Metabolic implications of body fat distribution.

Per Bjomtorp, MD, PhD

Metabolic Implications of Body Fat Distribution

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 effects on adipose lipolysis and therefore amplify lipolytic stimulation; FFA, cortisol, and testosterone thus nave 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, N I D D M , 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 From the Department of Medicine I, University of Goteborg, Sahlgren's Hospital, Goteborg, Sweden. Address correspondence and reprint requests to Per Bjorntorp, MD, PhD, Department of Medicine I, Sahlgren's Hospital, S-41345 Goteborg, Sweden.

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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. Diabetes Care 14:1132-43,1991

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on-insulin-dependent diabetes mellitus (NIDDM) is considered to develop from a combination of a relative insulin insensitivity (insulin resistance) precipitating an insufficiency of insulin production from the pancreatic (3-cells. It is also believed that NIDDM is a disease with polygenic origin, mainly localized to the insulin-producing genes, although there is evidence suggesting an involvement of genetic factors in the development of insulin resistance. However, it seems probable that environmental factors are of major dominating importance in the development of insulin resistance. Although little progress seems to have been made regarding defining the polygenic defects of insulin secretion, several factors have been identified that cause insulin resistance. Obesity is clearly one, and many patients with NIDDM are also obese. Previous research has shown that the insulin resistance associated with obesity is clearly more pronounced in subjects with centrally localized obesity. Indeed, some studies have defined intra-abdominal visceral fat masses to show the strongest correlations to insulin resistance masses (1). There is evidence that suggests the specific fat depots that are drained by the portal vein (mesenteric and omental adipose tissues) are important for

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this association. This evidence consists of strong statistical correlations between the mass and metabolic functions of portal adipose tissue and systemic insulin resistance, although such associations are considerably weaker or absent with subcutaneous abdominal or intra-abdominal retroperitoneal adipose tissues (2). In addition to this cross-sectional evidence, central obesity, measured as the waist-hip circumference ratio (WHR) in epidemiological studies, is a strong independent risk factor for the development of NIDDM in both men and women. Generalized obesity, measured as body mass index (BMI; kg/m2), seems to amplify this risk (3,4). Because WHR and visceral fat mass are highly correlated and both closely associated with insulin resistance, it seems likely that the risk subcompartment of the WHR is in fact the visceral fat mass. A study that used computerized tomography scanning showed that visceral fat mass constitutes the risk factor in question in Japanese on the West Coast of the United States (5). It then becomes important to try to understand how visceral fat accumulation is associated with insulin resistance. This might occur in a cause-effect relationship or in a parallel, coincidental way. There is evidence for both alternatives. First, we look into the descriptive evidence linking visceral obesity with factors that are known to produce insulin resistance.

FRE£ FATTY ACIDS (FFAs) The elevation of plasma FFA concentrations and turnover in generalized obesity has been established (6). There is evidence that this is most pronounced in abdominal obesity, where particularly nocturnal concentrations of FFA are elevated (7). Furthermore, fractional turnover rate has been reported to be increased (8). This is probably caused by a combination of several factors. First, there is an elevated sensitivity of enlarged obese adipocytes to lipolytic stimuli (9). In addition, subcutaneous abdominal adipocytes seem more sensitive than other fat cells, which drain their lipolytic products into the systemic circulation (10,11). The elevated concentrations of FFA in the systemic circulation may interfere with insulin sensitivity in muscles by the mechanisms described in the glucosefatty acid cycle (12). A confusing issue in this presumed chain of events is, however, that insulin resistance is associated with hyperinsulinemia, and insulin is a very efficient inhibitor of FFA mobilization. Because adipocytes in the subcutaneous adipose tissues are sensitive for such inhibition (13), the systemic elevations of FFA in the presence of high insulin concentrations are difficult to understand. Principally, under these conditions, the balance between the lipolytic driving force on one hand and inhibitory action of insulin on the other must be shifted to a dominance by the former. This might


be due to a strong lipolytic drive or a relative resistance to the antilipolytic effect of insulin in abdominal obesity. The latter alternative was suggested by Reaven (14), who examined obese subjects with impaired glucose tolerance. Although not characterized in terms of fat distribution, it may be assumed that most of these subjects were indeed abdominally obese, knowing the high prevalence of impaired glucose tolerance and insulin resistance associated with obesity. The visceral "portal" adipose tissues are of particular interest in this regard. These tissues are clearly more sensitive to lipolytic stimuli than subcutaneous depot fat, including the abdominal regions (15,16). This is further amplified in abdominally obese men and women (17). In addition, these cells are less sensitive to the inhibitory action of insulin on the lipolytic process (13), apparently associated with a low density of insulin receptors (18). The site of the insensitivity seems localized to the level of the phosphodiesterase regulating the cyclic AMP concentrations driving the lipolytic cascade (2). This information provides two interesting possibilities. First, FFA concentrations in systemic circulation in abdominal obesity might originate from the enlarged visceral depots. Although not measured directly, estimations from lipolytic rates in vitro from different adipose tissue regions, combined with the relative masses of subcutaneous and visceral adipose tissues, might reveal the quantitative relationships. Portal lipolytic sensitive fat mass constitutes —20% of total fat mass in abdominally obese men (2,19). The lipolytic sensitivity is higher in this than subcutaneous fat by two to four times (16,17). Allowing also for adipocyte enlargement, thus further elevating lipolytic sensitivity, a contribution of lipolysis in visceral depots of 2:50% of FFA in systemic circulation could be estimated, even if hepatic uptake and metabolism of FFA are accounted for. This fraction of FFA should be relatively insensitive to insulin inhibition because of the inherent characteristics of visceral adipocytes. With hyperinsulinemia, inhibiting mainly lipolysis of insulin-sensitive subcutaneous adipocytes, the fraction of systemic FFA originating in visceral fat may be further expanded. In vivo tests of the capacity of insulin to lower systemic FFA concentrations would show insulin resistance of this process (Fig. 1). This mechanism might explain the high systemic FFA concentrations in combination with hyperinsulinemia in abdominal obesity and may be followed by the peripheral insulin resistance in muscle (20-22). Another mechanism may occur because of elevated portal concentrations of FFA produced by the active visceral adipocytes in visceral obesity. As a result, the liver would be exposed to excess FFA concentrations, which would be followed by several consequences. In regard to NIDDM are the demonstrated effects of FFA to stimulate gluconeogenesis, depending on the oxidation of fatty acids in the liver. Furthermore, excess FFA probably also produces insulin resistance in the liver

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FAT DISTRIBUTION AND METABOLISM

NORMAL SUBC. A.T.

VISC. A.T. FFA INS FFA

VISCERAL OBESITY FFA INS FFA FIG. 1. Contribution of visceral adipose tissue to systemic free-fatty acid (FFA) concentrations with low and high insulin (INS) concentrations in normal and visceral obese condition. Subcutaneous adipose tissue (left) and visceral adipose tissue (right) contribute to systemic FFA concentrations in postabsorptive phase in normal condition (panel 7). In presence of higher concentrations of insulin, visceral adipose tissue lipolysis is less inhibited and therefore contributes larger fraction to systemic FFA concentrations (panel 2). In visceral obesity, contribution of visceral adipose tissue to FFA is higher (panel 3). In presence of insulin, fraction of FFA contributed by visceral adipose tissue is therefore still higher (panel 4).

Because these studies were performed with established hyperinsulinemia, which itself may cause such insulin resistance in both muscle and liver (28), interpretation is difficult. It is logical to assume, however, that the mechanisms would be triggering insulin resistance before hyperinsulinemia is established, because the inherent lipolytic activity of visceral adipocytes would produce excess FFA as a primary event once visceral fat obesity is established. The lipolytic drive in abdominal obesity, which causes elevated circulating FFA, requires consideration. Although the visceral adipocytes are sensitive to lipolytic stimuli, they require these stimuli to produce FFA. The main stimulatory factor of lipolysis in humans is probably the sympathetic nervous system (9). Studies from our laboratory showed circulatory phenomena associated with abdominal obesity that probably result from increased activity in the sympathetic nervous system. The phenomena include increases in blood pressure, heart rate, and cardiac output (P. Pettersson, J. Wikstrand, P.B., unpublished observations). This is the typical precursor to primary hypertension in humans and may be caused by central arousal of the sympathetic nervous system, because it embraces several separate peripheral sympathetic branches (29,30). A similar mechanism might be at work in abdominal obesity, a condition closely associated with primary hypertension (31). The lipolytic drive of abdominal obesity may be an additional symptom of increased sympathetic nervous system activity (7,8). This type of central arousal is reminiscent of the defense reaction in experimental animals (32,33). Increased activity of the central sympathetic nervous system may thus be a factor causing elevated lipolytic activity in adipose tissue in abdominal obesity.

STEROID HORMONES (23). Finally, experiments suggest that FFA decreases hepatic clearance of portal insulin, which, like gluconeogenesis, is apparently dependent on fatty acid oxidation (24-27). Taken together, this evidence suggests that portal FFA has powerful effects on hepatic glucose output, which becomes insulin insensitive, and on systemic hyperinsulinemia, partly caused by the diminished hepatic clearance. These phenomena are early ingredients in the development of impaired glucose tolerance and NIDDM and have been demonstrated in abdominal obesity (21). If these derivations from available data on the importance of FFA derived from portal adipose tissues are correct, visceral fat lipolysis would be responsible for insulin resistance in the two major tissues causing systemic insulin resistance, i.e., muscle and liver. Both these tissues are insulin insensitive in abdominal obesity (21,22).

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The potential role of the adrenal corticosteroids and sex-steroid hormones in the pathogenesis of NIDDM has attracted surprisingly little attention. Work on the syndrome of abdominal obesity has revealed multiple perturbations of steroid-hormone concentrations and kinetics, which may be intimately involved in the pathogenesis of the insulin resistance of that condition and may lead to the development of N I D D M . Cortisol. The increased secretion of cortisol in obesity has been well established (34). It may be due to a primary increase in metabolic clearance rate in the periphery, leading to normal or low serum concentrations, and a subsequent inhibition of the negative feedback of corticotropin-releasing factor (CRF)-ACTH secretion (35). This chain of events then requires a primary increase of peripheral cortisol clearance. We examined this question in abdominal and peripheral obesity. The aberrations described in nonselected groups of obese subjects seem to be characteristic solely of abdominal obesity. When these subjects are examined


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under field conditions, they seem to excrete increased amounts of urinary cortisol, which is a consequence of elevated serum levels of free cortisol. This observation confirms previous findings of increased excretion of corticosteroid metabolites in android obesity (36). However, this is difficult to reconcile with a primary increase of cortisol metabolic clearance rate, leading to low serum cortisol concentrations. Other observations might explain the apparent controversy. Abdominal obese subjects show an increased responsiveness to stimulation of cortisol secretion. This was found by direct stimulation of the adrenal cortex by ACTH analogues and by physical and mental stress tests (P. Marin, unpublished observations). These studies suggest an increased sensitivity and preparedness of the CRF-ACTH-cortispl axis in abdominal obese subjects. The results of the stress tests suggest that this has a central origin. The situation then becomes complex, including signs of an increased metabolic clearance rate of cortisol combined with centrally induced sensitivity to stimuli increasing cortisol secretion. An increased peripheral clearance rate of cortisol is probably mediated via binding to the glucocorticoid receptor, which is present in glucocorticoid-responding tissues. A high peripheral density of this receptor would thus be followed by an increased cortisol metabolic clearance rate. The enlarged visceral adipose tissue in abdominal obesity could therefore be the site where this occurs, because this tissue seems to have a higher density of glucocorticoid receptors than other adipose tissues (37,38). In addition, this characteristic of visceral fat depots would consequently result in intensive exposure of adipocytes to cortisol in these regions. A high sensitivity of the CRF-ACTH-cortisol axis thus seems to be a characteristic of abdominal obesity, as reflected in sensitive responses to physical and mental stressors. A consequence might be occasional increases in secretion of cortisol under field conditions. This may occur under circumstances where such individuals are subjected to stressful stimuli in their environment, leading to increased cortisol production. The condition of abdominal obesity might then be associated with a relative functional hypercortisolism. The analogy with Cushing's syndrome is obvious: both are characterized by hypercortisolism, although of different degree and causes, and both have visceral fat accumulation. In addition, they have several clinical sequelae in common, including insulin resistance and risk for the development of NIDDM, hypertension, and hyperlipidemia. An important question is the origin of the relative functional hypercortisolism of abdominal obesity. Increased cortisol secretion through central mechanisms in response to particular types of mental stressors is a well-known phenomenon from studies in experimental animals (32,33). This type of neuroendocrine response to stress is considered to originate from hypothalamic arousal and expresses itself as a defeat reaction and an increased secretion of cortisol. The defeat or submissive reaction to stress is also followed by a decreased secretion of sex

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steroid hormones (32), probably due to inhibition by CRF of gonadotropin secretions (39). Low sex-steroid-hormone secretion is also found in abdominal obese men and women (40,41) and may thus be a part of the CRFACTH-cortisol hyperactivity of central origin. Abdominal obesity is probably characterized by several signs of hypothalamic arousal in the central sympathetic nervous system. There is also evidence for arousal along the CRF-ACTH-cortisol axis, with inhibiting consequences for the secretion of gonadotropins. These observations suggest that visceral accumulation of body fat is associated with hypothalamic arousal of the types described as the defense and the defeat reactions (32,33). The accompanying endocrine aberrations may not only explain several of the metabolic and circulatory sequelae of the syndrome in question but may also provide an explanation for the accumulation of visceral fat. The decreased insulin sensitivity and glucose tolerance caused by cortisol is well established. Hepatic gluconeogenesis is increased at the tissue level (42). Muscle tissue rapidly becomes insulin resistant (an effect exerted most pronounced on the insulin-sensitive red muscle fibers, where glycogen synthesis and glycogen synthase becomes insulin resistant; 43), whereas direct effects on the insulin receptor have not been demonstrated (44). There are also effects of cortisol on adipose tissue. Because glucose uptake in adipose tissue does not seem to contribute much directly to total glucose homeostasis (45), the effects of cortisol on other pathways in adipocyte metabolism might be more significant. Cortisol has effects on both lipid accumulation and mobilization. Lipoprotein lipase (LPL) activity, the main enzymatic controller of triglyceride uptake, is increased (46). Furthermore, there is a permissive effect of glucocorticoids on lipid mobilization stimulated by catecholamines (47). It is not clear, however, how this is exerted, particularly in human adipose tissue. An interesting study suggests that cortisol inhibits the antilipolytic effect of insulin in human adipocytes (48). This may be particularly pronounced in visceral fat, which contains a high density of the glucocorticoid receptor, and may provide a background for the observed insulin insensitivity of these adipocytes to the antilipolytic response of insulin. Sex-steroid hormones. Information on the effects of sexsteroid hormones on energy metabolism regulation is surprisingly scarce. There are reports indicating that administration of excess androgenic hormones, to men and women, is followed by insulin resistance (49,50), suggesting that the association between hyperandrogenicity and hyperinsulinemia in women in the polycystic ovary syndrome may be caused by the increased concentrations of free testosterone (51). There is also evidence for the reverse sequence, i.e., insulin causing hyperandrogenism in women (52). We have, however, shown that administration of moderate doses of testosterone to female rats is followed by marked insulin resistance, localized to muscle, that changes morphology toward less insulin-sensitive red muscle fibers and capillaries (53). The effects are already seen after 1-2 days of testosterone exposure and, similar to the effects of

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SHBG

WHR (BMI)

f

INSULIN

ABDOMINAL OBESITY

HYPERANDROGENISM

INSULIN RESISTANCE JNIDDM 1

t GENETICS FIG. 2. Risk factors for non-insulin-dependent diabetes mellitus (NIDDM) in women (top) and attempt to understand cause-effect relationships between these factors. SHBG, sex-hormone-binding globulin; WHR, waist-hip circumference ratio; BMI, body mass index.

cortisol, seem to be localized mainly to the insulin sensitivity of glycogen synthesis-glycogen synthase (43,54). Furthermore, male rats show the same reaction to excess testosterone administration. Interestingly, castration is also followed by marked insulin resistance that is abolished by testosterone substitution (55). The latter observation might be relevant to a relationship between relative hypogonadism in men and insulin resistance (56). The assumption of a cause-effect relationship is strongly supported by the finding that testosterone given to hypogonadal men seems to improve their insulin sensitivity (57). A relative hypogonadism, characteristic of abdominally obese men, may thus amplify or at least partly cause their insulin resistance. The role of female sex hormones is not known. However, several laboratories found that the increase in central fat mass in women is followed by a relative hyperandrogenicity (40,58,59). The origin and cause of this abnormality are not known. Such hyperandrogenism may be a cause of the insulin resistance in these women, as suggested by experiments in rats (43,54). The potential significance of hyperandrogenicity in women in relation to the development of NIDDM is illustrated by a prospective epidemiological study (59). A low level of sex-hormone-binding globulin (SHBG) was a strong independent predictor for the development of NIDDM in women. It was closely associated with plasma insulin concentrations and central obesity, as measured by the WHR. These three risk factors were the primary predictors for NIDDM development and could not be dissociated with statistical methods. From a mechanistic view, hyperandrogenicity, as mir-

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rored by a low SHBG, and visceral obesity may be triggering factors for insulin resistance and then NIDDM (Fig. 2). This suggested chain of events is amenable to further testing and is of interest because it explains a large fraction of the exogenous factors leading to NIDDM in women. The effects of androgens on the hepatic handling of glucose and insulin are less studied. Studies of insulin binding to hepatocytes do not suggest any important effect in this regard (J. Svedberg, P.B., unpublished observations), but this problem needs further elucidation. Although insulin resistance in muscle is a prominent feature in nonobese hyperandrogenic women, the inhibition by insulin of hepatic glucose production may not be decreased (60). These observations indicate that the insulin resistance associated with hyperandrogenicity in women is mainly localized to muscle tissue. Androgens clearly have effects on adipose tissue metabolism, including enhancement of the lipolytic sensitivity by expression of lipolytic p-adrenergic receptors via an androgen receptor, which is positively autoregulated by testosterone (61-63). Furthermore, LPL is lower after testosterone treatment of men, with regional localization of the effect to abdominal adipose tissue (64). Female sex hormones also have effects on adipose tissue distribution and metabolism. This is illustrated by differences between women before and after menopause and after administration of female sex hormones to menopausal women (65). The main characteristics of adipose tissue metabolism in the presence of female sex hormones are a higher LPL activity and a lower lipolytic response, found mainly in the subcutaneous femoral region (65). There might also be a lower lipolytic activity in visceral adipocytes of younger women (16). In addition, men treated with estrogens for prostate carcinoma show a specific increase in gluteal adipocyte size (66). The mechanism for these phenomena remains unclear, however. It is improbable that the metabolic effects are mediated via cellular receptors of these steroid hormones in adipose tissue because of the apparent absence of these receptors in women in physiologically significant concentrations (38). Furthermore, no direct effects of female sex-steroid hormones can be demonstrated on human adipose tissue in culture (M. Ottosson, P.B., unpublished observations). Other explanations are necessary to understand the apparent effects of female sex-steroid hormones on adipose tissue. One alternative is an interaction between progesterone and the glucocorticoid receptor (37,67). With high progesterone concentrations, such as those during the luteal phase of the menstrual cycle or during pregnancy, a protection from cortisol effects might be exerted. It is, however, difficult to understand how such a competition over the glucocorticoid receptor would cause the adipose tissue metabolic characteristics. For example, cortisol causes LPL expression over this receptor, and LPL is elevated in the femoral region in the presence of progesterone. Other mechanisms may explain the effects of female

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sex hormones on adipocyte metabolism. There is considerable evidence for indirect effects of sex-steroid hormones on growth and metabolism of several tissues. These effects are mediated by indirect mechanisms via the regulation of growth hormone secretion. Growth hormone is secreted in a specific male and female pattern (68). The male secretion consists of peaks with low concentrations between, whereas females secrete growth hormone more evenly throughout the day. This secretion pattern is probably mediated via influence of sex-steroid hormones (69). Adipose tissue LPL activity might be regulated via such mechanisms, and this phenomenon varies in different adipose regions (K. Wikman, M. Ottosson, P.B., unpublished observations). This might provide an explanation for the effects of adipose tissue metabolism of female sex-steroid hormones. Taken together, there is considerable evidence that steroid hormones, particularly cortisol and androgens, exert an important regulation of insulin sensitivity in muscle and liver. This is particularly the case for increased cortisol secretion in both sexes. For androgens, a sex-specific increase is apparently also followed by insulin resistance, and more relevant to the clinical situation, this seems to be the case with low androgen secretion in men. The role of female sex-steroid hormones in this regard is less studied. Direct effects on glucose homeostasis and insulin resistance of steroid-hormone actions on adipose tissue metabolism seem unlikely, considering the probably insignificant quantitative role of adipose tissue glucose uptake for the regulation of total-body glucose homeostasis and insulin sensitivity (48). Steroid-hormone effects on adipose tissue may, however, contribute to regulation of total-body insulin sensitivity by indirect mechanisms. These may include effects on the mobilization of FFA, which is regulated by permissive effects on catecholamine-induced lipolysis by both cortisol and testosterone. Furthermore, cortisol might have additional importance by inhibiting the antilipolytic balance exerted by insulin. The key role of cortisol is therefore apparent, i.e., exerting effects to cause insulin resistance in both muscle and liver and increased hepatic gluconeogenesis. In addition, cortisol amplifies these primary metabolic events by permitting higher lipolytic responsiveness and less inhibition by insulin of this process, allowing a high outflux of FFA from adipose tissue. The role of androgens may contribute to these phenomena in muscle when present in excess in both sexes and then may exert a permissive effect for adipose tissue lipolysis and FFA efflux. Hypogonadism in men would presumably also increase muscular insulin resistance. The integrated role, if any, of female sex-steroid hormones is not sufficiently known. In summary, cortisol plays a central role in the adaptation of the organism toward a prediabetic metabolism, a well-known clinical observation seen in conditions with glucocorticoid hormone excess. The role of androgens is probably most important in hyperandrogenic conditions in women and in relative hypogonadism in men—both prevalent clinical conditions. Relative hypercortisolism in


INSULIN RESISTANCE

HEPATIC GLUCONEOGENESIS

LIPOLYSIS IN ADIPOSE TISSUE

FFA

FFA

CORTISOL

CORTISOL

CORTISOL

TESTOSTERONE

TESTOSTERONE

(IN MEN, J) FIG. 3. Enhancing effects of free fatty acids (FFAs), cortisol, and testosterone on insulin resistance in muscle (and/or liver), hepatic gluconeogenesis, and "permissive" effects of adipose tissue lipolysis, promoting FFA release. These actions would increase insulin resistance and hepatic gluconeogenesis, established precursors to non-insulin-dependent diabetes mellitus. combination with hyperandrogenism in women and hypogonadism in men are than expected to be conditions prone to cause NIDDM. These endocrine aberrations are typical of women and men with visceral fat accumulation and raise the question of a potential cause-effect relationship. The effects of FFA and steroid hormones on the promotion of a prediabetic state are summarized in Fig. 3.

RELATIONSHIP BETWEEN ENDOCRINE ABERRATIONS OF ABDOMINAL OBESITY AND REGULATION OF VISCERAL FAT MASS As reviewed above, abdominal accumulation of body fat is associated with a combined endocrine aberration. This consists of a functional hyperactivity of the CRF-ACTH-cortisol axis combined with hyperandrogenism in women and hypogonadism in men. There is also evidence of a decreased secretion of sex-steroid hormones in women, probably due to an aberration of gonadotropin hormone release, resulting in deficient progesterone secretion. Estrogen secretion is apparently not affected. The perturbations in the CRF-ACTH axis might actually cause the inhibition in gonadotropin secretion, because CRF has been shown to inhibit gonadotropin-releasing hormone secretion. Therefore in both sexes, there seems to be a combination of relative hypercortisolism and a decrease in sex-hormone secretions, with low testosterone in men and low progesterone in women. These aberrations may be causally related via a primary increase in CRF secretion. The cause of hyperandrogenism in women with abdominal obesity is, however, not known. The combination of increased cortisol and low sexsteroid-hormone concentrations in abdominal obesity has interesting implications for a potential cause-effect relationship. This field has recently been reviewed in detail (46). The key observation here is a high density of glucocorticoid receptors in visceral adipose tissue, which directs cortisol effects to that depot fat region. The consequence of hypercortisolemia is cortisol effects on visceral fat. Although the mechanisms are not clear, the net result is best illustrated by the marked

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accumulation of visceral fat in Cushing's syndrome. Total reversibility of this phenomenon after successful treatment of this syndrome further indicates the causeeffect relationship between hypercortisolemia and visceral fat accumulation (70). Expression of LPL activity via the glucocorticoid receptor is probably a key event (46). The effects of cortisol on the lipid mobilization machinery are not clear but might involve a decrease in the net capacity of lipolysis to release FFA, because lipolysis in abdominal subcutaneous fat is diminished in Cushing's syndrome (71). Both androgens and progesterone might counteract these effects of cortisol. Androgens decrease LPL activity and increase lipolysis via a specific receptor (46,61-63). Both mechanisms decrease fat accumulation. In addition, testosterone seems to upregulate the density of the androgen receptor, which could amplify these testosterone effects (63). Hypogonadism in men would thus add to the net accumulation of visceral fat by cortisol and has been observed (56). The effects of progesterone are less clear. Progesterone might protect visceral adipose tissue from cortisol effects by interactions with the glucocorticoid receptor (37,67). Because of the higher density of this receptor in visceral fat than in other adipose tissues, the protective phenomenon might be more pronounced (37,38). Although these mechanisms remain speculative, there is considerable circumstantial clinical evidence to support the validity of the net effect of the interactions between corticosteroid and sex-steroid hormones on visceral adipose tissue. The important factor is therefore the balance between cortisol effects on one hand and testosterone (men) and progesterone (women) on the other. Abdominal localization of a large proportion of body fat mass has been observed in several conditions with such an imbalance. These include Cushing's syndrome (high cortisol secretion, low sex-hormone secretion), smoking, and excess alcohol intake with the same endocrine aberrations, although to a more limited degree. Aging in men and women is also followed by such a dysbalance, with a normal cortisol secretion but lower sex-hormone secretion. The negative relationship between testosterone and visceral fat mass in men may be important from this aspect, as well as the empirical observation of an increased preponderance of the abdomen in aging men. Women increase their WHR with menopause, when progesterone secretion ceases. The condition polycystic ovary syndrome, where an increased WHR is an accompanying phenomenon to deranged sex-hormone secretion, may be added to the list. Of particular importance for the causal relationship between the combined endocrine aberrations and visceral fat accumulation are the results of intervention studies to correct and improve endocrine imbalance. These include treatment of Cushing's syndrome, sex-hormone substitution for aging men and women, smoking cessation,

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and hormonal treatment of the polycystic ovary syndrome, which are followed by a total or partial correction of visceral fat accumulation (46).

CONSEQUENCES OF VISCERAL FAT ACCUMULATION There are also possibilities that visceral fat accumulation may further derange energy metabolism. As reviewed above, visceral fat has a higher turnover than other adipose tissue regions. The lipolytic potential and the propensity for FFA release, probably amplified by the low effectiveness of insulin to inhibit lipolysis in these adipose tissues are considerable. Taken together, this would result in increased concentrations of portal FFA, particularly on enlargement of visceral adipose tissues. Furthermore, with a putative increase in the activity of the sympathetic nervous system, the main regulator of lipolytic activity in human portal FFA would frequently be considerably elevated. Increased portal FFA has not been measured in humans with abdominal obesity. In addition to the considerations derived from results of measurements of lipolysis in vitro in combination with mass and adipose cellularity at visceral adipose tissue, evidence strongly points to the possibility that portal FFA flux is elevated in abdominal obesity. First, measurements in vivo of triglyceride uptake in adipose tissue in humans show 50-100% higher values in visceral than other fat depots (2). In the steady state, this means FFA release of the same proportional elevation. Furthermore, studies have shown that, on energy intake restriction, visceral fat mass decreases more rapidly than other tissues in humans (72). Taken together, this evidence suggests that portal FFA concentrations are elevated in abdominal obesity. Portal FFA has several effects on hepatic metabolism. These include an increased drive of gluconeogenesis, which becomes insulin resistant (23). Furthermore, insulin clearance becomes considerably diminished, an effect apparently dependent on fatty acid oxidation (24-27), parallel to the effects on gluconeogenesis. Portal FFA is probably the rate-limiting factor for the assembly and secretion of very-low-density lipoproteins (73). The expected results of these interferences by portal FFA on hepatic metabolism are increased hepatic gluconeogenesis and peripheral hyperinsulinemia. These are important precursors to NIDDM. In addition, this suggested mechanism might explain the hyperlipidemia frequently associated with NIDDM. Finally, several lines of evidence suggest a relationship between peripheral hyperinsulinemia and hypertension (74,75). The possibility that this mechanism may also be of importance for the pathogenesis of primary hypertension must, however, be considered hypothetical. The suggested interactions between visceral obesity and hepatic metabolism seem to explain most of the phenomena recently called the metabolic syndrome,


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from which both NIDDM and cardiovascular disease may be recruited (14). Visceral obesity may be an important part of this syndrome. Attempts to estimate the quantitative significance of this relationship in the population have been made but were hampered because limits for the presence of the various components of the metabolic syndrome are arbitrary. In women selected at random, the distribution of values of fasting insulin, blood pressure, and triglycerides above 2SD in the total population was analyzed in relation to quintiles of WHR. It was found that —50% were localized in the fifth quintile of WHR (L. Lapidus and P.B., unpublished observations). This shows the impact of abdominal obesity in the metabolic syndrome and that there is a large group in which the metabolic perturbations, including blood pressure, may be present without abdominal obesity.

INTEGRATION OF POTENTIAL PATHOGENETIC FACTORS FOR INSULIN RESISTANCE IN PREDIABETIC CONDITION The summary of available data focuses on putative factors, known to produce insulin resistance, and their presence in abdominal obesity, an important clinical precursor to NIDDM. Briefly, it is possible that a primary endocrine aberration associated with abdominal obesity may be responsible for the generation of powerful triggers of insulin resistance. In addition, the abdominal depot fat accumulation may actually result from this endocrine disturbance. Finally, visceral fat accumulation, the essential part of abdominal obesity, may cause the metabolic syndrome and thus contribute to insulin resistance. This chain of events is illustrated in Fig. 4. One interesting question is the extent of contribution of these two mechanisms for the resulting insulin resistance. One way to approach this question is to intervene in different parts of the chain of events. This has been done by correcting the hypogonadism of men by administration of testosterone. Several such studies have been performed with increasing duration for safety reasons (57,64). It was found that early signs of decreased insulin resistance were noted already after a few weeks of testosterone administration, before any signs of diminished visceral or total fat mass. This observation suggests that endocrine aberrations may be of more importance than visceral fat accumulation, at least for insulin resistance. Such observations do not, however, exclude a role for visceral fat depots in the contribution to insulin resistance and, particularly, to the metabolic syndrome. I believe that both mechanisms may be of importance. Further intervention studies directed toward other points of the endocrine aberration and specifically toward portal FFA efflux are important to elucidate this point. Unfortunately, there does not seem to be a means to perform the latter intervention.


NIDDM HYPERANDR0GENICITY HYPERTENSION-*- INSULIN

GLUCO NEOGENESIS F F A

INSULIN

FIG. 4. Effects of portal free fatty acids (FFAs) on hepatic metabolism. FFA drives synthesis of very-low-density lipoprotein (VLDL) and gluconeogenesis and inhibits hepatic clearance of insulin. When exaggerated, this may lead to increasing concentrations of VLDL, low-density lipoprotein (LDL), apolipoprotein B-100 (apoB-100), glucose, insulin, and perhaps secondarily, hypertension. These are main risk factors for cardiovascular disease (CVD) and non-insulin-dependent diabetes mellitus (NIDDM). By these mechanisms, visceral fat may generate risk factors for diseases mentioned via portal FFA and thus provide explanation for "metabolic syndrome." From Bjorntorp (74), by permission of the American Heart Association, Inc.

ORIGIN OF ENDOCRINE ABERRATION The endocrine aberration in abdominal obesity seems to be the central background of the metabolic and disease companions of this syndrome. The cause of this disturbance therefore becomes a problem of considerable importance. The endocrine aberration of central obesity is complex and comprises several components. These include 7) an increase in central sympathetic nervous system activity and 2) a cluster of steroid-hormone secretion disturbances. The simplest way to regard the latter is to consider it a primary increase in CRF secretion followed by a secondary inhibition of gonadotropin. Arousal along these two axes is elicited through neuroendocrine mechanisms at the hypothalamic level of the central nervous system. These neuroendocrine responses correspond to different reactions to stress, i.e., the so-called defense and defeat reactions. These phenomena are well established in animal research (32,33). When exposed to various socioenvironmental

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pressures, various types of reactions occur, depending on the outcome of attempts to regain control. The defense reaction occurs via the sympathetic pathways to help gain control by increasing the readiness of circulatory factors and to mobilize substrate needed to meet the challenges. When the individual loses control and ends up in a defeated, submissive, helpless situation, the activity along the CRF-ACTHcortisol axis increases, and sex-hormone secretion diminishes (32,33). Note that this type of reaction has been shown to be followed by centralization of adipose tissue and metabolic aberrations, including signs of insulin resistance (78). The regions of the brain from which these reactions originate are similar in primitive mammals and humans, perhaps due to their direct coupling to survival mechanisms (33). Reactions of similar types to those described in animal experiments have also been observed in humans. They are, however, covered by various compensatory counterreactions and therefore are difficult to discover and probably not as easily identified as in standardized animal experiments (33,78). A defense type of reaction has clearly been demonstrated in early stages of primary hypertension with circulatory arousal and increased secretion of catecholamines (33,79,80). A defined clinical counterpart to the defeat reaction has not been described. The endocrine and metabolic symptoms after abdominal obesity are those of a neuroendocrine response to an arousal syndrome, analogous to a mixture of the defense and defeat reactions to sociobiological stress in animal experiments. The question is whether there is evidence suggesting the presence of such stressors in subjects with abdominal preponderance of body fat and with the typical endocrine abnormalities that suggest neuroendocrine responses to such challenges. Population studies of both men and women have shown that an elevated WHR is associated with low social class, poor education, low income, and physical types of employment among men. It is also associated with long and frequent periods of sick leave, often due to psychosomatic and psychiatric diseases, including depression. Use of tobacco, alcohol, and psychotropic drugs is frequent (81,82). These psychosocial and socioeconomic conditions may be followed by hypothalamic arousal syndrome and a defense reaction, leading to a situation that is "out of control" and resulting in a defeat reaction. This would be followed by the typical neuroendocrine and endocrine responses also observed in subjects with elevated WHR and accumulation of visceral fat. Based on the evidence reviewed above, this neuroendocrine response may result in both the typical body fat distribution and its typically associated metabolic associations (Fig. 5). Psychosocial pressures would therefore be a precursor to the development of NIDDM. There is little evidence for this in the literature, but the question has not

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PERCEIVED STIMULUS COPING REACTION

/ THREAT OF CONTROL CON

LOSS OF CONTROL

I FIGHT - FL,IGHT|

I DEPRESSION I

IDEFENS • REACTION 1

I DEFEAT REACTION |

CENTRAL SYMPATHETIC AROUSAL

1

[STRIVING | ADRENAL INE \

I

I

|LOSS OF CONTROL |

I CONTROL I NOR ADRENAL INE t

FFAf

FFAt

CRF • ACTHf

GLYCOGENOLYSISt GLUCOCORTICOIDS •-•GLUCOCORTICOIDS f OVULATION \ TESTOSTERONEt TESTOSTERONE\ [HYPERTENSIONI

METABOLIC ABBERATIONS VISCERAL FAT ACCUMULATION

DISEASE

FIG. 5. Coping reactions to perceived stimulus. Threat of control leads to fight-flight or defense reaction or to situation with loss of control with depressive defeat reaction. Defense reaction might lead to control via phase of striving with its associated circulatory adaptations and mobilization of energy substrates via arousal of sympathetic nervous system. This pattern has been considered a precursor stage to primary hypertension (30,33). Defeat reaction is followed by arousal via the corticotropinreleasing factor (CRF)- ACTH-cortisol axis, with inhibition of gonadotropic secretions (39). This might lead to metabolic aberrations and visceral fat accumulation. Reaction pattern may shift from one type to another due to perceived stimulus, varying between and among individuals. FFA, free fatty acid. Modified from Henry and Grimm (81).

been rigorously tested. However, physical stressors such as infectious disease or trauma often are triggers for diabetes. Furthermore, it is also known that depressive states are followed by a worsening of diabetes control. These conditions are often followed by increased cortisol production. Therefore, repeated psychological pressures, acute or chronic, may provide a prediabetic condition with insulin resistance. Controlled prospective studies are needed to gain more information on this question.

ACKNOWLEDGMENTS This work was supported by the Swedish Medical Research Council (Project B92-19X-251).

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