Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin’s effects on food intake are ...mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp−/−;Npy−/− and Mc3r−/−;Mc4r−/− double knockout mice as well as Npy−/− and Agrp−/− single knockout mice with either ghrelin or an orally active nonpeptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. Although deletion of either NPY or AgRP caused only a modest or nondetectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.
Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The ...molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.
Background and purpose: Melanin‐concentrating hormone (MCH) is an orexigenic neuropeptide expressed in the lateral hypothalamus that is involved in feeding and body weight regulation. ...Intracerebroventricular infusion of a peptidic MCH1 receptor antagonist ameliorated obesity in murine models. Recently, small molecule MCH1 receptor antagonists have been developed and characterized for the treatment of obesity. However, little is known of the mechanism of the anti‐obesity effects of MCH1 receptor antagonists.
Experimental approach: To examine the mechanisms of action of the anti‐obesity effect of MCH1 receptor antagonists more precisely, we conducted a pair‐feeding study in mice with diet‐induced obesity (DIO), chronically treated with an orally active and highly selective MCH1 receptor antagonist and examined changes in mRNA expression levels in liver, brown and white adipose tissues. We also assessed the acute effects of the MCH1 receptor antagonist in energy expenditure under thermoneutral conditions.
Key results: Treatment with the MCH1 receptor antagonist at 30 mg·kg−1 for 1 month moderately suppressed feeding and significantly reduced body weight by 24%. In contrast, pair‐feeding resulted in a smaller weight reduction of 10%. Treatment with the MCH1 receptor antagonist resulted in a higher body temperature compared with the pair‐fed group. TaqMan and calorimetry data suggested that the MCH1 receptor antagonist also stimulated thermogenesis.
Conclusions and implications: Our results indicate that an MCH1 receptor antagonist caused anti‐obesity effects im mice by acting on both energy intake and energy expenditure.
IntroductionAgeing in place (AIP) for persons with dementia is encouraged by European governments and societies. Healthcare packages may need reassessment to account for the preferences of care ...funders, patients and informal caregivers. By providing insight into people’s preferences, discrete choice experiments (DCEs) can help develop consensus between stakeholders. This protocol paper outlines the development of a Dutch national study to cocreate a healthcare package design methodology built on DCEs that is person-centred and helps support informal caregivers and persons with dementia to AIP. A subpopulation analysis of persons with dementia with a migration background is planned due to their high risk for dementia and under-representation in research and care.Methods and analysisThe DCE is designed to understand how persons with dementia and informal caregivers choose between different healthcare packages. Qualitative methods are used to identify and prioritise important care components for persons with dementia to AIP. This will provide a list of care components that will be included in the DCE, to quantify the care needs and preferences of persons with dementia and informal caregivers. The DCE will identify individual and joint preferences to AIP. The relative importance of each attribute will be calculated. The DCE data will be analysed with the use of a random parameters logit model.Ethics and disseminationEthics approval was waived by the Amsterdam University Medical Center (W23_112 #23.137). A study summary will be available on the websites of Alzheimer Nederland, Pharos and Amsterdam Public Health institute. Results are expected to be presented at (inter)national conferences, peer-reviewed papers will be submitted, and a dissemination meeting will be held to bring stakeholders together. The study results will help improve healthcare package design for all stakeholders.
To assess the contribution of potential central nervous system pathways implicated in the control of appetite regulation and energy metabolism, it is essential to first identify appropriate animal ...models. Melanin-concentrating hormone (MCH), a conserved cyclic neuropeptide implicated in the modulation of food intake, has been shown to bind and activate two G-protein-coupled receptors, called GPR24 and MCHR2, expressed in human brain and other tissues. Here we show that several non-human species (rat, mouse, hamster, guinea pig, and rabbit) do not have functional MCHR2 receptors, or encode a nonfunctional MCHR2 pseudogene while retaining GPR24 expression. We identified three species for further evaluation that express both MCH receptor subtypes. We cloned and functionally characterized dog, ferret, and rhesus GPR24 and MCHR2 in mammalian cells and studied their brain distribution patterns by in situ hybridization. The homology, expression profile, and functional similarity of the receptors in the dog, ferret, and rhesus to that of human support the potential use of these species as preclinical animal models in the development of therapeutic agents for obesity or other MCH-mediated disorders.
Melanin-concentrating hormone (MCH) is a cyclic 19-aa hypothalamic neuropeptide derived from a larger prohormone precursor of MCH (Pmch), which also encodes neuropeptide EI (NEI) and neuropeptide GE ...(NGE). Pmch-deficient (Pmch-/-) mice are lean, hypophagic, and have an increased metabolic rate. Transgenic mice overexpressing Pmch are hyperphagic and develop mild obesity. Consequently, MCH has been implicated in the regulation of energy homeostasis. The MCH 1 receptor (MCH1R) is one of two recently identified G protein-coupled receptors believed to be responsible for the actions of MCH. We evaluated the physiological role of MCH1R by generating MCH1R-deficient (Mch1r-/-) mice. Mch1r-/-mice have normal body weights, yet are lean and have reduced fat mass. Surprisingly, Mch1r-/-mice are hyperphagic when maintained on regular chow, and their leanness is a consequence of hyperactivity and altered metabolism. Consistent with the hyperactivity, Mch1r-/-mice are less susceptible to diet-induced obesity. Importantly, chronic central infusions of MCH induce hyperphagia and mild obesity in wild-type mice, but not in Mch1r-/-mice. We conclude that MCH1R is a physiologically relevant MCH receptor in mice that plays a role in energy homeostasis through multiple actions on locomotor activity, metabolism, appetite, and neuroendocrine function.
Abstract A decrease in bone density at the hip or spine has been shown to increase the risk of fracture. A limitation of the bone mineral density (BMD) measurement is that it provides only a measure ...of a bone sample's average density when projected onto a 2D surface. Effectively, what determines bone fracture is whether an applied load exceeds ultimate strength, with both bone tissue material properties (can be approximated through bone density), and geometry playing a role. The goal of this project was to use bone geometry and BMD obtained from radiographs and DXA measurements respectively to estimate fracture risk, using a two-dimensional finite element model (FEM) of the sagittal plane of lumbar vertebrae. The Canadian Multicentre Osteoporosis Study (CaMos) data was used for this study. There were 4194 men and women over the age of 50 years, with 786 having fractures. Each subject had BMD testing and radiographs of their lumbar vertebrae. A single two dimensional FEM of the first to fourth lumbar vertebra was automatically generated for each subject. Bone tissue stiffness was assigned based on the BMD of the individual vertebrae, and adjusted for patient age. Axial compression boundary conditions were applied with a force proportional to body mass. The resulting overall strain from the applied force was found. Men and women were analyzed separately. At baseline, the sensitivity of BMD to predict fragility fractures in women and men was 3.77% and 0.86%, while the sensitivity of FEM to predict fragility fractures for women and men was 10.8% and 11.3%. The FEM ROC curve demonstrated better performance compared to BMD. The relative risk of being considered at high fracture risk using FEM at baseline, was a better predictor of 5 year incident fragility fracture risk compared to BMD.
The expression pattern of mRNA encoding two orexin receptors (OX
1R and OX
2R) in the rat brain was examined. OX
1R and OX
2R exhibited marked differential distribution. Within the hypothalamus, OX
...1R mRNA is most abundant in the ventromedial hypothalamic nucleus whereas OX
2R is predominantly expressed in the paraventricular nucleus. High levels of OX
1R mRNA were also detected in tenia tecta, the hippocampal formation, dorsal raphe, and locus coeruleus. OX
2R mRNA is mainly expressed in cerebral cortex, nucleus accumbens, subthalamic and paraventricular thalamic nuclei, anterior pretectal nucleus. The presence of orexin receptor mRNA in the hypothalamus is in support of its proposed role in feeding regulation. Broad central distribution of orexin receptors may indicate additional functions for orexins.
The objectives were to estimate genetic parameters needed to elucidate the relationships of a molecular breeding value (MBV) for marbling, intramuscular fat (IMF) of yearling bulls measured with ...ultrasound, and marbling score (MRB) of slaughtered steers, and to assess the utility of MBV and IMF in predicting the breeding value for MRB. Records for MRB (n = 38,296) and IMF (n = 6,594) were from the American Angus Association database used for national cattle evaluation. A total of 1,006 records of MBV were used in this study. (Co)variance components were estimated with ASREML, fitting an animal model with fixed contemporary groups for MRB and IMF similar to those used in the Angus national genetic evaluation. The overall mean was the only fixed effect included in the model for MBV. Heritability estimates for carcass measures were 0.48 ± 0.03, 0.31 ± 0.03, and 0.98 ± 0.05 for MRB, IMF, and MBV, respectively. Genetic correlations of IMF and MBV with MRB were 0.56 ± 0.09 and 0.38 ± 0.10, respectively. The genetic correlation between IMF and MBV was 0.80 ± 0.22. These results indicate the MBV evaluated may yield a greater genetic advance of approximately 20% when used as an indicator trait for genetic prediction of MRB compared with IMF. However, neither of these indicators alone provides sufficient information to produce highly accurate prediction of breeding value for the economically relevant trait MRB. Given that the goal is a highly accurate prediction of true breeding value for MRB, results of this work point to the need to 1) continue progeny testing, and 2) continue increasing the genetic correlation between the MBV and MRB.
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