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Biomedical subjects

M Tschöp

Publications and source records attributed to M Tschöp.

At least 19 recordsLinked to original sources
PubMed2006

Growth hormone secretagogue (ghrelin-) receptors--a complex drug target for the regulation of body weight.

The growth hormone secretagogue receptor (GHS-R) is expressed in several tissues and seems to mediate the different actions of the synthetic growth hormone secretagogues (GHS) and the endogenous ligand of this receptor, ghrelin. The GHS-R belongs to the family of G-protein coupled receptors (GPCR). Two different receptor variants, type 1a and 1b, have been described and they seem to mediate different actions in different tissues. In addition to their functions on growth hormone (GH) secretion and food intake, ghrelin and its receptor are involved in several cardiovascular mechanisms, pancreatic functions, adipogenesis, gonadal function, immune system actions or tumoral cells. This review will summarize data regarding the structure of the GHS-R gene, reports investigating the expression, control and functions of the GHS-R in various tissues, and studies of the underlying transcriptional mechanisms and the genetic manipulation of both ghrelin and GHS-R. Thus, it seems clear the possibility that ghrelin and/or GHS analogs, acting as either agonists or antagonists on different activities, might have clinical impact.

Animals↗
PubMed2005

A prospective study of serum ghrelin levels in patients treated with clozapine.

We investigated serum ghrelin levels (SGL) in 12 patients with schizophrenia over a 10-week period after initiation of clozapine treatment. In contrast to increments of body mass indices (BMI, kg/m2) and serum leptin levels (SLL), no significant change in SGL was detected. Inverse correlations between delta SGL and delta SLL did not reach statistical significance. Linear mixed model analysis could not detect effects of age, sex, BMI, SLL and serum clozapine levels on SGL. Our results do not support a causal involvement of ghrelin in clozapine-related weight gain.

Adult↗
PubMed2005

Postprandial ghrelin release in anorectic patients before and after weight gain.

The appetite-modulating hormone ghrelin transmits changes in food intake to the central nervous system. In patients with anorexia nervosa, weight gain reduces elevated fasting ghrelin levels to normal, however, less is known about the effects on postprandial ghrelin levels. In 20 female anorectic in-patients (25.6 +/- 1.0 years; body mass index (BMI) 15.1 +/- 0.3 kg/m2) a standardized test with 250 ml fluid meal (250 kcal: 9.4 g protein, 34.4 g carbohydrates, and 8.3 g fat) was performed at three different times (at admission, after partial weight gain of at least 2 kg, and at discharge) and compared to healthy controls (n = 6; BMI 21.1 +/- 0.7 kg/m2). Plasma ghrelin levels were measured preprandially as well as 20 and 60 min postprandially by a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA). At admission plasma ghrelin levels significantly decreased postprandially (from 871.9 +/- 124 to 620.3 +/- 80 pg/ml 60 min after meal; P < 0.005). After partial weight gain (2.8 +/- 0.1 kg; BMI 16.1 +/- 0.3 kg/m2) postprandial ghrelin concentrations decreased from 597.0 +/- 79 to 414.7 +/- 39 pg/ml (P < 0.0001), at discharge (weight gain: 7.6 +/- 0.5 kg; BMI 17.9 +/- 0.4 kg/m2) from 570.4 +/- 78 to 395.4 +/- 44 pg/ml (P < 0.0001). Mean postprandial ghrelin decrease was not significantly different between the three tests (29, 25, and 26%, respectively) or to controls (20%). In anorectic patients mean postprandial ghrelin decrease did not change during weight gain. These findings indicate that in anorexia nervosa the suppression of ghrelin release by acute changes of energy balance (feeding) is not disturbed and that it is independent from chronic changes in energy balance (weight gain).

Adult↗
PubMed2005

PYY3-36 as an anti-obesity drug target.

The neuropeptide Y (NPY)/peptide YY (PYY) system has been implicated in the physiology of obesity for several decades. More recently ignited enormous interest in PYY3-36, an endogenous Y2-receptor agonist, as a promising anti-obesity compound. Despite this interest, there have been remarkably few subsequent reports reproducing or extending the initial findings, while at the same time studies finding no anti-obesity effects have surfaced. Out of 41 different rodent studies conducted (in 16 independent labs worldwide), 33 (83%) were unable to reproduce the reported effects and obtained no change or sometimes increased food intake, despite use of the same experimental conditions (i.e. adaptation protocols, routes of drug administration and doses, rodent strains, diets, drug vendors, light cycles, room temperatures). Among studies by authors in the original study, procedural caveats are reported under which positive effects may be obtained. Currently, data speak against a sustained decrease in food intake, body fat, or body weight gain following PYY3-36 administration and make the previously suggested role of the hypothalamic melanocortin system unlikely as is the existence of PYY deficiency in human obesity. We review the studies that are in the public domain which support or challenge PYY3-36 as a potential anti-obesity target.

Animals↗
PubMed2005

Glucagon inhibits ghrelin secretion in humans.

OBJECTIVE: It is well known that i.m. glucagon administration stimulates GH and cortisol release in humans, although the mechanisms are unclear. These effects are similar to those described for ghrelin on somatotroph and corticotroph function. The aim of the present study was to investigate the role of ghrelin in mediating the stimulatory effects of glucagon and to evaluate the effect of glucagon on ghrelin secretion. DESIGN AND METHODS: We studied the endocrine and metabolic response to i.m. glucagon administration in 24 subjects (14 men, 10 women; age 19-65 years; body mass index, 25.3 +/- 1 kg/m(2)), who were shown to have an intact anterior pituitary function as evaluated before enclosure. RESULTS: Serum ghrelin concentrations fell significantly at 30, 60, 120 and 180 min after glucagon administration (means +/- s.e.m.; baseline, 377.9 +/- 34.5 pg/ml; nadir, 294.6 +/- 28.3 pg/ml (60 min); P < 0.01). Conversely, i.m. glucagon elicited an increase in GH (baseline, 1.5 +/- 0.4 microg/l; peak, 14.2 +/- 2.7 microg/l (180 min); P < 0.01) and cortisol concentrations (baseline, 452.6 +/- 35.2 nmol/l; peak, 622.1 +/- 44 nmol/l (180 min); P < 0.01). The changes in ghrelin concentration at both 120 and 180 min were still significant after correction for glucose and insulin (P < 0.05). CONCLUSIONS: We show that i.m. glucagon decreases ghrelin significantly. Therefore, the already known stimulatory effects of i.m. glucagon on cortisol and GH are not mediated by a change in ghrelin concentrations. The mechanisms underlying the ghrelin suppression after i.m. glucagon are unlikely to include glucose or insulin variations and need to be further elucidated.

Adult↗
PubMed2004

Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.

Animals↗
PubMed2004

Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.

OBJECTIVE: The orexigenic and adipogenic peptide hormone ghrelin is predominantly produced and secreted by the stomach and seems to transduce changes in food intake to specific neuronal circuits in the brain. The activity of ghrelin also includes stimulatory effects on the corticotropic system. However, little is known about the influence of glucocorticoids on ghrelin levels. We therefore studied human plasma ghrelin levels in the presence and absence of elevated glucocorticoid levels of either endogenous or exogenous origin. METHODS: Plasma ghrelin levels were measured in five patients with chronic hypercortisolism (aged 29-58, median 46 years) due to Cushing's syndrome before and after successful surgery for the adenoma, and in eight healthy controls (aged 24-39, median 27.5 years) before and after 30 mg prednisolone (for 5 days) once a day in the morning (median body mass index (BMI) 22.7 kg/m(2)). Plasma ghrelin levels were measured with a commercially available radioimmunoassay. RESULTS: In patients with Cushing's syndrome, plasma ghrelin levels were low (median 363.2 pg/ml, range 161.9-525.7 pg/ml) and significantly increased by 26.6% (P=0.04) after successful surgery, while BMI decreased (median 26.2-24.0 kg/m(2), P=0.04). A strong negative correlation (r=-0.9, P=0.04) between changes in BMI and plasma ghrelin was observed. In healthy controls, plasma ghrelin levels (median 288.7 pg/ml, range 119.6-827.8 pg/ml) were significantly suppressed by 18.3% (P=0.04) after prednisolone treatment. CONCLUSIONS: We have shown for the first time that plasma ghrelin levels are decreased under endogenously or exogenously induced hypercortisolism, making ghrelin an unlikely candidate for causing the changes in energy balance or body composition characteristic of Cushing's disease. However, the reduced ghrelin secretion could reflect a compensation mechanism in reaction to the metabolic consequences of chronic hypercortisolism.

Adult↗
PubMed2003

Anti-androgen treatment increases circulating ghrelin levels in obese women with polycystic ovary syndrome.

In a previous study we were the first to describe a negative correlation between circulating ghrelin concentrations and androgen levels in human plasma, suggesting an interaction between ghrelin and the endocrine regulation of reproductive physiology. We now investigated a potential direct regulatory influence of circulating androgens on plasma ghrelin levels. Fourteen obese women with polycystic ovary syndrome (PCOS) on a hypocaloric diet were randomly assigned to treatment groups (open-labeled design), receiving either placebo (no.=7) or the antiandrogen flutamide (no.=7) for 6 months. Anthropometry, visceral (VAT) and subcutaneous (SAT) adipose tissue (quantified by computerized tomography), plasma hormone levels, insulin sensitivity indexes (Quantitative Insulin-Sensitivity Check Index-QUICKI) and Homeostatic Model Assessment applied to the oral glucose tolerance test (HOMA(OGTT)) were evaluated at baseline and at the end of the study. Body weight decreased and insulin resistance indexes improved in both groups. A tendency toward a greater loss of VAT was observed in the flutamide group. Only in the flutamide group was a significant reduction of androgens levels observed. Plasma ghrelin levels significantly increased following treatment with flutamide, while ghrelin remained unchanged in the placebo group. We observed a negative correlation between changes of ghrelin levels and changes of androgen plasma concentration in the flutamide-treated group. In the same group a positive correlation was found between plasma ghrelin changes and insulin sensitivity as expressed by HOMA(OGTT). Analysis in a multiple regression model, however, showed that plasma ghrelin changes were mainly due to changes of androgen levels rather than improved insulin sensitivity. We, therefore, conclude that androgens are independent modulators of circulating ghrelin concentrations.

Adult↗
PubMed2003

Post-prandial decrease of human plasma ghrelin in the absence of insulin.

Ghrelin is the most powerful orexigenic hormone in mammalian physiology. Ghrelin plasma concentrations increase prior to meal onset, but decrease post-prandially. We and others reported previously that insulin reduces circulating ghrelin levels and might therefore be a driving force for post-prandial suppression of ghrelin. To test the influence of insulin on post-prandial ghrelin regulation, a patient with Type I diabetes with complete insulin deficiency received a low glycemic index meal and subsequently an additional high glycemic index meal in the absence of insulin substitution. Subsequently, a sc injection of 0.08 IU Lispro insulin per kg body weight was given. Results were compared to those of a healthy control subject matched for sex, age and body mass index, which was undergoing the same test series (without Lispro bolus) in the presence of endogenous post-prandial insulin secretion. A substantial decrease of plasma ghrelin levels was observed in the insulin-deficient patient following low glycemic index carbohydrate load (27% plasma ghrelin decrease). The subsequent exposure to a high glycemic index meal resulted in a slight additional reduction of ghrelin levels (32% from baseline), while Lispro bolus did not induce further changes in circulating ghrelin (27% of baseline at termination). This post-prandial response was comparable to that of the healthy control subject (33% reduction after the first meal, 40% after the second meal). These data tentatively suggest that post-prandial secretion of ghrelin is not exclusively regulated by plasma insulin or plasma glucose but may depend on other metabolic factors yet to be identified.

Adult↗
PubMed2002

Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans.

The orexigenic and anabolic gastric hormone ghrelin is secreted in response to acute and chronic energy requirements. While pre-prandial increases and post-prandial decreases of plasma ghrelin levels in rodents and humans seem to indicate a role for the novel peptide hormone as an afferent meal initiator or "hunger hormone", the precise mechanisms which are suppressing ghrelin secretion in response to caloric intake remain largely unknown. We show here that human ghrelin levels decrease by almost 50% under hyperinsulinemic euglycemic clamp conditions (no.=4, p=0.001), revealing physiologically relevant increases of insulin levels as an independent determinant of circulating ghrelin levels. In a second study, 3-4-fold increased plasma free fatty acid levels, as another metabolic candidate for the modulation of circulating ghrelin concentrations, were generated by constant lipid infusion, but failed to change plasma ghrelin. Simultaneous elevation of free fatty acids and insulin again markedly decreased ghrelin concentration (no.=4, p=0.01). Insulin induced suppression of circulating ghrelin levels (or the lack thereof) could be a mechanism with relevance for the understanding of the (patho-) physiology of meal initiation and termination, the pathogenesis of the metabolic syndrome and for the development of respective therapeutic perspectives.

Adult↗
PubMed2001

Weight loss at high altitude.

Loss of appetite and weight are frequently observed at altitudes above 5000 m. However, the pathophysiology behind changes in body composition at extreme altitude is still not fully understood. Proper acclimatization to altitude and high caloric intake minimizes, but can not completely prevent significant weight loss under the influence of hypobaric hypoxia. The discovery of leptin in 1994 has initiated a new research area investigating molecular networks that connect peripheral organs with the central nervous system to sense and regulate energy intake as well as energy expenditure. Since then, a whole microcosm of new hormones, neurotransmitters and receptors has been discovered and studied with respect to body weight control. Those agents include neuropeptide Y (NPY), agouti-related protein (AGRP), melanocortin receptors (MC-R), cocaine-amphetamine regulated transcript (CART), pro-opiomelanocortin (POMC), orexin A and B (hypocretins), melanin-concentrating hormone (MCH) and ghrelin (endogenous ligand of the growth hormone secretagogue receptor). This overview will introduce the current concepts of the molecular control of energy homeostasis and attempt to reexamine the effects of altitude on appetite and body composition in light of these concepts. An overview of studies on changes of appetite and body composition at high altitude will be followed by the presentation of recent data on changes of endocrine parameters at hypobaric hypoxia that could be involved in the pathophysiology of weight loss.

Altitude↗
PubMed2001

Post-prandial decrease of circulating human ghrelin levels.

Ghrelin, an endogenous ligand of the GH secretagogue-receptor, has recently been shown to stimulate GH secretion and to have orexigenic and adipogenic effects in rodents, but little is known about its regulation and biological function in humans. Gastric motor function is under control of the central nervous system; however, the afferent and efferent loops of this feedback control mechanism remain to be elucidated. In the study presented here we investigated the effect of nutrient intake on circulating human ghrelin levels, and a possible association between ghrelin levels and gastric emptying. Ten healthy volunteers received a standard meal after an overnight fast. Food intake significantly decreased plasma ghrelin levels from 248.5 +/- 15.0 to 179.5 +/- 17.9 fmol/ml (120 min after meal, p=0.047). Gastric emptying half-time (non-invasive 13C-octanoic acid breath test) was correlated with fasting plasma ghrelin levels (r=0.74, p=0.0013). Ghrelin appears to be one possible candidate to provide feedback signaling between nutrient intake, gastric motor function and the central nervous system.

Adult↗
PubMed2001

Rodent obesity models: an overview.

Animal obesity models differ widely in type and extent of obesity. They are either based on environmental factors (eg. high fat diet induced obesity), spontaneous mutants (i.e. ob/ob mice), genetically engineered animals (eg. mice with melanocortin receptor subtype-4 gene disruption (knock-out)) or mechanical intervention (eg. chemical lesion of the ventromedial hypothalamus). This article reviews available rodent models to study obesity and attempts to highlight the greatest utility for each model.

Animals↗
PubMed2001

Minireview: ghrelin and the regulation of energy balance--a hypothalamic perspective.

The recently discovered hormone, ghrelin, has been recognized as an important regulator of GH secretion and energy homeostasis. Orexigenic and adipogenic ghrelin is produced by the stomach, intestine, placenta, pituitary, and possibly in the hypothalamus. The concentration of circulating ghrelin, principally derived from the stomach, is influenced by acute and chronic changes in nutritional state. To date, most studies focused on the role of ghrelin in GH secretion or its function in complementing leptin action to prevent energy deficits. The potential significance of ghrelin in the etiology of obesity and cachexia as well as in the regulation of growth processes is the subject of ongoing discussions. A large quantity of information based on clinical trials and experimental studies with ghrelin and previously available synthetic ghrelin receptor agonists (GH secretagogues) must now be integrated with a rapidly increasing amount of data on the central regulation of metabolism and appetite. In this overview, we summarize recent findings and strategies on the integration of ghrelin into neuroendocrine networks that regulate energy homeostasis.

Animals↗
PubMed2001

Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins.

Central (intracerebral ventral) and peripheral (subcutaneous and intraperitoneal) administration of ghrelin causes obesity in rodents by increasing food intake and decreasing fat oxidation. Recent studies in humans have shown that plasma ghrelin concentration was inversely related to body fat and was lower in Pima Indians, a population susceptible to obesity. Whether ghrelin plays a role in the etiology of obesity in humans is unknown. We, therefore, measured plasma ghrelin concentration before and after two interventions in monozygotic twins previously studied at Laval University, Quebec City. Twelve pairs of monozygotic twins were overfed by 84,000 kcal over a 100-day period, whereas another seven pairs of monozygotic twins were submitted to a 53,000 kcal negative energy balance induced by exercise over a 93-day period. At baseline, for all the subjects, plasma ghrelin concentration was negatively correlated with body mass and body fatness (r varying from 0.36 to 0.45). The intraclass coefficient for the twin resemblance (r(I) = 0.75; p = 0.006) indicated that plasma ghrelin concentration is a familial trait. In response to the 100-day intervention, plasma ghrelin exhibited a non-significant decrease of 61 +/- 30 fmol/l (p = 0.18) with overfeeding and a non-significant increase of 58 +/- 34 fmol/l (p = 0.17) with negative energy balance. However, there was no relationship between baseline plasma ghrelin concentration and the magnitude of body weight change in both interventions. These first experimental data under "clamped energy balance conditions" do not provide evidence that plasma ghrelin is involved in the etiology of human obesity. However, studies in free-living individuals are needed to clarify this question.

Adipocytes↗