unclear. Tumor necrosis factor-α (TNF-α), an inducer of angiotensinogen in hepatocytes, is elevated in hyperinsulinemic, obese individuals and may provide a link in mediating insulin upregulation of the RAS in adipose tissue. Furthermore, thiazolidinediones lower blood pressure in vivo, and downregulation of the RAS in adipose tissue may contribute to this effect. We therefore examined the effect of rosiglitazone (RSG) on the insulin-mediated upregulation of the RAS. Methods and Results—Sera were obtained from the arterial circulation and from venous blood by draining subcutaneous abdominal adipose tissue. Isolated human abdominal subcutaneous adipocytes (n=12) were treated with insulin (1 to 1000 nmol/L), insulin in combination with RSG (10 nmol/L), and RSG (10 nmol/L) alone to determine angiotensinogen expression and angiotensin II, bradykinin, and TNF-α secretion. Subcutaneous adipocytes were also treated with TNF-α (10 to 100 ng/mL) to examine the direct effect on angiotensinogen expression and angiotensin II secretion. The findings showed that the arteriovenous difference in angiotensin II levels was significant (>23%; P<0.001). Insulin increased TNF-α secretion in a concentration-dependent manner (P<0.01), whereas RSG (10 nmol/L) significantly reduced the insulin-mediated rise in TNF-α (P<0.001), as well as angiotensin and angiotensin II. TNF-α also increased angiotensinogen and angiotensin II in isolated adipocytes. Conclusions—The present in vivo data suggest that human subcutaneous adipose tissue is a significant source of angiotensin II. This study also demonstrates a potential TNF-α–mediated mechanism through which insulin may stimulate the RAS and may contribute to explain obesity-associated hypertension. RSG downregulates the RAS in subcutaneous adipose tissue, and this effect may contribute to the long-term effect of RSG on blood pressure.

Arteriovenous differences across human adipose and forearm tissues after overnight fast

Measurements of arteriovenous differences across subcutaneous abdominal tissue (mainly adipose) and deep forearm tissue (mainly muscle) were made on 25 occasions in normal subjects after an overnight fast. Adipose tissue was shown to be strongly lipolytic (releasing nonesterified fatty acids and glycerol), to clear circulating triacylglycerol, glucose, ketone bodies and acetate, and to produce lactate. Uptake of circulating carbohydrate and ketones was sufficient to account for only 51% of the adipose tissue oxygen consumption, implying that adipose tissue utilizes fuel(s) stored within it. The mean fractional re-esterification rate of fatty acids in adipose tissue was 13% to 19%. Arteriovenous differences were converted to fluxes of carbon atoms to compare the movements of different fuels. (Amino acids were not included in these calculations.) Adipose tissue after an overnight fast was a net exporter of carbon, whereas in resting muscle the uptake of carbon atoms from circulating carbohydrate and lipid fuels approximately balanced the CO2 production. Fatty acids were the main form in which carbon left adipose tissue, and the main source of carbon atoms entering the resting forearm.

Human triacylglycerol-rich lipoprotein subfractions as substrates for lipoprotein lipase

In order to test the hypothesis that lipoprotein lipase (LPL) acts preferentially on larger lipoprotein particles, we determined the susceptibility of triacylglycerol-rich lipoprotein (TRL) subfractions to hydrolysis by LPL in vitro. Chylomicrons (Sf > 400), very low density lipoproteins (VLDL)1 (Sf 60-400) and VLDL2 (Sf 20-60) were isolated from six subjects with a range of plasma-triacylglycerol (TAG) concentrations following an overnight fast and for up to 6 h after the consumption of a mixed meal (41% fat). The percent of TRL-TAG hydrolysed by LPL in subfractions isolated following overnight fast was VLDL1 > VLDL2 (46.8 +/- 10.2 vs. 25.9 +/- 7.4%, P = 0.006) and 3 h after the meal it was chylomicrons > VLDL1 > VLDL2 (81.0 +/- 12.6 vs. 52.8 +/- 10.2 vs. 27.7 +/- 6.2%, chylomicrons vs. VLDL1 and VLDL1 vs. VLDL2, both P < or = 0.005). The percent of VLDL1-TAG hydrolysed increased both within and between subjects as VLDL1-TAG concentrations increased. This relationship could be explained by the positive correlation observed between VLDL1-TAG and VLDL1-TAG:apolipoprotein B. In conclusion, increasing the size and TAG content of a lipoprotein particle increases its susceptibility to hydrolysis by LPL.

Periprandial regulation of lipid metabolism in insulin-treated diabetes mellitus.

We have examined the regulation of lipid and glucose metabolism in the postabsorptive and postprandial states in six subjects with insulin-treated diabetes mellitus, and compared them with eight nondiabetic subjects. Blood or plasma concentrations of metabolites and fluxes across forearm and subcutaneous adipose tissue were studied after an overnight fast and for 6 hours after a mixed meal (3.1 MJ, 41% from fat). In the postabsorptive state, regulation of lipid metabolism in the two groups appeared basically similar except that a wider spread of plasma (free) insulin concentrations in the diabetic group led to a wider range of values of plasma nonesterified fatty acid (NEFA) release from adipose tissue, plasma NEFA concentrations, and blood ketone body concentrations. Extraction of ketone bodies across adipose tissue was positively correlated with arterial concentration in both groups (as it was in the forearm), confirming the ability of human adipose tissue to utilize ketone bodies. A single subcutaneous injection of insulin before the meal in the diabetic group produced a plasma free-insulin profile that was blunted and prolonged compared with the postprandial response in the control group. Postprandial forearm glucose uptake followed very closely the plasma (free) insulin concentration. Postprandial suppression of NEFA release from adipose tissue was essentially normal in the diabetic group, and the normal postprandial decrease in plasma NEFA concentrations was reproduced extremely closely. Forearm and adipose tissue blood flow did not differ between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic responses of forearm and adipose tissues to acute ethanol ingestion

Although excess ethanol consumption is often considered to lead to adiposity, the metabolic routes by which this might occur are not clear. We have investigated some metabolic consequences of acute ethanol ingestion by measuring arteriovenous differences across forearm muscle and subcutaneous adipose tissue for 6 hours after ingestion of 47.5 g ethanol, in seven normal subjects fasted overnight. The expected systemic effects of ethanol ingestion were observed: slight lowering of the plasma glucose concentration, depression of plasma nonesterified fatty acid (NEFA) concentrations, and elevation of the blood lactate/pyruvate and 3-hydroxybutyrate/acetoacetate ratios. There was a marked reduction in blood total ketone bodies in relation to plasma NEFA concentrations. However, the only major change observed in peripheral tissue metabolism was an increased uptake of acetate into forearm muscle, equivalent, in whole-body terms, to only 3% of the ethanol load. Adipose tissue appeared to show a reduced cytoplasmic state in that it exported an increased ratio of lactate to pyruvate after ethanol ingestion. However, this reduced state did not lead to increased fatty acid reesterification within adipose tissue. No mechanism was clearly identified whereby ethanol ingestion might lead to net deposition of triacylglycerol in adipose tissue.

Age, weight and obesity.

The western world is facing the consequences of higher standards of medical care and improved living conditions. While people are living longer the prevalence of overweight and obesity is escalating which increases the risk of developing non-communicable diseases. However it must be noted that there is a U shaped relationship between weight and mortality with both under and overweight increasing risk. This review examines possible contributory factors for overweight and obesity in older people: life style, depression, changes in body composition, endocrine alterations, sympathetic tone, oxidative stress and concomitant disease.

Fasting plasma triacylglycerol concentrations predict adverse changes in lipoprotein metabolism after a normal meal

The changes in lipoprotein metabolism which follow the ingestion of a large fat load have been well described. The hypothesis was tested that similar changes in lipoprotein metabolism would occur after a relatively normal meal. Plasma and lipoprotein triacylglycerol, cholesterol and apolipoprotein concentrations were determined in twenty subjects (ten female) given a mixed meal containing approximately one-third of the daily intake of major nutrients in the typical Western diet. Fasting plasma triacylglycerol concentrations (range 0.38-2.70 mm/l) and the postprandial rise in plasma triacylglycerol varied considerably between subjects and were significantly associated (P < 0.01). The rise in plasma triacylglycerol corresponded to marked increases in the triacylglycerol concentration of the triacylglycerol-rich lipoproteins (TRL; chylomicrons and very-low-density lipoproteins). TRL cholesterol also increased after the meal. An increase in high-density-lipoprotein (HDL)-triacylglycerol following the meal was accompanied by a decrease in HDL-cholesterol concentration, presumably due to the action of the cholesteryl-ester transfer protein. The increases in HDL-triacylglycerol and in TRL-cholesterol were correlated with the postprandial rise in triacylglycerol in the TRL (P < 0.01). We conclude that potentially adverse changes occur in both triacylglycerol-rich and high-density lipoproteins following a typical mixed meal, as they do after large fat loads. The changes are exaggerated in those subjects with greater fasting plasma triacylglycerol concentrations.

Oedema in obesity; role of structural lymphatic abnormalities

Oedema is a common finding in obesity and its cause is not always clear. Possible causes include impairment of cardiac, respiratory and/or renal function, chronic venous insufficiency and lymphatic problems. Lymphoscintigraphy is the best method to detect structural lymphatic abnormalities that can cause lymphoedema. We reviewed 49 female subjects with pitting oedema who had undergone lymphoscintigraphy, divided in three groups. The first group was comprised of severely obese patients in whom cardiorespiratory causes for oedema had been excluded. The second group consisted of non-obese patients with recognized causes for oedema and the third group was non-obese patients with ‘idiopathic’ oedema. A standard classification was used to interpret lymphoscintigraphy results. The frequency and severity of lymphoscintigraphic abnormalities was greatest in patients with clinical diagnoses of oedema related to ‘recognized causes’ (any abnormality in 50% of legs with obstruction in 22%). Obese patients and those with ‘idiopathic’oedema had fewer (P=0.02 for both) and milder lymphoscintographic abnormalities (any abnormality 32 and 25%, respectively, obstruction 5 and 3%, respectively), and although the clinical oedema was invariably bilateral, the lymphoscintigraphy abnormalities were usually unilateral. In conclusion, structural lymphoscintigraphic abnormalities are uncommon in obesity and do not closely correlate with the clinical pattern of oedema.