keyword
https://read.qxmd.com/read/38481681/evolutionary-identification-of-the-requirement-of-the-second-intracellular-loop-for-the-constitutive-activity-of-melanocortin-4-receptors
#1
JOURNAL ARTICLE
Bingxin Xu, Jindong Yao, Wenqi Song, Xinyi Yan, Ming Zhu, Jiangtao Li, Zhonglin Ma, Yanchuan Li, Yihao Li, Yanbin Fu, Liu Liu, Lei Li, Jianjun Lyu, Chao Zhang
Melanocortin-4 receptor (MC4R) functions as a crucial neuroendocrine G protein-coupled receptor (GPCR) in the central nervous system of mammals, displaying agonist-independent constitutive activity that is mainly determined by its N-terminal domain. We previously reported that zebrafish MC4R exhibited a much higher basal cAMP level in comparison to mammalian MC4Rs. However, the functional evolution of constitutive activities in chordate MC4Rs remains to be elucidated. Here we cloned and compared the constitutive activities of MC4Rs from nine vertebrate species and showed that the additive action of the N-terminus with the extracellular region or transmembrane domain exhibited a combined pharmacological effect on the MC4R constitutive activity...
March 8, 2024: ACS Pharmacology & Translational Science
https://read.qxmd.com/read/38458231/-improved-care-and-treatment-options-for-patients-with-hyperphagia-associated-obesity-in-bardet-biedl-syndrome
#2
JOURNAL ARTICLE
Metin Cetiner, Carsten Bergmann, Markus Bettendorf, Johanna Faust, Anja Gäckler, Bernarda Gillissen, Matthias Hansen, Maximilian Kerber, Günter Klaus, Jens König, Laura Kühlewein, Jun Oh, Annette Richter-Unruh, Julia von Schnurbein, Martin Wabitsch, Susann Weihrauch-Blüher, Lars Pape
Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk...
March 8, 2024: Klinische Pädiatrie
https://read.qxmd.com/read/38454158/%C3%AE-melanocyte-stimulating-hormone-alleviates-pathological-cardiac-remodeling-via-melanocortin-5-receptor
#3
JOURNAL ARTICLE
Anni Suominen, Guillem Saldo Rubio, Saku Ruohonen, Zoltán Szabó, Lotta Pohjolainen, Bishwa Ghimire, Suvi T Ruohonen, Karla Saukkonen, Jani Ijas, Sini Skarp, Leena Kaikkonen, Minying Cai, Sharon L Wardlaw, Heikki Ruskoaho, Virpi Talman, Eriika Savontaus, Risto Kerkelä, Petteri Rinne
α-Melanocyte-stimulating hormone (α-MSH) regulates diverse physiological functions by activating melanocortin receptors (MC-R). However, the role of α-MSH and its possible target receptors in the heart remain completely unknown. Here we investigate whether α-MSH could be involved in pathological cardiac remodeling. We found that α-MSH was highly expressed in the mouse heart with reduced ventricular levels after transverse aortic constriction (TAC). Administration of a stable α-MSH analog protected mice against TAC-induced cardiac hypertrophy and systolic dysfunction...
March 7, 2024: EMBO Reports
https://read.qxmd.com/read/38397265/syndromic-and-monogenic-obesity-new-opportunities-due-to-genetic-based-pharmacological-treatment
#4
REVIEW
Kallirhoe Kalinderi, Vasiliki Goula, Evdoxia Sapountzi, Vasiliki Rengina Tsinopoulou, Liana Fidani
Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence...
January 25, 2024: Children
https://read.qxmd.com/read/38253222/melanocortin-agonism-in-a-social-context-selectively-activates-nucleus-accumbens-in-an-oxytocin-dependent-manner
#5
JOURNAL ARTICLE
Charles L Ford, Anna A McDonough, Kengo Horie, Larry J Young
Social deficits are debilitating features of many psychiatric disorders, including autism. While time-intensive behavioral therapy is moderately effective, there are no pharmacological interventions for social deficits in autism. Many studies have attempted to treat social deficits using the neuropeptide oxytocin for its powerful neuromodulatory abilities and influence on social behaviors and cognition. However, clinical trials utilizing supplementation paradigms in which exogenous oxytocin is chronically administered independent of context have failed...
January 20, 2024: Neuropharmacology
https://read.qxmd.com/read/38185389/activation-of-the-melanocortin-1-receptor-attenuates-neuronal-apoptosis-after-traumatic-brain-injury-by-upregulating-merlin-expression
#6
JOURNAL ARTICLE
Jinqi Lu, Jin Wang, Haibo Ni, Bing Li, Jingjing Yang, Jie Zhu, Jie Qian, Rong Gao, Rong Xu
Traumatic brain injury (TBI) is a common disease worldwide with high mortality and disability rates. Besides the primary mechanical injury, the secondary injury associated with TBI can also induce numerous pathological changes, such as brain edema, nerve apoptosis, and neuroinflammation, which further aggravates neurological dysfunction and even causes the death due to the primary injury. Among them, neuronal apoptosis is a key link in the injury. Melanocortin-1 receptor (MC1R) is a G protein coupled receptor, belonging to the melanocortin receptor family...
January 5, 2024: Brain Research Bulletin
https://read.qxmd.com/read/38175730/a-human-obesity-associated-mc4r-mutation-with-defective-gq-11%C3%AE-signaling-leads-to-hyperphagia-in-mice
#7
JOURNAL ARTICLE
Peter J Metzger, Aileen Zhang, Bradley A Carlson, Hui Sun, Zhenzhong Cui, Yongqi Li, Marshal T Jahnke, Daniel R Layton, Meenakshi B Gupta, Naili Liu, Evi Kostenis, Oksana Gavrilova, Min Chen, Lee S Weinstein
Melanocortin 4 receptor (MC4R) mutations are the most common cause of human monogenic obesity and are associated with hyperphagia and increased linear growth. While MC4R is known to activate Gsα/cAMP signaling, a significant proportion of obesity-associated MC4R mutations do not affect MC4R/Gsα signaling. To further explore the role of specific MC4R signaling pathways in regulation of energy balance, we examined the signaling properties of one such mutant MC4R (F51L), as well as the metabolic consequences of MC4RF51L mutation in mice...
January 4, 2024: Journal of Clinical Investigation
https://read.qxmd.com/read/38147963/cotadutide-glp-1-glucagon-dual-receptor-agonist-modulates-hypothalamic-orexigenic-and-anorexigenic-neuropeptides-in-obese-mice
#8
JOURNAL ARTICLE
Renata Spezani, Thatiany Souza Marinho, Thiago Santos Reis, Marcia Barbosa Aguila, Carlos A Mandarim-de-Lacerda
The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n=20) or a high-fat diet (HF group, n=20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART)...
December 24, 2023: Peptides
https://read.qxmd.com/read/38116320/musclin-prevents-depression-like-behavior-in-male-mice-by-activating-urocortin-2-signaling-in-the-hypothalamus
#9
JOURNAL ARTICLE
Koji Ataka, Akihiro Asakawa, Haruki Iwai, Ikuo Kato
INTRODUCTION: Physical activity is recommended as an alternative treatment for depression. Myokines, which are secreted from skeletal muscles during physical activity, play an important role in the skeletal muscle-brain axis. Musclin, a newly discovered myokine, exerts physical endurance, however, the effects of musclin on emotional behaviors, such as depression, have not been evaluated. This study aimed to access the anti-depressive effect of musclin and clarify the connection between depression-like behavior and hypothalamic neuropeptides in mice...
2023: Frontiers in Endocrinology
https://read.qxmd.com/read/38110615/peripheral-mc1r-activation-modulates-immune-responses-and-is-neuroprotective-in-a-mouse-model-of-parkinson-s-disease
#10
JOURNAL ARTICLE
Pranay Srivastava, Shuhei Nishiyama, Fang Zhou, Sonia H Lin, Akriti Srivastava, Chienwen Su, Yuehang Xu, Weiyi Peng, Michael Levy, Michael Schwarzschild, Xiqun Chen
BACKGROUND: Melanocortin 1 receptor (MC1R) is a key pigmentation gene, and loss-of-function of MC1R variants that produce red hair may be associated with Parkinson's disease (PD). We previously reported compromised dopaminergic neuron survival in Mc1r mutant mice and dopaminergic neuroprotective effects of local injection of a MC1R agonist to the brain or a systemically administered MC1R agonist with appreciable central nervous system (CNS) permeability. Beyond melanocytes and dopaminergic neurons, MC1R is expressed in other peripheral tissues and cell types, including immune cells...
December 2023: Journal of Neuroimmune Pharmacology: the Official Journal of the Society on NeuroImmune Pharmacology
https://read.qxmd.com/read/38106197/inhibition-of-the-melanocortin-3-receptor-mc3r-causes-generalized-sensitization-to-anorectic-agents
#11
Naima S Dahir, Yijun Gui, Yanan Wu, Patrick R Sweeney, Savannah Y Williams, Luis E Gimenez, Tomi K Sawyer, Stephen T Joy, Anna K Mapp, Roger D Cone
The melanocortin-3 receptor (MC3R) acts presynaptically to regulate GABA release from agouti-related protein (AgRP) nerve terminals and thus may be a negative regulator of multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of MC3R in regulating the response to various anorexigenic agents. Our findings reveal that genetic deletion or pharmacological inhibition of MC3R improves the dose responsiveness to Glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss...
December 7, 2023: bioRxiv
https://read.qxmd.com/read/38035762/effects-of-the-central-melanocortin-system-on-feed-intake-metabolic-hormones-and-insulin-action-in-the-sheep
#12
JOURNAL ARTICLE
Richard A Ehrhardt, Sarah L Giesy, Stanley M Hileman, Karen L Houseknecht, Yves R Boisclair
Voluntary feed intake is insufficient to meet the nutrient demands associated with late pregnancy in prolific ewes and early lactation in high yielding dairy cows. Under these conditions, peripheral signals such as growth hormone and ceramides trigger adaptations aimed at preserving metabolic well-being. Recent work in rodents has shown that the central nervous system-melanocortin (CNS-MC) system, consisting of alpha-melanocyte stimulating hormone (α-MSH) and agouti-related peptide (AGRP) acting respectively as agonist and antagonist on central MC receptors, contributes to the regulation of some of the same adaptations...
November 30, 2023: Journal of Animal Science
https://read.qxmd.com/read/37937009/advances-in-anti-obesity-pharmacotherapy-current-treatments-emerging-therapies-and-challenges
#13
REVIEW
Skyler Brandfon, Adi Eylon, Deepesh Khanna, Mayur S Parmar
Obesity is a major public health concern linked to health risks such as hypertension, hyperlipidemia, type 2 diabetes mellitus (T2DM), stroke, metabolic syndrome, asthma, and cancer. It is among the leading causes of morbidity and mortality worldwide caused by an unhealthy diet and lack of physical activity, but genetic or hormonal factors may also contribute. Over a third of adults in the United States are obese. Pharmacological agents have been designed to reduce weight gain caused by excessive calorie intake and low physical activity...
October 2023: Curēus
https://read.qxmd.com/read/37930356/glucagon-like-peptide-1-receptor-activation-stimulates-pka-mediated-phosphorylation-of-raptor-and-this-contributes-to-the-weight-loss-effect-of-liraglutide
#14
JOURNAL ARTICLE
Thao D V Le, Dianxin Liu, Gai-Linn K Besing, Ritika Raghavan, Blair J Ellis, Ryan P Ceddia, Sheila Collins, Julio E Ayala
The canonical target of the glucagon-like peptide-1 receptor (GLP-1R), Protein Kinase A (PKA), has been shown to stimulate mechanistic Target of Rapamycin Complex 1 (mTORC1) by phosphorylating the mTOR-regulating protein Raptor at Ser791 following β-adrenergic stimulation. The objective of these studies is to test whether GLP-1R agonists similarly stimulate mTORC1 via PKA phosphorylation of Raptor at Ser791 and whether this contributes to the weight loss effect of the therapeutic GLP-1R agonist liraglutide...
November 6, 2023: ELife
https://read.qxmd.com/read/37908575/beneficial-effects-of-setmelanotide-in-a-5-year-old-boy-with-pomc-deficiency-and-on-his-caregivers
#15
Beatrice Dubern, Alexandre Lourdelle, Karine Clément
The melanocortin-4 receptor agonist setmelanotide is now recommended for the treatment of genetic obesity due to proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency in patients aged 6 years and older. Here, we describe the clinical benefit of setmelanotide administration in a 5-year-old child with severe hyperphagia and obesity due to POMC deficiency. Daily administration of 0.5 mg setmelanotide for 12 months resulted in significant weight loss of -30 kg from baseline (-36% of weight loss) and improvements in hyperphagia and metabolic status...
May 2023: JCEM Case Rep
https://read.qxmd.com/read/37888071/efficacy-and-safety-of-setmelanotide-a-melanocortin-4-receptor-agonist-for-obese-patients-a-systematic-review-and-meta-analysis
#16
REVIEW
Bárbara Ferraz Barbosa, Francisco Cezar Aquino de Moraes, Camila Bordignon Barbosa, Plínio Takashi Karubi Palavicini Santos, Izael Pereira da Silva, Bruno Araujo Alves da Silva, Jamile Cristine Marques Barros, Rommel Mario Rodríguez Burbano, Ney Pereira Carneiro Dos Santos, Marianne Rodrigues Fernandes
BACKGROUND: A malfunction in the melanocortin-4 receptor (MC4R) is associated with obesity in rare genetic syndromes; setmelanotide is a new drug that activates this receptor and is being used to treat severe obesity. This meta-analysis evaluated the efficacy and safety of setmelanotide for weight loss in severe obesity linked to human MC4R deficiency. METHODS: We searched PubMed, Embase, and Cochrane for randomized and nonrandomized clinical trials using setmelanotide...
October 4, 2023: Journal of Personalized Medicine
https://read.qxmd.com/read/37854631/development-of-melanocortin-4-receptor-agonists-by-exploiting-animal-derived-macrocyclic-disulfide-rich-peptide-scaffolds
#17
JOURNAL ARTICLE
Edin Muratspahić, Despoina Aslanoglou, Andrew M White, Claudia Draxler, Xaver Kozisek, Zara Farooq, David J Craik, Peter J McCormick, Thomas Durek, Christian W Gruber
G protein-coupled receptors are among the most widely studied classes of drug targets. A major challenge in this field is to develop ligands that will selectively modulate a single receptor subtype to overcome the disadvantages of undesired "off target" effects caused by lack of target and thus signaling specificity. In the current study, we explored ligand design for the melanocortin 4 receptor (MC4R) since it is an attractive target for developing antiobesity drugs. Endogenously, the receptor is activated by peptide ligands, i...
October 13, 2023: ACS Pharmacology & Translational Science
https://read.qxmd.com/read/37804223/label-free-quantitative-thermal-proteome-profiling-reveals-target-transcription-factors-with-activities-modulated-by-mc3r-signaling
#18
JOURNAL ARTICLE
Friederike A Sandbaumhüter, Mariya Nezhyva, Per E Andrén, Erik T Jansson
Thermal proteome profiling with label-free quantitation using ion-mobility-enhanced LC-MS offers versatile data sets, providing information on protein differential expression, thermal stability, and the activities of transcription factors. We developed a multidimensional data analysis workflow for label-free quantitative thermal proteome profiling (TPP) experiments that incorporates the aspects of gene set enrichment analysis, differential protein expression analysis, and inference of transcription factor activities from LC-MS data...
October 17, 2023: Analytical Chemistry
https://read.qxmd.com/read/37689110/milestones-in-the-journey-towards-addressing-obesity-past-trials-and-triumphs-recent-breakthroughs-and-an-exciting-future-in-the-era-of-emerging-effective-medical-therapies-and-integration-of-effective-medical-therapies-with-metabolic-surgery
#19
JOURNAL ARTICLE
Michail Kokkorakis, Angeliki Katsarou, Niki Katsiki, Christos S Mantzoros
The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon...
September 7, 2023: Metabolism: Clinical and Experimental
https://read.qxmd.com/read/37677000/efficacy-and-safety-of-the-melanocortin-pan-agonist-pl9643-in-a-phase-2-study-of-patients-with-dry-eye-disease
#20
JOURNAL ARTICLE
David Evans, Kenneth Kenyon, George Ousler, Michael Watson, Patrick Vollmer, Eugene B McLaurin, Gail Torkildsen, Jason Winters, John Dodd, Robert Jordan, Stephen T Wills, Carl Spana
Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms...
September 7, 2023: Journal of Ocular Pharmacology and Therapeutics
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