Axis In Obesity Research Articles

Modulation of the IL-33/IL-13 Axis in Obesity by IL-13Rα2.

In obesity, IL-13 overcomes insulin resistance by promoting anti-inflammatory macrophage differentiation in adipose tissue. Endogenous IL-13 levels can be modulated by the IL-13 decoy receptor, IL-13Rα2, which inactivates and depletes the cytokine. In this study, we show that IL-13Rα2 is markedly elevated in adipose tissues of obese mice. Mice deficient in IL-13Rα2 had high expression of IL-13 response markers in adipose tissue, consistent with increased IL-13 activity at baseline. Moreover, exposure to the type 2 cytokine-inducing alarmin, IL-33, enhanced serum and tissue IL-13 concentrations and elevated tissue eosinophils, macrophages, and type 2 innate lymphoid cells. IL-33 also reduced body weight, fat mass, and fasting blood glucose levels. Strikingly, however, the IL-33-induced protection was greater in IL-13Rα2-deficient mice compared with wild-type littermates, and these changes were largely attenuated in mice lacking IL-13. Although IL-33 administration improved the metabolic profile in the context of a high fat diet, it also resulted in diarrhea and perianal irritation, which was enhanced in the IL-13Rα2-deficient mice. Weight loss in this group was associated with reduced food intake, which was likely related to the gastrointestinal effects. These findings outline both potentially advantageous and deleterious effects of a type 2-skewed immune response under conditions of metabolic stress, and identify IL-13Rα2 as a critical checkpoint in adipose tissues that limits the protective effects of the IL-33/IL-13 axis in obesity.

Role of renin–angiotensin system in obesity associated disorders

Activation of renin–angiotensin system (RAS) plays a key role in the maintenance of blood pressure, fluid, and electrolyte homeostasis through the action of the vasoactive peptide angiotensin II (Ang II). RAS has now been recognized to play an important role in metabolic diseases. Evidence from both animal and clinical studies suggest that blockade of RAS by reducing the synthesis of Ang II or its binding to angiotensin type 1 receptor (AT1R) via angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) prevents the activation of inflammatory signaling mechanism involved in obesity-associated metabolic disorders. Conversely, angiotensin converting enzyme 2 (ACE2)/Ang-(1–7)/Mas receptor (MasR) axis has been proposed as counter regulatory arm with effects opposite to those produced by ACE/Ang II/AT1R. This review summarizes the relevant studies enlightening the role of RAS in obesity-associated disorders with emphasis on the inhibitory effect of ACEi and ARBs on ACE/Ang II/AT1R and stimulation of ACE2/Ang-(1–7)/MasR axis in obesity.

Gastric bypass surgery stimulates the dormant gut-brain axis in obesity

To truly reduce the rates of chronic kidney disease, a root cause of kidney damage, obesity, must be targeted. Weight loss is often unsustainable because imbalances in satiety regulators are frequently not addressed to ensure maintenance of weight loss. In a recent study, gastric bypass surgery rebalanced satiety signals through resensitization of the gut-brain axis in obesity. This research may lead to noninvasive strategies to reduce obesity and obesity-related kidney disease.

CXCL17 is a stomach-expressed chemokine and plays a role in diet-induced obesity

Abstract CXCL17 is a mucosal chemokine that attracts dendritic cells and monocytes to specific tissues. CXCL17 is mainly expressed in the respiratory and gastrointestinal tracts and has been shown to have anti-inflammatory effects. Its recently described receptor, GPR35/CXCR8, is a GPCR that has been involved in metabolic functions. Given that macrophages are known to be involved in fat tissue homeostasis, we decided to study a possible role of the CXCL17/CXCR8 axis in obesity. To this end, we used a mouse model of diet-induced obesity to compare Cxcl17−/− mice and wild type (WT) C57BL/6 mice. Mice were fed either a 10% or 60% fat diet for four months. Their development and weight gain as well as several metabolism tests were monitored for two or four months. Plasma and fat tissue samples were used in adipokine assays and to measure levels of obesity-related cytokines and hormones. Gastrointestinal tract tissue, adipose and liver tissues were obtained to perform further RNA or protein assays. The results indicate that Cxcl17−/− mice fed a 60% fat diet gained significantly more weight than WT mice. We also determined that under homeostatic conditions CXCL17 is highly expressed in the upper gastrointestinal tract (oral cavity, esophagus and stomach) in WT mice. Obese Cxcl17−/− mice also exhibit impaired response to glucose in an insulin tolerance test. Adipokine assay results revealed differences in FGF-21 levels and in other obesity-associated molecules between WT and Cxcl17−/− mice. We conclude that CXCL17 influences development of obesity and systemic metabolic dysfunction. Our results suggest that CXCL17 may be a therapeutic target to treat obesity-related conditions.

Irisin improves perivascular adipose tissue dysfunction via regulation of the heme oxygenase-1/adiponectin axis in diet-induced obese mice

AimsTo determine whether irisin could improve perivascular adipose tissue (PVAT) dysfunction via regulation of the heme oxygenase-1 (HO-1)/adiponectin axis in obesity. Materials and methodsC57BL/6 mice were given chow or a high-fat diet (HFD) with or without treatment with irisin. The concentration-dependent responses of the thoracic aorta with or without PVAT (PVAT+ or PVAT−) to phenylephrine were studied in an organ bath. Protein levels of HO-1 and adiponectin were determined by western blot. UCP-1, Cidea, and TNF-α gene expression in PVAT were analyzed by real-time PCR. ResultsTreatment of obese mice with irisin improved glucose and lipid metabolism, reduced plasma levels of TNF-α and malondialdehyde, and increased plasma adiponectin levels (P<0.01). The anti-contractile effects of PVAT were attenuated in HFD mice and this attenuation was restored in HFD mice treated with irisin (P<0.05). Incubation of aortas (PVAT+) with the HO-1 inhibitor and adiponectin receptor blocking peptide in irisin-treated HFD mice abolished the beneficial effects of irisin on PVAT function. The same results were also observed in HFD mice treated with irisin ex vivo. Treatment of HFD mice with irisin significantly enhanced protein levels of HO-1 and adiponectin, and reduced superoxide production and TNF-α expression in PVAT. Irisin treatment enhanced brown adipocyte markers UCP-1 and Cidea expression in PVAT from HFD mice. ConclusionIrisin improved the anti-contractile properties of PVAT from the thoracic aorta in diet-induced obese mice. The mechanism for protective effects of irisin appeared to be related to upregulation of the HO-1/adiponectin axis in PVAT and browning of PVAT.

Cross-talk between adipose tissue and the HPA axis in obesity and overt hypercortisolemic states.

In addition to its roles in providing insulation and mechanical support, adipose tissue (AT) has been recognised as the major site for storage of surplus fuel. Since leptin was discovered, white AT (WAT) has been recognised as an endocrine organ and an important source of biologically active substances with local and/or systemic action called adipokines. The metabolic and endocrine activities of AT are under the control of several hormones: a particular role has been played by glucocorticoids (GC), which able to participate, along with other hormones, both in recruitment of progenitor cells and in differentiation and secretive activities. AT is also able to generate cortisol from cortisone through 11β-hydroxysteroid-dehydrogenase (11β-HSD). There are controversial reports in the literature, showing a hyperactivity of 11β-HSD in obesity. It has been postulated that obesity, particularly the visceral body fat distribution (V-BFD), may be considered a maladaptation to stress exposure, thus leading to hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, and higher-than-normal cortisol levels. In this review, we will examine the cross-talk between the HPA axis and AT, their relationship under stressful events, depending on steroid hormones and different adipokine secretions.

The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations

Obesity has become one of the most common medical problems in developed countries, and this disorder is associated with high incidences of hypertension, dyslipidaemia, cardiovascular disease, type 2 diabetes mellitus and specific cancers. Growth hormone (GH) stimulates the production of insulin-like growth factor 1 in most tissues, and together GH and insulin-like growth factor 1 exert powerful collective actions on fat, protein and glucose metabolism. Clinical trials assessing the effects of GH treatment in patients with obesity have shown consistent reductions in total adipose tissue mass, in particular abdominal and visceral adipose tissue depots. Moreover, studies in patients with abdominal obesity demonstrate a marked effect of GH therapy on body composition and on lipid and glucose homeostasis. Therefore, administration of recombinant human GH or activation of endogenous GH production has great potential to influence the onset and metabolic consequences of obesity. However, the clinical use of GH is not without controversy, given conflicting results regarding its effects on glucose metabolism. This Review provides an introduction to the role of GH in obesity and summarizes clinical and preclinical data that describe how GH can influence the obese state.

High‐normal tsh values in obesity: Is it insulin resistance or adipose tissue's guilt?

Clinical evidences reported subclinical alterations of thyroid function in obesity, although the relationship between thyroid status and obesity remains unclear. We cross-sectionally investigated the influence of metabolic features on hypothalamic-pituitary-thyroid axis in obesity. We enrolled 60 euthyroid subjects with no history of type 2 diabetes mellitus and assessed the relationship of thyroid function with insulin resistance, measured using euglycemic clamp, and abdominal fat volume, quantified by computed tomography scan (CT scan). Thyroid stimulating hormone (TSH) correlated with BMI (r = 0.46; P = 0.02), both visceral (r = 0.58; P = 0.02) and subcutaneous adipose tissue volumes (r = 0.43; P = 0.03) and insulin resistance (inverse relationship with insulin sensitivity-glucose uptake: r = -0.40; P = 0.04). After performing multivariate regression, visceral adipose tissue volume was found to be the most powerful predictor of TSH (β = 3.05; P = 0.01), whereas glucose uptake, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, subcutaneous adipose tissue volume, and triglycerides were not. To further confirm the hypothesis that high-normal TSH values could be dependent on adipose tissue, and not on insulin resistance, we restricted our analyses to moderately obese subjects' BMI ranging 30-35 kg/m(2). This subgroup was then divided as insulin resistant and insulin sensitive according to the glucose uptake (≤ or >5 mg · kg(-1) · min(-1), respectively). We did not find any statistical difference in TSH (insulin resistant: 1.62 ± 0.65 µU/ml vs. insulin sensitive: 1.46 ± 0.48; P = not significant) and BMI (insulin resistant: 32.2 ± 1.6 kg/m(2) vs. insulin sensitive: 32.4 ± 1.4; P = not significant), thus confirming absence of correlation between thyroid function and insulin sensitivity per se. Our study suggests that the increase in visceral adipose tissue is the best predictor of TSH concentration in obesity, independently from the eventual concurrent presence of insulin resistance.

The Hypothalamic-Pituitary-Adrenal Axis, Obesity, and Chronic Stress Exposure: Sleep and the HPA Axis in Obesity

Obesity, exposure to stress and inadequate sleep are prevalent phenomena in modern society. In this review we focus on their relationships and critically evaluate causality. In obese individuals, one of the main stress systems, the hypothalamic-pituitary-adrenal axis, is altered, and concentrations of cortisol are elevated in adipose tissue due to elevated local activity of 11β-hydroxysteroid dehydrogenase (HSD) type 1. Short sleep and decreased sleep quality are also associated with obesity. In addition, experimental sleep curtailment induces HPA-axis alterations which, in turn, may negatively affect sleep. These findings implicate that obesity, stress and sleep loss are all related in a vicious circle. Finally, we discuss new strategies to combat obesity through modulating cortisol levels in adipose tissue by 11β-HSD(1) inhibitors or by improving sleep duration.

Activation of Natural Killer T Cells Promotes M2 Macrophage Polarization in Adipose Tissue and Improves Systemic Glucose Tolerance via Interleukin-4 (IL-4)/STAT6 Protein Signaling Axis in Obesity

Natural killer T (NKT) cells are important therapeutic targets in various disease models and are under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type 1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance. Although loss-of-function of NKT cells had no effect on glucose tolerance in animals with prolonged high fat diet feeding, activation of NKT cells by lipid agonist α-galactosylceramide enhances alternative macrophage polarization in adipose tissue and improves glucose homeostasis in animals at different stages of obesity. Furthermore, the effect of NKT cells is largely mediated by the IL-4/STAT6 signaling axis in obese adipose tissue. Thus, our data identify a novel therapeutic target for the treatment of obesity-associated inflammation and type 2 diabetes.

Targeting the GCC endocrine signaling axis to reduce appetite in obesity

In light of our discovery that the transmembrane receptor guanylyl cyclase C (GCC) regulates appetite through a novel gut‐brain endocrine axis, we aimed to further define hypothalamic GCC expression and, moreover, determine the consequence of obesity to this GCC signaling axis. Nuclei were microdissected from mouse hypothalamus and GCC expression was quantified by RT‐PCR. Mouse brains were also cryosectioned and hypothalamic slices were immunostained for GCC. Further, hypothalamus and intestine were harvested from lean and obese mice, and GCC and GCC ligand expression was quantified by RT‐PCR, immunoblot, and immunofluorescence. Our studies revealed the suppression of intestinal ligand expression with the concomitant overexpression of hypothalamic GCC in obese mice. Further, our studies suggested that GCC was enriched in the arcuate nucleus, a key regulator of appetite. Our results suggest a corruption of the GCC axis in obesity, which in part reflects an endocrine deficiency of GCC ligands that could be therapeutically targeted to supersensitized receptors by hormone replacement. Thus, GCC represents a new target to develop anti‐obesity pharmacotherapies against this accelerating pandemic. This research was supported by the Thomas Jefferson University Doctoral Student Research Fellowship.

Role of Advanced Glycation End Products (AGEs) in Adipogenesis in Senescent Preadipocytes

Obesity contributes to the development of metabolic syndromes and accelerates to onset of multiple aging‐related disorders. Adipogenesis is the main process to increase not only lipid accumulation, but also elevate inflammation and oxidative stress. Within aging, preadipocyte capacity to replicate and differentiate declines. Advanced glycation end products (AGEs), through its receptor (RAGE), have been shown to be implicated to aging‐associated chronic diseases. The inhibition of the AGE‐RAGE interaction has been proposed as a target to treat or prevent these diseases; however the role of AGE‐RAGE axis in obesity has not been delineated. The objective of this study was to characterize the function of AGE‐RAGE axis in adipogenic capacity of senescent 3T3‐L1 preadipocytes. We found that the high passage preadipocytes (HPP) (more than 15 passages) exhibited the elevated levels of replicative senescent markers, including upregulation of tumor suppressor protein 53, interleukin‐6 levels and beta‐galactosidase activity compared to low passage cells (equals to or less than 5 passages). Additionally, HPP had reduction of insulin sensitivity and adipogenic ability. Interestingly, HPP treated with AGEs restored adipogenic capacity assessed by Oil Red O staining and increased adipogenic gene expression such as peroxisome proliferator‐activated receptor gamma, CAATT/enhancer binding protein alpha, and fatty acid synthase. Moreover, AGE‐stimulated adipogenesis in HPP is related to increased RAGE protein expression. We further demonstrated that the blockage of RAGE by a neutralizing antibody blunted the pro‐adipogenic function of AGEs. Taken together, our results suggest that AGEs induce adipogenesis in a RAGE‐dependent manner in senescent preadipocytes.Grant Funding Source: Scholarship from the Ministry of Education of Taiwan

M1734 The Role of the Insulin-Like Growth Factor I Axis in Obesity and Esophageal Adenocarcinoma

Introduction: Anorexia and hypermetabolism are a problem of paramount importance in children with cirrhosis. Plasma levels of both leptin and ghrelin are altered in patients with starvation and chronic diseases associated with anorexia. Ghrelin has an important role on feeding and weight homeostasis. Aim: We aimed to assess ghrelin and leptin levels in cirrhotic children and adolescents in comparison with controls. Methods: Forty children with cirrhosis (biliary atresia as etiology in 67.5%) aged between 3.7 and 188.7 months, 50% male, were evaluated, 50% were Child-Pugh A; 40%, B and 10%, C. Other 40 healthy children matched for sex and age, taken as controls, were also evaluated. Blood samples were collected at least after 3-hours fasting. Fasting leptin and acylated ghrelin levels were measured using a newly developed ELISA kit (Linco Research, St Charles-MI, USA). Body composition including body mass index (BMI), body fat mass and height for age were determined and classified according to WHO 2009 and Frisancho 2008 standard reference. All controls were eutrophic as well as 77.5% of cirrhotic patients. Other cirrhotics were either undernourished (21.3%) or overweighed (1.3%). Results: Ghrelin and leptin in both groups did not correlate with sex (P=0.023). Median values (25-75 centile) of acylated ghrelin were significantly lower in cirrhotics than in healthy controls [140.3 (93.9-269.7) pg/mL vs 277.8 (209.9-557.8) pg/mL, P=0.003]. Median values of total ghrelin and desacyl ghrelin of children with cirrhosis were 913.4 pg/mL (760.8-1443.7) and 1397.8 pg/mL (815.27-2047) respectively. Median values of leptin were not significantly different between cirrhotics and controls (P=0,26)]. From the cirrhotic group there was a significant difference between undernourished and well-nourished pactients [1.45ng/mL (0.66-1.88) 2.68 ng/mL (1.31-4.38)], P=0.023. Median values of Child-Pugh C were significantly lower than B and A [0.67 (0.17-1.11) ng/mL; 1.83 (1.24-4.04) ng/mL; 1.88 (0.67-3.67) ng/mL], P=0.033. Conclusions: Cirrhotic children showed lower plasma levels of acylated ghrelin compared with controls. This might be representative of the anorexia that consequently contributes to the malnourishment and illness severity of cirrhotic patients.

Cortisol Production Rate Is Similarly Elevated in Obese Women with or without the Polycystic Ovary Syndrome

The pituitary-adrenal axis in obesity and polycystic ovary syndrome (PCOS) is marked by increased urinary excretion of cortisol and its metabolites. It is not as yet clear whether the increased cortisol production in PCOS is related to obesity per se. We investigated 15 obese PCOS women with a body mass index of 30-54 kg/m(2) and 15 healthy obese controls (body mass index 31-60 kg/m(2)) with a regular menstrual cycle. Patients and control women underwent 24-h blood sampling at 20-min intervals. Cortisol concentrations were measured with a sensitive assay. Data were analyzed with a new deconvolution program, approximate entropy, and cosinor regression. Basal, pulsatile, and total cortisol production expressed per liter distribution volume, per square meter body surface, and as absolute amount per 24 h was similar in PCOS patients and matched healthy control women. In addition, the regularity of cortisol secretion and the diurnal properties were identical. Compared with 10 lean control women, mean cortisol production per liter distribution volume was similar in the three groups, but the total 24-h cortisol production was increased in obese control women and PCOS women. This study demonstrates equally increased cortisol production in PCOS women and obese healthy control women.

Stress and obesity: the role of the hypothalamic–pituitary–adrenal axis in metabolic disease

Chronic stress, combined with positive energy balance, may be a contributor to the increased risk for obesity, especially upper body obesity, and other metabolic diseases. This association may be mediated by alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In this review, we summarize the major research that has been conducted on the role of the HPA axis in obesity and metabolic disease. Dysregulation in the HPA axis has been associated with upper body obesity, but data are inconsistent, possibly due to methodological differences across studies. In addition to systemic effects, changes in local cortisol metabolism in adipose tissue may also influence the risk for obesity. HPA axis dysregulation may be the causal link between conditions such as maternal malnutrition and sleep deprivation with metabolic disease. The present review provides evidence for the relationship between chronic stress, alterations in HPA activity, and obesity. Understanding these associations and its interactions with other factors will be important in developing effective treatments for obesity and related metabolic diseases.

Oxidized LDL impair adipocyte response to insulin by activating serine/threonine kinases

Oxidized LDL (oxLDL) increase in patients affected by type-2 diabetes, obesity, and metabolic syndrome. Likewise, insulin resistance, an impaired responsiveness of target tissues to insulin, is associated with those pathological conditions. To investigate a possible causal relationship between oxLDL and the onset of insulin resistance, we evaluated the response to insulin of 3T3-L1 adipocytes treated with oxLDL. We observed that oxLDL inhibited glucose uptake (-40%) through reduced glucose transporter 4 (GLUT4) recruitment to the plasma membrane (-70%), without affecting GLUT4 gene expression. These findings were associated to the impairment of insulin signaling. Specifically, in oxLDL-treated cells insulin receptor (IR) substrate-1 (IRS-1) was highly degraded likely because of the enhanced Ser(307)phosphorylation. This process was largely mediated by the activation of the inhibitor of kappaB-kinase beta (IKKbeta) and the c-Jun NH(2)-terminal kinase (JNK). Moreover, the activation of IKKbeta positively regulated the nuclear content of nuclear factor kappaB (NF-kappaB), by inactivating the inhibitor of NF-kappaB (IkappaBalpha). The activated NF-kappaB further impaired per se GLUT4 functionality. Specific inhibitors of IKKbeta, JNK, and NF-kappaB restored insulin sensitivity in adipocytes treated with oxLDL. These data provide the first evidence that oxLDL, by activating serine/threonine kinases, impaired adipocyte response to insulin affecting pathways involved in the recruitment of GLUT4 to plasma membranes (PM). This suggests that oxLDL might participate in the development of insulin resistance.

The Bone-Adipose Axis in Obesity and Weight Loss

Body fat and lean mass are correlated with bone mineral density, with obesity apparently exerting protection against osteoporosis. The pathophysiological relevance of adipose tissue in bone integrity resides in the participation of adipokines in bone remodeling through effects on deposition and resorption. On the other hand, the skeleton has recently emerged as an endocrine organ with effects on body weight control and glucose homeostasis through the actions of bone-derived factors such as osteocalcin and osteopontin. The cross-talk between adipose tissue and the skeleton constitutes a homeostatic feedback system with adipokines and molecules secreted by osteoblasts and osteoclasts representing the links of an active bone-adipose axis. Given the impact of bariatric surgery on absorption and the adipokine secretory pattern, to focus on the changes taking place following surgical-induced weight loss on this dynamic system merits detailed consideration.

Innate Immune Pathway Links Obesity to Insulin Resistance

See related article, pages 1589–1596 The prevalence of obesity, especially among adolescents, has increased considerably over the past 20 years because of increased caloric intake and reduced physical activity. It has been estimated that 20% of the world’s population is overweight and nearly 300 million are obese (BMI >30 kg/m2).1,2 Excess body weight and obesity are associated with the development of metabolic syndrome and type II diabetes, both of which are associated with insulin resistance and increased risk of cardiovascular complications.1,2 Atherothrombotic vascular disease, resulting from a complex interplay between dyslipidemia and vascular immunoinflammatory processes, is responsible for a majority of the excess morbidity and mortality that characterizes metabolic syndrome and type II diabetes.1,2 Several studies have shown that obesity is associated with activation of inflammatory pathways and that inflammatory responses are associated with impaired insulin signaling and insulin resistance.3–8 Considerable progress has been made in the last 2 decades in our understanding of molecular events that link obesity to inflammation, insulin resistance, type II diabetes, and enhanced vascular disease. Obesity-mediated skeletal muscle insulin resistance has been linked to defects in cellular signaling events triggered by insulin.3–8 In obesity, the skeletal muscle levels of several kinases such as protein kinase C isoforms (PKC), I Kappa B Kinase-β …

The GH/IGF-1 Axis in Obesity: Physiological and Pathological Aspects

The cluster of cardiovascular risk factors-abdominal obesity, dyslipidaemia, insulin resistance and hypertension-has been recognized as the core of the metabolic syndrome. Adults with severe growth hormone (GH) deficiency have, to a large extent, features of the metabolic syndrome, and there is a strong inverse association between visceral fat accumulation and blunted GH secretion in adults. Hyposomatotropism in abdominal obesity has therefore been suggested to be of importance for its metabolic consequences. However, the underlying pathophysiological mechanisms are poorly understood. Prevalence of the metabolic syndrome is steadily increasing worldwide. Overnutrition and sedentary habits are the stigmata of modern society that predispose genetically susceptible individuals to develop central obesity and other features of the metabolic syndrome including glucose intolerance, hypertension and dyslipidemia. Although there are still no unified definitions of the syndrome, it is clear that this condition is associated with an increased risk for development of cardiovascular disease (CVD) and diabetes mellitus (DM). In this review, we discuss current evidence regarding alterations in the GH-IGF- 1 axis in abdominal obesity and its possible impact on other features of the metabolic syndrome.

Effects of gastric bypass on the GH/IGF-I axis in severe obesity – and a comparison with GH deficiency

Overfeeding suppresses GH secretion and makes evaluation of a suspected GH deficiency (GHD) difficult. In normal weight subjects, gender is known to influence GH concentrations, which is most apparent in the ambulatory, morning-fasted state. In this study, we examined the GH/IGF-I axis in obese men and women and the effect of surgically induced weight loss. Sixty-three subjects (body mass index (BMI) 45 +/- 6 kg/m2; 54 women, 9 men) were studied prior to, and 6 and 12 months following Roux-en-Y gastric bypass (RYGBP) surgery. Fifty-four patients with classic GHD (BMI 27 +/- 6 kg/m2; 35 men, 19 women) were included for comparison. Hormones were analysed in fasting morning serum samples. RYGBP resulted in a decreased BMI to 35 +/- kg/m2 at 6 months and 32 +/- 6 kg/m2 at 12 months. GH and IGF-I increased at 6 months in the women and at 12 months in both sexes by > or = 300 and 11% respectively. Prior to RYGBP, GH concentrations were low in the obese men and similar to those of GHD men (mean 0.09 mU/l). Obese women had tenfold higher values than obese men and sevenfold higher than GHD women. IGF-I levels were in the low reference range in the obese and below -2 S.D. for age in 13%. Surgically induced weight loss partially restores GH secretion. Despite a marked suppression of GH values, a gender influence is maintained in severe obesity. In obese women, single morning GH and IGF-I values seem sufficient to exclude a suspicion of classic GHD.