Publications by authors named "R D Cone"

575 Publications

Cardiac phenotype and tissue sodium content in adolescents with defects in the melanocortin system.

J Clin Endocrinol Metab 2021 May 24. Epub 2021 May 24.

Department of Congenital Heart Disease, Deutsches Herzzentrum Berlin, Berlin, Germany.

Context: Pro-opiomelanocortin (POMC) and the melanocortin-4 receptor (MC4R) play a pivotal role in the leptin-melanocortin pathway. Mutations in these genes lead to monogenic types of obesity due to severe hyperphagia. In addition to dietary-induced obesity, a cardiac phenotype without hypertrophy has been identified in MC4R knockout mice.

Objective: We aimed to characterize cardiac morphology and function as well as tissue Na + content in humans with mutations in POMC and MC4R genes.

Participants: A cohort of 42 patients (5 patients with bi-allelic POMC mutations, 6 heterozygous MC4R mutation carriers, 19 obese controls without known monogenic cause and 12 normal-weight controls) underwent cardiac magnetic resonance (CMR) imaging and 23Na-MRI.

Results: Monogenic obese patients with POMC or MC4R mutation respectively had a significantly lower left ventricular mass/body surface area (BSA) compared to non-monogenic obese patients. Left ventricular end-diastolic volume/BSA was significantly lower in POMC- and MC4R-deficient patients than in non-monogenic obese patients. Subcutaneous fat and skin Na + content was significantly higher in POMC- and MC4R-deficient patients compared to non-monogenic obese patients. In these compartments, the water content was significantly higher in patients with POMC and MC4R mutation than in control-groups.

Conclusions: Patients with POMC or MC4R mutations carriers had a lack of transition to hypertrophy, significantly lower cardiac muscle mass/BSA and stored more Na + within the subcutaneous fat tissue compared to non-monogenic obese patients. The results point towards the role of the melanocortin pathway for cardiac function, tissue Na + storage and the importance of including cardiologic assessments into the diagnostic work-up of these patients.
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http://dx.doi.org/10.1210/clinem/dgab368DOI Listing
May 2021

Observational cohort study of the effect of a single lubricant exposure during transvaginal ultrasound on cell-shedding from the vaginal epithelium.

PLoS One 2021 3;16(5):e0250153. Epub 2021 May 3.

Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, United States of America.

The outer layers of the vaginal epithelium (VE) are important because they accumulate glycogen which, under optimal conditions, Lactobacillus spp. consume to grow and acidify the vaginal microenvironment with lactic acid. We hypothesized that exposure to lubricant, for example in the conduct of a transvaginal ultrasound (TVUS), may contribute to the shedding of mature epithelial cells, exposing immature cells. Cervicovaginal fluid (CVF) was sampled at four time points by menstrual cup (Softdisc™) from 50 women referred for TVUS, during which a controlled volume of lubricant was applied to the TVUS wand. Samples were collected (1) immediately before TVUS and (2) 6-12 hours, (3) within one week, and (4) two weeks after TVUS. Clinical vaginal lubricants are similar to commercial lubricants, and often have a high osmolality or pH, and contain bactericides such as methylparaben and propylparaben. The number and maturity of epithelial cells in each CVF sample were measured by quantitative and differential fluorimetry (maturity index, MI). Comparisons of cell-counts and maturity were made by paired Wilcoxon signed-rank tests. Among women with a high pre-TVUS MI (> 3), there was a decrease in median cell-count and mean MI in the sample collected 6-12 hours after TVUS (p<0.001, n = 26 and p < 0.001, n = 26, respectively). For these women, cell-count and MI remained lower in the sample collected within the subsequent week (p<0.001, n = 29 and p<0.01, n = 29, respectively), and MI remained lower in the sample collected within two weeks of TVUS (p<0.01, n = 25), compared to the pre-TVUS sample. Among participants with a low pre-TVUS MI (< 3), cell-count was higher in the sample collected within two weeks of TVUS compared to the pre-TVUS sample (p = 0.03, n = 15), but no significant changes in MI were observed. Results were similar when restricted to reproductive-age women. This preliminary data indicates hypertonic vaginal lubricants may increase vaginal epithelial cell shedding.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092793PMC
May 2021

The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.

Sci Transl Med 2021 Apr;13(590)

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.

Ablation of hypothalamic AgRP (Agouti-related protein) neurons is known to lead to fatal anorexia, whereas their activation stimulates voracious feeding and suppresses other motivational states including fear and anxiety. Despite the critical role of AgRP neurons in bidirectionally controlling feeding, there are currently no therapeutics available specifically targeting this circuitry. The melanocortin-3 receptor (MC3R) is expressed in multiple brain regions and exhibits sexual dimorphism of expression in some of those regions in both mice and humans. MC3R deletion produced multiple forms of sexually dimorphic anorexia that resembled aspects of human anorexia nervosa. However, there was no sexual dimorphism in the expression of MC3R in AgRP neurons, 97% of which expressed MC3R. Chemogenetic manipulation of arcuate MC3R neurons and pharmacologic manipulation of MC3R each exerted potent bidirectional regulation over feeding behavior in male and female mice, whereas global ablation of MC3R-expressing cells produced fatal anorexia. Pharmacological effects of MC3R compounds on feeding were dependent on intact AgRP circuitry in the mice. Thus, the dominant effect of MC3R appears to be the regulation of the AgRP circuitry in both male and female mice, with sexually dimorphic sites playing specialized and subordinate roles in feeding behavior. Therefore, MC3R is a potential therapeutic target for disorders characterized by anorexia, as well as a potential target for weight loss therapeutics.
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http://dx.doi.org/10.1126/scitranslmed.abd6434DOI Listing
April 2021

Network dynamics of hypothalamic feeding neurons.

Proc Natl Acad Sci U S A 2021 Apr;118(14)

Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;

Mutations in the melanocortin 4 receptor (MC4R) result in hyperphagia and obesity and are the most common cause of monogenic obesity in humans. Preclinical rodent studies have determined that the critical role of the MC4R in controlling feeding can be mapped in part to its expression in the paraventricular nucleus of the hypothalamus (paraventricular nucleus [PVN]), where it regulates the activity of anorexic neural circuits. Despite the critical role of PVN MC4R neurons in regulating feeding, the in vivo neuronal activity of these cells remains largely unstudied, and the network activity of PVN MC4R neurons has not been determined. Here, we utilize in vivo single-cell endomicroscopic and mathematical approaches to determine the activity and network dynamics of PVN MC4R neurons in response to changes in energy state and pharmacological manipulation of central melanocortin receptors. We determine that PVN MC4R neurons exhibit both quantitative and qualitative changes in response to fasting and refeeding. Pharmacological stimulation of MC4R with the therapeutic MC4R agonist setmelanotide rapidly increases basal PVN MC4R activity, while stimulation of melanocortin 3 receptor (MC3R) inhibits PVN MC4R activity. Finally, we find that distinct PVN MC4R neuronal ensembles encode energy deficit and energy surfeit and that energy surfeit is associated with enhanced network connections within PVN MC4R neurons. These findings provide valuable insight into the neural dynamics underlying hunger and energy surfeit.
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http://dx.doi.org/10.1073/pnas.2011140118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040641PMC
April 2021

Structure-Based Design of Melanocortin 4 Receptor Ligands Based on the SHU-9119-hMC4R Cocrystal Structure†.

J Med Chem 2021 01 14;64(1):357-369. Epub 2020 Nov 14.

Research Group of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.

The melanocortin receptors (MC1R-MC5R) belong to class A G-protein-coupled receptors (GPCRs) and are known to have receptor-specific roles in normal and diseased states. Selectivity for MC4R is of particular interest due to its involvement in various metabolic disorders, including obesity, feeding regulation, and sexual dysfunctions. To further improve the potency and selectivity of MC4R (ant)agonist peptide ligands, we designed and synthesized a series of cyclic peptides based on the recent crystal structure of MC4R in complex with the well-characterized antagonist (Ac-Nle-c[Asp-His-DNal(2')-Arg-Trp-Lys]-NH). These analogues were pharmacologically characterized , giving key insights into exploiting binding site subpockets to deliver more selective ligands. More specifically, the side chains of the Nle, DNal(2'), and Trp residues in , as well as the amide linkage between the Asp and Lys side chains, were found to represent structural features engaging a hMC4R/hMC3R selectivity switch.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01620DOI Listing
January 2021