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Background: Leptin is a peptide secreted by white adipose tissue which has been shown to have a major influence on body weight regulation, while animal studies have revealed widespread interconnections between leptin and other endocrine systems, especially with insulin. However, its acute regulation has been little studied in the human. We have therefore investigated the effect of a 1000 kcal meal and fasting on the levels of leptin, insulin and cortisol, in both normal and obese subjects., Subjects and Design: We have studied the effect of food and fasting on circulating leptin levels in 20 subjects of normal body mass index (BMI range 18-25) and in a group of 12 moderately-severely obese subjects (BMI range 34-61). We also studied the effect of food and fasting in a patient both before and after the successful removal of a pancreatic insulinoma as a model of excess insulin secretion., Results: Mean leptin levels were significantly higher in the obese than in the lean group (42.7 +/- 3.41 vs 5.35 +/- 1.55 micrograms/l, mean +/- SEM; P < 0.001), and showed a positive correlation with body mass index (r = +0.71; P < 0.001). Frequent (every 20 minutes) sampling for 3 hours after food did not show any acute changes in circulating leptin levels. On the fasting day we observed a small but significant fall in circulating leptin levels in the last 4 hours of a 20-hour fast in our subjects as a group (92 +/- 0.03% of basal, P = 0.03); however, in the lean subjects the fall was greater (86 +/- 0.04% of basal, P = 0.02) than in the obese, where it did not reach statistical significance (96 +/- 0.05% of basal). Pre-meal and peak insulin levels showed a positive correlation with circulating mean leptin levels (r = +0.65; P < 0.001 and r = +0.78; P < 0.001, respectively) in all subjects, while pre-meal and peak serum cortisol levels showed an inverse relation with leptin levels (r = -0.53; P = 0.002 and r = -0.41; P = 0.02, respectively); this effect was independent of BMI in the obese subjects. In the patient with the insulinoma the markedly elevated insulin and leptin levels measured before the operation returned to normal after removal of the tumour, in accord with reports of experimental animal data that long-term insulin excess per se is associated with increased circulating leptin concentrations., Conclusion: Leptin is a robust indicator of BMI and insulin levels, both basal and stimulated, but does not change acutely following food. Fasting causes a proportionately greater decline in leptin levels in lean subjects than in obese subjects. Circulating leptin is inversely correlated with the activity of the hypothalamo-pituitary-adrenal axis: whether this is a direct influence of leptin on hypothalamo-pituitary-adrenal activity, or whether both are indirect indicators of body fat stores, requires further investigation.

Background: It has been previously shown that food intake elevates circulating ACTH and cortisol levels, but no report has been published regarding the changes in circulating dehydroepiandrosterone (DHEA). DHEA was originally described as a weak androgen, but more recently it has been associated with a wide range of metabolic functions. In addition, previous studies have described a hyper-responsive hypothalamo-pituitary-adrenal axis in obese subjects in response to various stimuli, but the specific response to food has not been studied., Subjects and Design: We studied the effect of food on the hypothalamo-pituitary-adrenal axis in 20 subjects of normal body mass index (BMI range 18-25) and also in a group of 12 obese subjects (BMI range 34-61). Levels of glucose, insulin, ACTH, cortisol and dehydroepiandrosterone were measured every 20 minutes., Results: A small rise in DHEA accompanies the rise in circulating ACTH and cortisol in response to food in both lean and obese subjects, but DHEA rose independently of cortisol and ACTH on the fasting day. In the obese subjects, food induced a significantly greater change in serum cortisol (peak cortisol rise (mean +/- SEM); normal-weight group, 169 +/- 14%; obese group, 294 +/- 23%) and in the cortisol/DHEA ratio (area under the curve; normal-weight group, 202 +/- 15%; obese group, 292 +/- 29%) than in the normal-weight subjects. This difference was particularly notable in those with central-type obesity (waist/hip ratio > 0.80). A group of the normal, jean female subjects showed no cortisol rise after food intake., Conclusion: Our results suggest that DHEA may vary independently of circulating cortisol, and that the cortisol response to food is enhanced in obese subjects, particularly in those with central obesity. We speculate that there may be a caused connection between the cortisol response to food in normal subjects, and the subsequent distribution of fat if such subjects overeat sufficiently to become obese.

This review highlights the considerable advances in the understanding of the inheritance of fatness and the possible genetic mechanisms. The investigation of animal models confirms the fundamental importance of genes in determining fatness and demonstrates a genetic link between adipocyte function, derangements of steroid metabolism, insulin secretion and hypothalamic regulation. The heterogeneous nature of human obesity makes it unwise to extrapolate directly from the findings in animals but these findings do provide important clues to the situation in man. It is crucial that advances in the knowledge of genes involved in human obesity are paralleled by an understanding of gene-gene interactions and the influence of environmental factors. The rapidly increasing prevalence of obesity in society underlines the paramount influence of the environment.

Objective: The purpose of this study was to determine whether alterations in the hypothalamo-pituitary-adrenal axis and arginine vasopressin secretion, which have been associated with animal obesity, also occur in man., Design: Cross-sectional analysis of extremely obese women and normal weight controls., Patients: Thirty-three obese premenopausal, non-diabetic women (mean age 31 years, mean body mass index (BMI) 41), and 15 normal weight controls (mean age 24 years, mean BMI 22)., Measurements and Results: Arginine vasopressin (AVP), ACTH, beta-lipotrophin and cortisol responses to insulin-induced hypoglycaemia (0.2 units Actrapid/kg body weight for obese; 0.15 unit/kg for controls) were measured. The obese women were further characterized by anthropometric measurements (weight, body mass index, fat distribution) and indices of insulin secretion/resistance: fasting insulin, insulin secretion during 75-g oral glucose tolerance test area under curve, insulin-stimulated glucose disposal and an index of insulin resistance. No significant differences were found in the basal levels of ACTH, AVP, beta-lipotrophin or cortisol. An augmented peak beta-LPH (n = 16, P < 0.02, the difference of the mean 3.65, 95% confidence interval 1.33-10) and ACTH (n = 16, P = 0.05, the difference of the mean 2.12, 95% CI 1.0-4.5) response were found in obese as compared with normal weight controls. Both ACTH and AVP areas under the curve were similar in both groups studied. There was additionally a direct positive association between the integrated ACTH response (area under the curve) and the weight of the obese subjects (P < 0.05, r2 = 0.265). The cortisol response was negatively correlated with insulin-stimulated glucose disposal (P < 0.01, r2 = 0.23), but not with other indices of insulin secretion/resistance (fasting insulin, oral glucose tolerance test area under the curve, index of insulin resistance) or fat distribution. Comparable responses to hypoglycaemia were seen for AVP and cortisol. There was no correlation between the ACTH, AVP or cortisol responses., Conclusion: Obesity is associated with increased activity of the hypothalamo-pituitary-adrenal axis as supported by augmented ACTH and beta-lipotrophin secretion in response to insulin-induced hypoglycaemia and the positive association between the ACTH response and the body weight of obese women studied.

Objective: The aim was to investigate a possible relationship between measures of insulin secretion and glucose disposal and hypothalamic-pituitary function in extreme obesity., Design: A cross-sectional analysis of obese subjects attending the Obesity Clinic at the Royal London Hospital and normal weight volunteers was undertaken. Investigations were performed on separate occasions and in random order., Patients: The subjects were 34 extremely obese women, menstruating and with normal glucose tolerance (mean Body Mass Index, BMI = 42) and 15 normal weight female controls (mean BMI = 22)., Measurements: The following were measured: fasting insulin, relative insulin resistance calculated using fasting insulin and plasma glucose by the homeostatic model of assessment, insulin release during a 75-g oral glucose tolerance test (insulin area under the curve), steady-state plasma glucose level achieved during a simultaneous intravenous infusion of dextrose, insulin and somatostatin, and the prolactin and growth hormone (GH) responses to insulin-induced hypoglycaemia., Results: In the obese group an impaired prolactin response to hypoglycaemia (mean area under the curve obese 54 U/l min, controls 155 U/l min; P = 0.0001) was inversely correlated to fasting insulin, r2 = 0.142, P = 0.03; relative insulin resistance, r2 = 0.134, P = 0.03 and steady-state plasma glucose level, r2 = 0.345, P = 0.0004 whereas the impaired GH response (mean GH area under the curve obese 1.9 U/l min, controls 65.7 U/l min; P = 0.0001) was inversely correlated to steady-state plasma glucose level, r2 = 0.196, P = 0.01. Backward procedure for stepwise regression analysis confirmed the steady-state plasma glucose level to be the most important variable associated with the prolactin and growth hormone response among the remaining indices of insulin secretion/resistance., Conclusion: We conclude from these findings that hyperinsulinaemia in obesity is an important association with altered hypothalamic-pituitary function indicated by impaired prolactin and growth hormone secretion to insulin-induced hypoglycaemia.

Obesity may be characterized by abnormal sex steroid secretion and reduced sex hormone binding globulin (SHBG) which in turn is related to fat distribution and insulin secretion. Recent in-vitro and in-vivo evidence suggests that insulin is the common mechanism regulating the secretion of SHBG and insulin-like growth factor small binding protein (IGFBP-1). IGFBP-1 appears not only to be a carrier for insulin growth factors (IGFs) but also to play an active role in growth processes, independent of growth hormone secretion. We have examined the possible relationship between fasting insulin, SHBG, testosterone, IGF-1, IGFBP-1 and fat distribution in 25 extremely obese, menstruating women (mean weight 107 +/- 3 kg) with normal glucose tolerance. Fat distribution was assessed from measurements of the waist to hip ratio (W/H). The obese women showed an elevated fasting insulin (mean +/- SEM; 21 +/- 2 mumol/l), a normal IGF-1, but reduced IGFBP-1 (14.6 +/- 2 micrograms/l); in 15 women IGFBP-1 levels were undetectable by the present assay. In addition, SHBG levels were reduced in the obese women (24 +/- 2 nmol/l) but total testosterone values (1.9 +/- 0.1 nmol/l) were normal. The elevated fasting insulin levels were positively correlated with increasing upper segment obesity as expressed by a rising W/H ratio (P less than 0.01, r2 = 0.306) and inversely correlated with SHBG (P less than 0.01, r2 = 0.483). Similarly, reduced SHBG values showed an inverse correlation with increasing W/H ratio (P less than 0.001, r2 = 0.383). No correlation was found between IGFBP-1 and W/H ratio but a strong positive correlation was seen between IGFBP-1 and SHBG (P less than 0.001, r2 = 0.466). Furthermore, an equally significant inverse correlation was found between IGFBP-1 and insulin levels (P less than 0.001, r2 = 0.474).(ABSTRACT TRUNCATED AT 250 WORDS)

Human obesity shows clustering within families. The hypothesis for the presence of a major gene or genes acting in human obesity is supported by recent evidence from studies of obesity in adoptees and their biological parents and siblings. The heterogeneity of obesity may be demonstrated by the shape of fat distribution and the prolactin response to insulin hypoglycaemia. Fat distribution has been shown to have a genetic background whereas a primary disorder of hypothalamic function is suspected in obese women who show an impaired prolactin response to insulin-induced hypoglycaemia. We have investigated the possible association between fat distribution and hypothalamic function in 23 extremely obese, nondiabetic premenopausal women who have been characterized using their absolute body weight, body mass index (BMI), fat distribution (expressed as waist to hip ratio), fasting insulin, basal prolactin and prolactin response to hypoglycaemia. Fasting insulin values showed a significant correlation (P less than 0.05, R = 0.604) with increasing waist to hip ratio (upper body segment obesity), whereas the graded prolactin response to hypoglycaemia of the obese women showed a negative association with increasing upper body segment obesity (P less than 0.05; R = -0.446). No relationship was observed between fasting insulin and the prolactin response to hypoglycaemia. We suggest that this previously unrecognized association of an impaired prolactin response to hypoglycaemia and upper body segment fatness may be useful for the investigation of the genetics of obesity.

We have previously reported that the hypothalamo-pituitary-adrenal response to insulin-induced hypoglycaemia is normal while the cortisol release to pituitary stimulation by corticotrophin releasing factor (CRF-41) is reduced in obesity. Impaired growth hormone (GH) secretion is also found in obesity which may result from altered central levels of somatostatin (SMS). We have investigated, by giving a simultaneous infusion of SMS to six volunteer normal weight men during a CRF test, whether it is possible for SMS to modify pituitary-adrenal function. Each subject received intravenous CRF-41 (0.5 micrograms/kg) on two occasions during an infusion of isotonic saline or SMS (4 micrograms/min) in a randomized double-blind study. Plasma GH, cortisol, ACTH and SMS were measured. Three subjects demonstrated GH peaks during saline infusion but no peaks were seen in any subject during SMS infusion. No significant difference was found between peak cortisol responses during saline or SMS infusion (SMS cortisol 443 +/- 61 nmol/l, saline cortisol 485 +/- 52 nmol/l); neither was there any difference in the ACTH responses. We conclude that SMS does not alter the pituitary response to CRF in normal weight men and is thus less likely to be responsible for the altered pituitary-adrenal function seen in obesity. Further studies of alternative mechanisms are required to explain the cause of this abnormality.

We have previously reported increased testosterone and androstenedione concentrations and decreased sex hormone binding globulin (SHBG) concentrations in the plasma of massively obese women. We now report that these plasma hormone concentrations return to normal in twelve of the same women after substantial weight reduction and these changes are associated with more normal menstrual cycles. We conclude that body weight and fat are important determinants of sex steroid secretion and binding and thus influence menstrual function.

We have measured the plasma concentrations of sex steroids and sex hormone-binding globulin (SHBG) in twenty-three massively obese women and ten age-matched lean female volunteers. In the obese women increased plasma testosterone (obese 3.2 +/- 0.5 nmol/l controls 1.7 +/- 0.5 nmol/l, P less than 0.3) and androstenedione concentrations (obese 9.7 +/- 1.2 nmol/l, controls 4.4 +/- 0.6 nmol/l, P = less than 0.01) an increased ratio of oestrone:oestradiol (obese 2.4 +/- 0.4, controls 1.0 +/- 0.1, P = less than 0.1) and decreased SHBG levels (obese 30 +/- 4 nmol/l, controls 60 +/- 8 nmol/l, P = less than 0.001) were found. Obesity differed from the polycystic ovary syndrome (in which a similar pattern of changes of sex steroid concentrations and binding are seen) in that it was associated with normal increases in serum luteinizing hormone (LH) follicle stimulating hormone (FSH) levels in response to the administration of LHRH. We conclude that the common occurrence of menstrual abnormalities in obesity results from abnormal secretion and binding of sex steroids. In addition, the unaltered secretion of LH and FSH in the presence of such changes is evidence for a disorder of hypothalamic function.

Abnormalities of the adrenal cortex may be associated with extreme obesity but there is little information about hypothalamic-pituitary function. We have investigated this by measuring plasma ACTH and cortisol responses to ovine corticotrophin releasing factor (CRF-41), 0.5 microgram/kg/body weight, in 10 obese women and seven age-matched normal weight women. The cortisol response to insulin-induced hypoglycaemia and intravenous synacthen (2.5 ng/kg/body weight) were also measured on different occasions in some of the subjects. The peak ACTH response to CRF was less in the obese but this was not significant (obese ACTH +/- SEM, 31 +/- 4 ng/l, controls 39 +/- 4 ng/l) whereas the peak cortisol was significantly reduced in the obese (obese cortisol, 456 +/- 21 nmol/l, controls 638 +/- 50 nmol/l). Doubling the dose of CRF did not significantly alter either ACTH or cortisol responses in six of the obese patients. The peak cortisol response to symptomatic hypoglycaemia and following i.v. low dose synacthen stimulation was similar in the obese and normal weight women. We conclude that obese women have a normal cortisol response to hypothalamic-pituitary stimulation by hypoglycaemia and direct adrenal stimulation by synacthen but an impaired adrenal response to pituitary stimulation with CRF. Although the explanation for these findings is uncertain, our study underlines the importance of considering an individual's body weight when assessing the cortisol response to CRF stimulation.

We have recently reported an impaired growth hormone (GH) response to a single i.v. bolus dose of growth hormone releasing factor (1 microgram/kg body weight) in obese women. We have now investigated whether the i.v. administration of low dose GHRF(1-29)NH2 (0.33 microgram/kg/h) by 15 min pulsed injections for 3 h followed by an i.v. bolus (1 microgram/kg) to four normal weight women and six obese women results in an enhancement of GH release. In the control women low dose GHRF, given either as a single 10 microgram injection or in pulses of equivalent total dosage, produced a GH response identical to that seen after a single bolus of 60 micrograms (mean peak GH low dose 30 +/- 2 mU/l, peak GH large dose 30 +/- 0.5 mU/l). In the obese women GH release was significantly less than the controls after low doses of GHRF (P less than 0.01) and the peak was delayed compared to that following a single large bolus dose (peak GH 7 +/- 1.2 mU/l). However, three of the obese women who previously showed no response to a large dose of GHRF did release GH after low dose pulsed injections. The final bolus of GHRF after 3 h of pulsed injections did not elicit any additional GH release in the subjects irrespective of body weight. We conclude that obesity may be characterized by impaired GH release to i.v. GHRF. The finding that some obese women do not respond to a single large dose injection of GHRF but do release GH after low dose pulsed injections supports the hypothesis of a hypothalamic disorder in these women.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased plasma concentrations of growth hormone (GH) are reported in diabetes and it is suggested that this may be important in the development of complications. We have investigated fasting GH levels and the response to 100 micrograms i.v. growth hormone releasing factor, GRF(1-29)NH2, in age-matched men: six normal weight controls, six obese controls, six insulin-dependent diabetics, six normal weight non-insulin dependent diabetics and six obese non-insulin dependent diabetics. None of the diabetic men had clinical evidence of diabetic complications. Fasting GH values did not differ significantly between the five groups. The peak GH response to GRF was similar in the controls, insulin-dependent diabetics (IDD) and non-insulin dependent (NIDD) normal weight diabetics (mean peak +/- SEM: controls 25.5 +/- 5 mU/l, IDD 26.5 +/- 6 mU/l, NIDD 19.7 +/- 5 mU/l) but was significantly reduced in the two obese groups (obese 6.4 +/- 3 mU/l, obese diabetics 4.5 +/- 1 mU/l, P less than 0.01). This impairment of GH secretion was unrelated to either fasting plasma insulin or glucose concentration. We conclude that our results do not confirm the previous reports of abnormal GH secretion in diabetes but do demonstrate a markedly impaired GH response to GRF to be a feature of obesity.

We have previously reported an impaired growth hormone (GH) response and abnormal prolactin release to insulin-hypoglycaemia in obesity. We suggested that obese women with an absent prolactin response to hypoglycaemia ('non-responders') have a disorder of hypothalamic function. We have now investigated the GH response to i.v. growth hormone releasing factor, GHRF (1-29)NH2, in 14 obese women and nine age-matched normal-weight women. We found a significantly reduced GH response to GHRF in the obese women as compared with controls (mean peak +/- SEM: obese 8.9 +/- 2 mu/l, controls 28 +/- 2 mu/l; P less than 0.01). When the obese women were divided on the basis of their prolactin response to insulin-hypoglycaemia (seven 'non-responders', mean weight 102 +/- 5 kg; seven responders, mean weight 108 +/- 8 kg) a similar GH response to GHRF was found between the two groups but the GH response to hypoglycaemia was significantly less in the 'non-responder' women (mean peak 'non-responders' 10.5 +/- 3 mu/l, responders 27 +/- 4 mu/l; P less than 0.05). We conclude that obesity may be characterized by an impaired GH response to both i.v. GHRF and insulin-hypoglycaemia, which suggests altered hypothalamic-pituitary function. The finding that the GH response to hypoglycaemia is significantly less in the obese prolactin 'non-responder' women supports the hypothesis for a hypothalamic disorder.