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Biomedical subjects

Matthias H Tschöp

Publications and source records attributed to Matthias H Tschöp.

17 recordsLinked to original sources
PubMed2006

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite.

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding.

Action Potentials↗
PubMed2006

Ghrelin action in the brain controls adipocyte metabolism.

Many homeostatic processes, including appetite and food intake, are controlled by neuroendocrine circuits involving the CNS. The CNS also directly regulates adipocyte metabolism, as we have shown here by examining central action of the orexigenic hormone ghrelin. Chronic central ghrelin infusion resulted in increases in the glucose utilization rate of white and brown adipose tissue without affecting skeletal muscle. In white adipocytes, mRNA expression of various fat storage-promoting enzymes such as lipoprotein lipase, acetyl-CoA carboxylase alpha, fatty acid synthase, and stearoyl-CoA desaturase-1 was markedly increased, while that of the rate-limiting step in fat oxidation, carnitine palmitoyl transferase-1alpha, was decreased. In brown adipocytes, central ghrelin infusion resulted in lowered expression of the thermogenesis-related mitochondrial uncoupling proteins 1 and 3. These ghrelin effects were dose dependent, occurred independently from ghrelin-induced hyperphagia, and seemed to be mediated by the sympathetic nervous system. Additionally, the expression of some fat storage enzymes was decreased in ghrelin-deficient mice, which led us to conclude that central ghrelin is of physiological relevance in the control of cell metabolism in adipose tissue. These results unravel the existence of what we believe to be a new CNS-based neuroendocrine circuit regulating metabolic homeostasis of adipose tissue.

Acetyl-CoA Carboxylase↗
PubMed2006

Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice.

Among polygenic mouse models of obesity, the New Zealand obese (NZO) mouse exhibits the most severe phenotype, with fat depots exceeding 40% of total body weight at the age of 6 mo. Here we dissected the components of energy balance including feeding behavior, locomotor activity, energy expenditure, and thermogenesis compared with the related lean New Zealand black (NZB) and obese B6.V-Lep(ob)/J (ob/ob) strains (11% and 65% fat at 23 wk, respectively). NZO mice exhibited a significant hyperphagia that, when food intake was expressed per metabolic body mass, was less pronounced than that of the ob/ob strain. Compared with NZB, NZO mice exhibited increased meal frequency, meal duration, and meal size. Body temperature as determined by telemetry with implanted sensors was reduced in NZO mice, but again to a lesser extent than in the ob/ob strain. In striking contrast to ob/ob mice, NZO mice were able to maintain a constant body temperature during a 20-h cold exposure, thus exhibiting a functioning cold-induced thermogenesis. No significant differences in spontaneous home cage activity were observed among NZO, NZB, and ob/ob strains. When mice had access to voluntary running wheels, however, running activity was significantly lower in NZO than NZB mice and even lower in ob/ob mice. These data indicate that obesity in NZO mice, just as in humans, is due to a combination of hyperphagia, reduced energy expenditure, and insufficient physical activity. Because NZO mice differ strikingly from the ob/ob strain in their resistance to cold stress, we suggest that the molecular defects causing hyperphagia in NZO mice are located distal from leptin and its receptor.

Adiposity↗
PubMed2006

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Animals↗
PubMed2006

A role for beta-melanocyte-stimulating hormone in human body-weight regulation.

Pro-opiomelanocortin (POMC) expressing neurons mediate the regulation of orexigenic drive by peripheral hormones such as leptin, cholecystokinin, ghrelin, and insulin. Most research effort has focused on alpha-melanocyte-stimulating hormone (alpha-MSH) as the predominant POMC-derived neuropeptide in the central regulation of human energy balance and body weight. Here we report a missense mutation within the coding region of the POMC-derived peptide beta-MSH (Y5C-beta-MSH) and its association with early-onset human obesity. In vitro and in vivo data as well as postmortem human brain studies indicate that the POMC-derived neuropeptide beta-MSH plays a critical role in the hypothalamic control of body weight in humans.

Amino Acid Sequence↗
PubMed2006

The brain is getting ready for dinner.

Every evening, as we get ready for dinner, in addition to the routine behaviors of preparing the meal itself, we also prepare our bodies to cope with the upcoming meal. This could take the form of making restaurant reservations, changing into appropriate attire, washing hands, priming ourselves with an aperitif, or even consciously avoiding snacks as the meal approaches. A study by Johnstone and colleagues in this issue of Cell Metabolism (Johnstone et al., 2006) provides evidence that in parallel to our learned preparatory behaviors, our central nervous system is going through comparable motions as it gets ready for the anticipated meal.

Animals↗
PubMed2005

Cannabinoids, opioids and eating behavior: the molecular face of hedonism?

Obesity represents nowadays one of the most devastating health threats. Published reports even project a decline in life expectancy of US citizens due to the rapidly increasing prevalence of obesity. This alarming increase is intimately linked with recent changes of environment and lifestyle in western countries. In this context, the rewarding or even addictive properties of popular food may represent one of the most serious obstacles to overcome for an effective anti-obesity therapy. Therefore, in addition to molecular networks controlling energy homeostasis, now researchers are starting to define central nervous mechanisms governing hedonic and addictive components of food intake. A recently emerging body of data suggests that the endogenous cannabinoid and opioid systems both represent key circuits responding to the rewarding value of food. This review focuses on the role of these two systems for the homeostatic and hedonic aspects of eating behavior and includes their anatomical and functional interactions. Independent from the degree to which eating can be considered an addiction, cannabinoid and opioid receptor antagonists are promising anti-obesity drugs, since they are targeting both hedonic and homeostatic components of energy balance control.

Animals↗
PubMed2005

Mechanisms of oleoylethanolamide-induced changes in feeding behavior and motor activity.

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-alpha. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-alpha agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

Animals↗
PubMed2005

Consuming fructose-sweetened beverages increases body adiposity in mice.

OBJECTIVE: The marked increase in the prevalence of obesity in the United States has recently been attributed to the increased fructose consumption. To determine if and how fructose might promote obesity in an animal model, we measured body composition, energy intake, energy expenditure, substrate oxidation, and several endocrine parameters related to energy homeostasis in mice consuming fructose. RESEARCH METHODS AND PROCEDURES: We compared the effects of ad libitum access to fructose (15% solution in water), sucrose (10%, popular soft drink), and artificial sweetener (0% calories, popular diet soft drink) on adipogenesis and energy metabolism in mice. RESULTS: Exposure to fructose water increased adiposity, whereas increased fat mass after consumption of soft drinks or diet soft drinks did not reach statistical significance (n = 9 each group). Total intake of energy was unaltered, because mice proportionally reduced their caloric intake from chow. There was a trend toward reduced energy expenditure and increased respiratory quotient, albeit not significant, in the fructose group. Furthermore, fructose produced a hepatic lipid accumulation with a characteristic pericentral pattern. DISCUSSION: These data are compatible with the conclusion that a high intake of fructose selectively enhances adipogenesis, possibly through a shift of substrate use to lipogenesis.

Adipose Tissue↗
PubMed2005

The many faces of ghrelin: new perspectives for nutrition research?

The appetite-modulating peptide ghrelin is predominantly produced and secreted by the stomach and shows a strong growth hormone-releasing activity, which is mediated by the activation of the so-called growth hormone secretagogue type 1a receptor. Ghrelin is involved in the regulation of energy balance by increasing food intake and reducing fat utilization. Additionally, it stimulates lactotroph and corticotroph function, influences the pituitary gonadal axis, inhibits pro-inflammatory cytokine expression, controls gastric motility and acid secretion and influences pancreatic exocrine and endocrine function, as well as impacting on glucose metabolism. This review summarizes the known functions of ghrelin and its role in the regulation of the gut-brain axis.

Eating↗
PubMed2005

Obesity and the neuroendocrine control of energy homeostasis: the role of spontaneous locomotor activity.

Obesity represents one of the most urgent global health threats as well as one of the leading causes of death throughout industrialized nations. Efficacious and safe therapies remain at large. Attempts to decrease fat mass via pharmacological reduction of energy intake have had limited potency or intolerable side effects. Increasingly widespread sedentary lifestyle is often cited as a major contributor to the increasing prevalence of obesity. Moreover, low levels of spontaneous physical activity (SPA) are a major predictor of fat mass accumulation during overfeeding in humans, pointing to a substantial role for SPA in the control of energy balance. Despite this, very little is known about the molecular mechanisms by which SPA is regulated. The overview will attempt to summarize available information on neuroendocrine factors regulating SPA.

Animals↗
PubMed2004

Inhibition of ghrelin action in vitro and in vivo by an RNA-Spiegelmer.

Employing in vitro selection techniques, we have generated biostable RNA-based compounds, so-called Spiegelmers, that specifically bind n-octanoyl ghrelin, the recently discovered endogenous ligand for the type 1a growth hormone secretagogue (GHS) receptor. Ghrelin is a potent stimulant of growth hormone release, food intake, and adiposity. We demonstrate that our lead compound, L-NOX-B11, binds ghrelin with low-nanomolar affinity and inhibits ghrelin-mediated GHS-receptor activation in cell culture with an IC(50) of 5 nM. l-NOX-B11 is highly specific for the bioactive, n-octanoylated form of ghrelin. Like the GHS receptor, it does not recognize the inactive unmodified peptide and requires only the N-terminal five amino acids for the interaction. The i.v. administration of polyethylene glycol modified l-NOX-B11 efficiently suppresses ghrelin-induced growth hormone release in rats. These results demonstrate that the neutralization of circulating bioactive ghrelin leads to inhibition of ghrelin's secretory effects in the CNS.

Amino Acid Sequence↗
PubMed2004

Negative relationship between fasting plasma ghrelin concentrations and ad libitum food intake.

Ghrelin is a novel GH secretagogue with orexigenic effects. We hypothesized that high fasting plasma ghrelin concentrations (FxGhr) might predict high ad libitum food intake. FxGhr were measured in 30 normoglycemic subjects: 15 Pima Indians (8 male/7 female; age, 32 +/- 7 yr; body weight, 87 +/- 21 kg; mean +/-sd) and 15 Caucasians (12 male/3 female, 36 +/- 8 yr, 94 +/- 26 kg) in energy balance for 3 d before testing. Subjects then self-selected their food ad libitum for the following 3 d. Mean daily energy intake (DEI) was calculated from the weight of foods consumed and expressed as a percent of weight maintenance energy needs. FxGhr were twice as high in Caucasians as in Pima Indians (103 +/- 53 vs. 52 +/- 18 fmol/ml, P < 0.001) and remained higher after adjustment for age, gender, and body weight (P < 0.0001). Neither DEI, nor percent of weight maintenance energy needs, nor percent of calories from fat differed between the races. In both groups, FxGhr were negatively correlated with DEI (r = -0.61, P = 0.01; r = -0.54, P = 0.04, respectively). These negative relationships were not explained by interindividual differences in age, gender, or body weight. This unexpected finding that low FxGhr predict ad libitum food intake suggests that the role of endogenous ghrelin in the regulation of energy homeostasis remains uncertain.

Adult↗
PubMed2003

Two birds with one stone: novel glucokinase activator stimulates glucose-induced pancreatic insulin secretion and augments hepatic glucose metabolism.

The hormones glucagon and insulin delicately regulate the concentration of blood glucose. When patients become resistant to the effects of insulin or produce too little of it to properly regulate glucose concentrations, then diabetes can result. Unfortunately, not all patients with insulin-resistant, type 2 diabetes mellitus respond to drugs that improve insulin sensitivity. However, there is reason to be hopeful. A new molecule that targets glucokinase (GK), the enzyme responsible for phosphorylating glucose in pancreatic beta cells and hepatic cells, acts to significantly reduce blood glucose concentrations in rodents. The GK activator RO-28-1675 increased the glucose affinity and Vmax of GK, and rats treated with RO-28-1675 had improved glucose tolerance and elevated glucose uptake in liver. These results provide the basis for improved drug design that may alleviate diabetes mellitus and the disorders that accompany it in patients.

Animals↗
PubMed2003

Cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with anthropometric measures in pima Indian children.

Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat (by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 +/- 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (beta = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.

Absorptiometry, Photon↗
PubMed2003

Ghrelin as a potential anti-obesity target.

In order to develop an effective pharmacological treatment for obesity, an endogenous factor that promotes a positive energy balance by increasing appetite and decreasing fat oxidation could represent the drug target scientists have been looking for. The recently discovered gastric endocrine agent ghrelin, which appears to be the only potent hunger-inducing factor to naturally circulate in our blood stream, was discovered in 1999. Since then the acylated peptide hormone ghrelin has evolved from an endogenous growth hormone secretagogue to a regulator of energy balance to a pleiotropic hormone with multiple sources, numerous target tissues and most likely several physiological functions. Although neither the exact mechanism of action by which ghrelin increases food intake and adiposity is known, nor the putatively differential effects of brain-derived and stomach-derived ghrelin on energy homeostasis have been determined, blocking or neutralizing ghrelin action still seems one of the more reasonable pharmacological approaches to reverse a chronically positive energy balance. However, based on growing experience with compounds targeting the neuroendocrine regulation of energy balance, it is quite possible that a ghrelin antagonist will either fail to cure obesity due to the existence of compensatory mechanisms or undesired effects might reveal the true biological function of ghrelin (e.g. cardiovascular mechanisms, anti-proliferative effects, reproduction).

Adipose Tissue↗