European Journal of Clinical Investigation (1984) 14, 239-241

EDITORIAL

Hazards in subgroups of human obesity

There are numerous observations suggesting that human obesity is not a homogenous entity, such as variations in age at dCbut, relationship to diabetes mellitus and other complicating diseases, prognosis of treatment, distribution of the enlarged fat depots, to mention only some examples. It seems likely that progress in research in this area is severely hampered by the fact that we have not been able to clearly characterize and recognize such subgroups of human obesity. Although treatment of obesity is still awaiting a breakthrough from the severe way of creating a long-lasting negative energy balance by decreasing eating and increasing exercise, subgrouping of human obesity might be of importance for the indications for treatment, prevention, and, perhaps most importantly, to understand the pathogenesis of the numerous, potentially dangerous associating complications of which diabetes mellitus, hypertension and hyperlipi- daemia are the most common. The importance of this question is stressed by the fact that the National Institutes of Health in the U.S., recently arranged a symposium (Poughkeepsie, New York, 1980) where studies on this question were initiated.

Recent work has been focussed on the enlarged adipose tissue and its heterogenicity in human obesity. There is very little evidence, if any, that there is a primary malfunction in the main functional cell in adipose tissue, the adipocyte. Nevertheless, this might be an avenue towards a better understanding, similar to that used by haematologists long ago. The erythro- cyte is not primarily sick in pernicious anaemia, sideropenia and sickle-cell anaemia, but studying this cell led to clearing up the aetiology of these diseases and their adequate clinical handling.

Human adipose tissue in non-obese subjects It is common knowledge that the distribution of adipose tissue is different in men and women. Both sexes have a central subcutaneous and intra-abdo- minal fat depot. In addition, women have a fat depot located on the upper part of the legs and in the gluteal region. There is not an absolute sex difference here, a few men having some fat on their legs, and some women having most of their adipose tissue in the abdominal region.

The author was chairman of a workshop during the Annual Meeting of the European Society for Clinical Investigation, Milan, April 1984.

There is now conclusive evidence that the adipocytes in both these depots are functionally different. Earlier observations that the adipocyte in the femoral-gluteal regions were enlarged in women suggested a specific metabolic regulation of lipid storage in these cells. Direct studies have now demonstrated that under ordinary conditions these cells tend to accumulate fat by having a high activity of lipoprotein lipase and low sensitivity to stimulation of lipolysis by catechola- mines. To these functional characteristics then may correspond the increased amount of triglyceride in each enlarged fat cell found previously. (For review, see [15].)

Very recent work is suggesting that the femoral adipocytes can only mobilize their accumulated trigly- cerides effectively during late pregnancy and, particu- larly, lactation [l]. This suggests that this specific female fat depot has a specific female function-to store fat to be used during lactation.

Human adipose tissue in obese subjects Regional measurements of adipose-tissue thickness with ultrasound as well as adipocyte size and number in a large material of subjects with varying degrees of obesity [2] may tentatively be utilized to try to understand how obese men and women store their excess fat. It seems that both sexes dispose of their surplus fat simply by utilizing the depots they have constitutionally. Consequently, women have enlarged depots in the abdominal plus gluteal-femoral regions, while men accumulate fat mainly in the abdominal regions. It is only when men are massively obese that they store fat on the upper part of their legs. The fat is stored, in both sexes and in all regions, first by enlarging adipocytes up to a critical size (correspond- ing to a weight of about 0.8 pg); thereafter the number of fat cells increase.

Obesity complications in relation to adipose-tissue distribution Comparing the risk of having obesity-associated dis- orders between men and women, at the same degree of obesity, shows that men have higher blood glucose, plasma insulin and triglyceride concentrations, and higher blood pressure. This generally goes for modera- tely obese subjects, women reach the male risk zone only when they become severely obese [2].

These phenomena were also examined in relation to

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adipose-tissue distribution within the sexes. For exam- ple, women were divided into groups with typical male and female adipose-tissue distribution along different variables. Such a simple and effective subdivision was obtained by measuring the circumferences in the waist and hip regions, and utilizing the ratio of these two circumference measurements. In this way an abdo- minal obesity measurement was obtained, a male characteristic when elevated, a female characteristic when low. Looking again at the risk for obesity complications it was found that they were more prevalent in women with male type of obesity (high waist/hip circumference ratio) than in women with female-type obesity (low ratio). Similar analyses with other male/female characteristics, within the group of men only, and with other statistical techniques (multi- ple regression analyses) gave similar results, the male type of obesity being more frequently associated with obesity complications than that of the female type [2].

These observations are not new, Vague [3] described the differences between android and gynoid obesity long ago, and Kissebah et al. [4] have recently reported similar results. The size of the material examined makes it, however, easier to draw valid conclusions because such factors as age, degree of obesity, etc., can be matched out.

Why is abdominal obesity associated with obesity complications? Several investigations have thus now given the result that abdominally located obesity is more dangerous than obesity with other location of the enlarged adipose tissue. This is all statistical evidence. The natural question then is, how this might be explained.

First, obviously a statistical association between an adipose-tissue location and obesity complications might not mean a causative relationship at all, they could both be consequences of a third factor. For example, recently reported endocrine differences between female and male type of obesities [ 5 ] might produce disease as well as regional accumulation of fat in abdominal regions.

Direct associations might, however, also be possible. It is tempting to associate the functional characteristics of abdominal adipocytes with the complications. The question then is, how can an enlarged fat depot of lipolytically sensitive adipocytes cause hyperinsulae- mia, diabetes mellitus, hypertriglyceridaemia and hypertension.

A enlarged fat depot with lively lipolysis produces large quantities of free fatty acids (FFA). If this depot, such as the subcutaneous abdominal depot, is empty- ing its FFA into systemic circulation then peripheral tissues would be exposed to large amounts of FFA. Randle et al. [6] have proposed that this might lead to deranged glucose metabolism in the periphery, sup- ported by recent studies by Deibert & De Fronzo [7], showing a decreased glucose flux to the periphery when circulating FFA are elevated with intravenous trigly-

ceride infusions with heparin, as measured with the glucose clamp technique.

The intra-abdominal fat depot empties its FFA into the portal vein. Excess FFA in the portal vein produces hypertriglyceridaemia [8]. Recent preliminary obser- vations suggest that increasing portal FFA in the in situ perfused rat interferes with insulin uptake in the liver [9]. If valid for the intact organism this would present the interesting possibility that an enlarged, lipolytically sensitive intra-abdominal fat depot would inhibit insulin uptake by the liver, produce peripheral hyperinsulinaemia, followed by a ‘down-regulation’ of insulin receptors and an insulin resistance. This in turn might be a first step towards the development of diabetes mellitus. In a longer, more hypothetical perspective, hypertension might be triggered via sodium retention caused by insulin effects on tubular reabsorption of sodium [ 101. Clearly, this possibility warrants further examination.

Prospective epidemiological studies The apparent lack of association between obesity and ischaemic heart disease (IHD) has been puzzling, particularly since a number of IHD risk factors are strongly associated with obesity such as hypertension, hyperinsulinaemia, hypertriglyceridaemia and dia- betes mellitus. When such associations have been found, a long ‘incubation time’ seems to have been required.

An example of such lack of association is the study by Larsson [ 1 11, examining longitudinally middle-aged men for about 12 years, finding that the obesity-asso- ciated complications were risk factors for IHD. Obes- ity itself was not, however. Reexamining this study, and including regional measurements of obesity reveals now, however, that the waist/hip circumference ratio (which fortunately was registered at the start of the examination) is indeed associated with IHD. Taking measurements of total body fat into the statistical calculations shows the interesting fact that the men with little body fat, but located in the abdominal area, were those with highest risk for IHD, while obese men, having their fat distributed evenly over the body were at less risk of developing IHD [ 121.

Similar results have also recently been found inde- pendently in another population study of men [13]. In addition, when women are examined the association seems even clearer [ 141.

Three independent longitudinal studies have thus recently found that the risk for IHD is elevated with abdominal location of adipose-tissue excess. Retros- pectively, it seems likely that the lack of association between obesity and IHD in previous examinations might have been due to statistical ‘dilution’ effects, the increased risk is found only in a subpopulation of obese subjects.

Future directions Evidence from various sources thus point in the same direction, as both experimental, transsectional and

EDITORIAL 241

longitudinal observations indicate that abdominal obesity is dangerous. This seems to provide enough basis for the practical, clinical handling of obesity. Clearly, obesity located in the abdominal region should be examined more liberally for complicating disorders, and treated early. It seems more rewarding to treat this kind of obesity [ 151. These findings should also have the consequence that obese men should be treated more often than obese women; at present it is probably the opposite. It is possible that more refined measurements of the abdominal fat mass might in- crease the possibilities for a correct and early diagnosis of abdominal obesity, and computerized tomography might be helpful here (L. Sjostrom, personal communi- cation). For the moment, however, circumference measurements seem adequate. Waist circumference is simply made at the level of the umbilicus and hip circumference over the widest part of the gluteal area. In men, a ratio here above 1 . k in other words, when the belly starts to be wider than the hips-indicates that the risk is increasing very rapidly not only for IHD but also cerebrovascular disease. The corresponding value for women is about 0.8. These are figures derived from middle-aged Swedish populations, and their usefulness for other populations are not known. They might, however, perhaps serve as rough rule of thumb.

PER BJORNTORP Department of Medicine I , Sahlgren 's Hospital, University of Goteborg, Sweden.

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