In a prospective study of risk factors for ischaemic heart disease 792 54 year old men selected by year of birth (1913) and residence in Gothenburg agreed to attend for questioning and a battery of anthropometric and other measurements in 1967. Thirteen years later these baseline findings were reviewed in relation to the numbers of men who had subsequently suffered a stroke, ischaemic heart disease, or death from all causes.Neither quintiles nor deciles of initial indices of obesity (body mass index, sum of three skinfold thickness measurements, waist or hip circumference) showed a significant correlation with any of the three end points studied. Statistically significant associations were, however, found between the waist to hip circumference ratio and the occurrence of stroke (p=0 002) and ischaemic heart disease (p = 0-04). When the confounding effect of body mass index or the sum of three skinfold thicknesses was accounted for the waist to hip circumference ratio was significantly associated with all three end points. This ratio, however, was not an independent long term predictor of these end points when

'Stress' embraces the reaction to a multitude of poorly defined factors that disturb homeostasis or allostasis. In this overview, the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system have been utilized as objective measurements of stress reactions. Although long-term activation of the sympathetic nervous system is followed by primary hypertension, consequences of similar activation of the HPA axis have not been clearly defined. The focus of this overview is to examine whether or not repeated activation of these two stress centres may be involved in the pathogenesis of abdominal obesity and its comorbidities. In population studies adrenal hormones show strong statistical associations to centralization of body fat as well as to obesity. There is considerable evidence from clinical to cellular and molecular studies that elevated cortisol, particularly when combined with secondary inhibition of sex steroids and growth hormone secretions, is causing accumulation of fat in visceral adipose tissues as well as metabolic abnormalities (The Metabolic Syndrome). Hypertension is probably due to a parallel activation of the central sympathetic nervous system. Depression and 'the small baby syndrome' as well as stress exposure in men and non-human primates are followed with time by similar central and peripheral abnormalities. Glucocorticoid exposure is also followed by increased food intake and 'leptin resistant' obesity, perhaps disrupting the balance between leptin and neuropeptide Y to the advantage of the latter. The consequence might be 'stress-eating', which, however, is a poorly defined entity. Factors activating the stress centres in humans include psychosocial and socioeconomic handicaps, depressive and anxiety traits, alcohol and smoking, with some differences in profile between personalities and genders. Polymorphisms have been defined in several genes associated with the cascade of events along the stress axes. Based on this evidence it is suggested that environmental, perinatal and genetic factors induce neuroendocrine perturbations followed by abdominal obesity with its associated comorbidities.

A B S T R A C T The distribution of adipose tissue thickness, fat cell weight (FCW), and number (FCN) were studied in four regions in randomly selected middleaged men and women and in 930 obese individuals. Both the obese and the randomly selected men were found to have the largest adipose tissue thickness in the abdominal region. Women, however, showed a relative preponderance for the gluteal and femoral regions. FCW increased with expanding body fat up to a maximal size of -0.7-0.8 ,ug/cell in each region.After this increase in FCW, a more rapid increase in FCN was found.For the same degree of relative overweight, men had higher triglyceride, fasting glucose, and insulin levels; higher sums of glucose and insulin levels during an oral glucose tolerance test; and higher blood pressure. Furthermore, elevated fasting glucose levels (>7.4 mM) occurred twice as often in the males. These differences between males and females persisted even after body fat matching.A male risk profile was seen in women characterized by abdominal obesity (high waist/hip circumference ratio) as compared to women with the typical peripheral obesity. Stepwise multiple regression analyses in both women and men showed the obesity complications to be associated in a first step to waist/hip circumference or body fat and in a second to abdominal fat cell size.It may thus be concluded that: (a) In both obese and nonobese subjects, regional differences exist between the sexes with regard to adipose tissue distribution.Portions of these data were presented at the International Conference on the Adipocyte and Obesity, 28-29 June 1982, Toronto, Canada. Address all correspondence to Dr. Ulf Smith, Department of Medicine II, Sahlgren's Hospital, Sweden. Received for publication 20 August 1982 and in revised form 10 March 1983. (b) Moderate expansion of body fat is mainly due to FCW enlargement, which is subsequently followed by increased FCN. (c) Men and women with a male abdominal type of obesity are more susceptible to the effect of excess body fat on lipid and carbohydrate metabolism.

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Insulin resistance is the cornerstone for the development of non-insulin-dependent diabetes mellitus (NIDDM). Free fatty acids (FFAs) cause insulin resistance in muscle and liver and increase hepatic gluconeogenesis and lipoprotein production and perhaps decrease hepatic clearance of insulin. It is suggested that the depressing effect of insulin on circulating FFA concentration is dependent on the fraction derived from visceral adipocytes, which have a low responsiveness to the antilipolytic effect of insulin. Elevated secretion of cortisol and/or testosterone induces insulin resistance in muscle. This also seems to be the case for low testosterone concentrations in men. In addition, cortisol increases hepatic gluconeogenesis. Cortisol and testosterone have "permissive" effect on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus have powerful combined effects, resulting in insulin resistance and increased hepatic gluconeogenesis. All these factors promoting insulin resistance are active in abdominal visceral obesity, which is closely associated with insulin resistance, NIDDM, and the "metabolic syndrome." In addition, the endocrine aberrations may provide a cause for visceral fat accumulation, probably due to regional differences in steroid-hormone-receptor density. In addition to the increased activity along the adrenocorticosteroid axis, there also seem to be signs of increased activity from the central sympathetic nervous system. These are the established endocrine consequences of hypothalamic arousal in the defeat and defense reactions. There is some evidence that suggests an increased prevalence of psychosocial stress factors is associated with visceral distribution of body fat. Therefore, it is hypothesized that such factors might provide a background not only to a defense reaction and primary hypertension, suggested previously, but also to a defeat reaction, which contributes to an endocrine aberration leading to metabolic aberrations and visceral fat accumulation, which in turn leads to disease.

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