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Roger A H Adan

Publications and source records attributed to Roger A H Adan.

At least 19 recordsLinked to original sources
PubMed2006

Difference in susceptibility to activity-based anorexia in two inbred strains of mice.

Food restricted rodents develop activity-based anorexia in the presence of a running wheel, characterised by increased physical activity, weight loss and decreased leptin levels. Here, we determined trait differences in the development of activity-based anorexia between C57BL/6J and DBA/2J inbred mouse lines previously reported as having low and high anxiety, respectively. C57BL/6J mice housed with running wheels and exposed to scheduled feeding reduced their wheel activity, in contrast to DBA/2J mice which exhibited increased behavioural activity under these conditions. Food restriction induced hypoleptinemia in both strains, but the decline in plasma leptin was stronger in DBA/2J mice and correlated with increased activity only in that strain. These data suggest that plasma leptin level dynamics rather than hypoleptinemia alone influences the development of activity-based anorexia and that recombinant inbred panels based on these progenitor lines offer opportunities for the identification of molecular determinants for anorexia nervosa related behavioural traits.

Animals↗
PubMed2006

To eat or not to eat; regulation by the melanocortin system.

The central melanocortin (MC) system is one of the best-characterized neuropeptidergic systems involved in the regulation of energy balance. This short review describes the role of the central MC system in feeding behavior. Pharmacological, anatomical and genetic studies show that activation of the MC system reduces meal size, whereas de-activation of the MC system increases meal size. Several brain regions, including distinct hypothalamic nuclei and the hindbrain, are involved in this process. Further dissection of MC pathways in feeding behavior is the subject of recent and probably future studies. As the MC system is involved in animal models of obesity and (possibly) anorexia, it appears that this is a target system for development of drugs for the treatment of disturbed human eating behavior.

Animals↗
PubMed2006

Constitutive receptor activity series: endogenous inverse agonists and constitutive receptor activity in the melanocortin system.

The recent discovery of melanocortin receptor mutations that selectively decrease constitutive receptor activity in obese individuals supports the physiological relevance of constitutive melanocortin receptor activity and its control by an endogenous inverse agonist. Furthermore, studies using mice that lack endogenous melanocortin receptor agonists show that differences in coat color are caused by different degrees of constitutive melanocortin receptor signaling regulated by an endogenous inverse agonist. Thus, the regulation of constitutive activity of melanocortin receptors is important for the normal control of pigmentation and body-weight homeostasis.

Agouti Signaling Protein↗
PubMed2006

Gold-enhanced biomolecular surface imaging of cells and tissue by SIMS and MALDI mass spectrometry.

Surface metallization by plasma coating enhances desorption/ionization of membrane components such as lipids and sterols in imaging time-of-flight secondary ion mass spectrometry (TOF-SIMS) of tissues and cells. High-resolution images of cholesterol and other membrane components were obtained for neuroblastoma cells and revealed subcellular details (resolving power 1.5 mum). Alternatively, in matrix-enhanced SIMS, 2,5-dihydroxybenzoic acid electrosprayed on neuroblastoma cells allowed intact molecular ion imaging of phosphatidylcholine and sphingomyelin at the cellular level. Gold deposition on top of matrix-coated rat brain tissue sections strongly enhanced image quality and signal intensity in stigmatic matrix-assisted laser desorption/ionization imaging mass spectrometry. High-quality total ion count images were acquired, and the neuropeptide vasopressin was localized in the rat brain tissue section at the hypothalamic area around the third ventricle. Although the mechanism of signal enhancement by gold deposition is under debate, the results we have obtained for cells and tissue sections illustrate the potential of this sample preparation technique for biomolecular surface imaging by mass spectrometry.

Animals↗
PubMed2006

Melanocortin receptors as drug targets for disorders of energy balance.

There is overwhelming evidence that the brain melanocortin system is a key regulator of energy balance, and dysregulations in the brain melanocortin system can lead to obesity. The melanocortin system is one of the major downstream leptin signaling pathways in the brain. In contrast to leptin, preclinical studies indicate that diet-induced obese animals are still responsive to the anorectic effects of melanocortin receptor agonists, suggesting the melanocortin system is an interesting therapeutic opportunity. Besides regulating energy balance, melanocortins are involved in a variety of other neuroendocrine processes, including inflammation, blood pressure regulation, addictive and sexual behavior, and sensation of pain. This review evaluates the melanocortin system function from the perspective to use specific melanocortin (MC) receptors as drug targets, with a focus on the treatment of obesity and eating disorders in humans, and the implications this may have on mechanisms beyond the control of energy balance.

Animals↗
PubMed2005

AgRP(83-132) and SHU9119 differently affect activity-based anorexia.

Activity-based anorexia (ABA) mimics starvation and hyperactivity of anorexia nervosa patients in rats. Activation of the melanocortin (MC) system leads to hypophagia and increased energy expenditure in ad libitum fed rats. Therefore, activation of the MC system might underlie the development and propagation of ABA. Pro-opiomelanocortin (POMC) gene expression is normally decreased during negative energy balance. Strikingly, we found a transient up-regulation of POMC mRNA levels in the arcuate nucleus during the development of ABA, indicating a hyperactive MC system. However, wheel running and food intake were not influenced by treating ABA rats with the competitive antagonist SHU9119. This suggests that agonism of MC receptors by endogenous alpha-melanocyte-stimulating hormone (alpha-MSH) levels does not underlie ABA. Instead, treatment with the inverse agonist AgRP(83-132) did ameliorate signs of ABA. This implies that modulation of constitutive MC receptor activity rather than antagonizing putative alpha-MSH release contributes to the development and propagation of ABA.

Agouti-Related Protein↗
PubMed2005

Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats.

Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.

Animals↗
PubMed2005

Functional analysis of the Ala67Thr polymorphism in agouti related protein associated with anorexia nervosa and leanness.

AgRP is a neuropeptide that stimulates food intake through inhibition of central melanocortin receptors (MCRs). In humans, the non-conservative amino acid substitution Alanine (Ala) 67 Threonine (Thr) has been associated with Anorexia Nervosa and with leanness. In the present study, the cellular distribution, processing and in vitro and in vivo activities of Ala67 and Thr67 AgRP were investigated. Western blots of media and lysates of BHK cells stably transfected with Ala67 or Thr67 expression constructs showed identical AgRP bands. Both Ala67 and Thr67 AgRP colocalised with the Golgi apparatus, but not with the ER or lysosomes when expressed in Att20 D16V cells. Also, no differences were observed between the potencies of bacterially expressed Ala67 and Thr67 AgRP to stimulate MC4R in a reporter gene assay or inhibit food intake in rats. Taken together, no evidence was found for a functional defect of Thr67 AgRP related to MC4R interactions.

Agouti-Related Protein↗
PubMed2005

Leptin treatment in activity-based anorexia.

BACKGROUND: Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding together with voluntary access to a running wheel results in increased running wheel activity (RWA), hypophagia, and body weight loss. Previously it was shown that leptin treatment reduced semi-starvation-induced hyperactivity in rats. The present study was performed to confirm and extend this finding, to evaluate leptin's effect on energy balance in ABA. METHODS: The effects of chronic leptin treatment (intracerebroventricular, 4 microg/day) in ABA rats, ad libitum-fed running rats, and sedentary rats exposed to ad libitum feeding or scheduled feeding were investigated. RESULTS: Leptin treatment decreased RWA in ABA rats. Additionally, leptin treatment reduced food intake and increased energy expenditure by thermogenesis in ABA rats. Ad libitum-fed running/sedentary rats or food-restricted sedentary rats did not reduce activity after leptin treatment, whereas all leptin-treated rats showed hypophagia. Body temperature was slightly increased in leptin-treated food-restricted sedentary rats. CONCLUSIONS: Although leptin treatment reduced RWA in ABA rats, it also prevented hypothermia and decreased food intake. Altogether, this resulted in a stronger negative energy balance and body weight loss in leptin-treated ABA rats.

Animals↗
PubMed2005

Olanzapine reduces physical activity in rats exposed to activity-based anorexia: possible implications for treatment of anorexia nervosa?

BACKGROUND: Anorexia nervosa (AN) patients often show extreme hypophagia and excessive physical activity. Activity-based anorexia (ABA) is considered an animal model of AN and mimics food restriction and hyperactivity in rats. This study investigated whether treatment with olanzapine (Zyprexa) reduces the development of ABA in rats. The effect of olanzapine treatment in AN patients was also evaluated in a small open-label study. METHODS: Rats were chronically (1 week) infused with olanzapine (7.5 mg/kg) and exposed to the ABA model or ad libitum feeding. Hyperactive AN patients were followed for up to 3 months of olanzapine treatment (5 mg/kg). RESULTS: Olanzapine treatment reduced development of ABA in rats by reducing running wheel activity, starvation-induced hypothermia and activation of the hypothalamus-pituitary-adrenal axis. Olanzapine treatment reduced activity levels of AN patients compared with untreated AN patients, without affecting body weight and plasma leptin levels. CONCLUSIONS: Olanzapine treatment reduced wheel running and thereby diminished development of ABA in rats. Olanzapine treatment also reduced physical activity in hyperactive AN patients in a small open-label study. These data support the need for controlled studies investigating the putative beneficial effects of olanzapine treatment in AN patients.

Adipose Tissue↗
PubMed2005

Synthesis of a novel potent cyclic peptide MC4-ligand by ring-closing metathesis.

The synthesis of a novel potent cyclic peptide MC4-ligand by ring-closing metathesis (RCM) is described. Based on the Ac-Nle-Gly-Lys-D-Phe-Arg-Trp-Gly-NH2-MC4 ligand, Ac-Nle-Alg-Lys-D-Phe-Arg-Trp-Alg-NH2 was designed and synthesized followed by cyclization using RCM. Both compounds are high affinity and selective MC4-R-agonists. The cyclic RCM-peptide was more potent in a rat-grooming assay.

Animals↗
PubMed2005

Peptoid-peptide hybrids as potent novel melanocortin receptor ligands.

All possible peptoid-peptide hybrids of an MC4 receptor agonist were synthesized and investigated on cells expressing different melanocortin (MC) receptor subtypes and for rat grooming behavior. In general, receptor selectivity remained while affinity and potency were decreased. The length of the functional group of Trp was more important for MC3 and MC5 than for MC4 receptor binding. In general, the potency of the peptoid-peptide hybrids to increase rat excessive grooming behavior correlated well with MC4 receptor pharmacology.

Amino Acid Sequence↗
PubMed2005

Voluntary access to a warm plate reduces hyperactivity in activity-based anorexia.

Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa. In ABA, scheduled feeding in combination with voluntary wheel running leads to hyperactivity, reduced food intake, severe body weight loss and hypothermia. In this study it was investigated whether hyperactivity in ABA could be reduced by introducing a warm plate (which was voluntary accessible and did not influence ambient temperature) into a part of the cage. In ad libitum fed rats, the presence of the warm plate did not influence body temperature, running wheel activity (RWA), body weight or food intake. During ABA, however, rats preferred the warm plate and hypothermia was prevented, while hyperactivity and body weight loss were significantly reduced when compared to ABA rats without a plate. Correlation analysis revealed a significant association between basal body temperature and RWA during the light phase in ABA rats. However, there was no evidence that initiation of light phase RWA was a result of hypothermia. These data suggest that ABA rats prefer to prevent hypothermia passively by choosing a warm plate rather than actively regulating body temperature by hyperactivity.

Animals↗
PubMed2005

Synthesis of cyclic peptidosulfonamides as scaffolds for MC4 pharmacophoric groups.

The synthesis of potential beta-turn mimetics based on cyclic sulfonamide peptoid/peptoid hybrids is described. These are readily synthesized using a solid phase protocol followed by cyclization in solution, and their suitability to combinatorial approaches is illustrated by the synthesis of a small but diversely functionalized library.

Cyclization↗
PubMed2005

alpha-MSH enhances activity-based anorexia.

Activity-based anorexia (ABA) is considered an animal model of anorexia nervosa (AN). In ABA, scheduled feeding in combination with voluntary access to running wheels, results in hyperactivity, hypophagia, body weight loss and activation of the HPA axis. Since stimulation of the melanocortin (MC) system has similar effects, this system is a candidate system involved in ABA. Here it is shown that chronic alpha-MSH treatment enhances ABA by increasing running wheel activity (RWA), decreasing food intake and increasing HPA axis activation.

Adrenocorticotropic Hormone↗
PubMed2005

Differential regulation of agouti-related protein and neuropeptide Y in hypothalamic neurons following a stressful event.

Stress affects eating behaviour in rodents and humans, suggesting that the regulation of energy balance and the stress response are coupled physiological processes. Neuropeptide Y (NPY) and agouti-related protein (AgRP) are potent food-stimulating neuropeptides that are highly co-localised in arcuate nucleus neurons of the hypothalamus. Recent studies have shown that NPY and AgRP mRNA levels in these neurons respond similarly to fasting and leptin, indicating functional redundancy of the neuropeptide systems in these orexigenic neurons. However, we have found that NPY and AgRP mRNA expression in arcuate nucleus neurons are dissociated immediately following a stressful event. Two hours following a brief session of inescapable foot shocks, AgRP mRNA levels are down-regulated (P < 0.0001). In contrast, NPY mRNA levels are up-regulated (P < 0.0001). To provide physiological relevance for this acute down-regulation of AgRP, an inverse agonist of melanocortin receptors, we have shown that acute intracerebroventricular injection of a melanocortin receptor agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), caused a significantly stronger activation of the hypothalamus-pituitary-adrenal-cortical (HPA) axis following a stressful event than in controls. Thus, AgRP and NPY mRNA levels in similar arcuate nucleus neurons are differentially regulated following a stressful event. This may contribute to increased sensitivity for alpha-MSH to activate the HPA axis following a repeated stressful experience.

Agouti-Related Protein↗