4.6 Review

Targeting the central melanocortin system for the treatment of metabolic disorders

Related references

Note: Only part of the references are listed.
Article Chemistry, Medicinal

Discovery of the Potent and Selective MC4R Antagonist PF-07258669 for the Potential Treatment of Appetite Loss

Michelle R. Garnsey et al.

Summary: MC4R is involved in the regulation of appetite and food intake, and deficiency in MC4R signaling leads to weight gain in humans. Through screening and optimization, a series of orally bioavailable, small-molecule MC4R antagonists were identified, and compound 23, a potent and selective MC4R antagonist, showed significant efficacy in an aged rat model of cachexia and has progressed into clinical trials.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Article Neurosciences

Organization of neural systems expressing melanocortin-3 receptors in the mouse brain: Evidence for sexual dimorphism

Michelle N. Bedenbaugh et al.

Summary: This study provides a comprehensive mapping of MC3R neural circuits, revealing their connections with multiple brain regions and their sexual dimorphism. The findings suggest that MC3R plays an important role in controlling various complex behaviors.

JOURNAL OF COMPARATIVE NEUROLOGY (2022)

Article Endocrinology & Metabolism

Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period

Andrea M. Haqq et al.

Summary: This study aimed to evaluate the effect of setmelanotide on bodyweight in patients with Bardet-Biedl syndrome and Alstrom syndrome. The results showed that setmelanotide resulted in significant bodyweight reductions in patients with Bardet-Biedl syndrome, but its effect on patients with Alstrom syndrome remains inconclusive.

LANCET DIABETES & ENDOCRINOLOGY (2022)

Article Chemistry, Medicinal

Development of a Therapeutic Peptide for Cachexia Suggests a Platform Approach for Drug-like Peptides

Kenneth A. Gruber et al.

Summary: During the development of a drug for treating cachexia, we discovered the importance of peptide transport across the blood-brain barrier. Through screening the medical literature, we found that bile salt transport peptides could effectively cross the BBB. We designed a drug peptide, TCMCB07, and made modifications to its C-terminal amino acid sequence to extend its half-life, providing a platform approach for producing similar drug peptides.

ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE (2022)

Article Cell Biology

Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-alpha-MSH and setmelanotide

Nicolas A. Heyder et al.

Summary: The study analyzed the structure of melanocortin-4 receptor and revealed the mechanism of agonist-induced receptor activation, as well as discussed the interactions between two anti-obesity drugs and the receptor.

CELL RESEARCH (2021)

Article Multidisciplinary Sciences

MC3R links nutritional state to childhood growth and the timing of puberty

B. Y. H. Lam et al.

Summary: MC3R regulates the timing of sexual maturation, linear growth rate, and accrual of lean mass, while MC4R controls appetite, food intake, and energy expenditure. Loss of MC3R leads to delayed puberty, reduced linear growth, and decreased lean mass, while loss of MC4R results in delayed sexual maturation and insensitivity of reproductive cycle length to nutritional perturbation.

NATURE (2021)

Article Multidisciplinary Sciences

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling

Hadar Israeli et al.

Summary: This study elucidated the mechanism of MC4R activation, identified a molecular switch for initiating satiation signaling, and suggested the involvement of calcium in agonist efficacy. These findings may guide the design of future weight-management drugs.

SCIENCE (2021)

Article Cell Biology

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

Patrick Sweeney et al.

Summary: Research has shown that MC3R plays a crucial role in controlling feeding behavior, primarily through its impact on the AgRP circuitry. While there is sexual dimorphism in the expression of MC3R in different brain regions, there is no sexual dimorphism in AgRP neurons. MC3R is considered a potential therapeutic target for disorders such as anorexia.

SCIENCE TRANSLATIONAL MEDICINE (2021)

Article Cell Biology

Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

Bas Brouwers et al.

Summary: Research on melanocortin-4 receptor (MC4R) mutations associated with obesity reveals the importance of endocytosis, intracellular trafficking, and homodimerization in regulating MC4R function, supporting the development of novel therapies for weight loss.

CELL REPORTS (2021)

Article Dermatology

A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

Varvara Kanti et al.

Summary: The study found that treatment with the MC4R agonist setmelanotide increased skin pigmentation and occasionally darkened hair color in both POMC and LEPR-deficient patients. Results suggest that tanning intensity levels may stabilize over time during continuous treatment, with lips and nevi also darkening. Regular skin examinations before and during MC4R agonist treatment are important for patient safety.

SKIN PHARMACOLOGY AND PHYSIOLOGY (2021)

Article Medicine, Research & Experimental

The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alstrom syndrome: Phase 3 trial design

Robert M. Haws et al.

Summary: This is a phase 3 trial investigating the efficacy and safety of the MC4R agonist setmelanotide for treating obesity and hyperphagia in individuals with BBS and Alstrom syndrome. The study aims to enroll 30 participants with the primary endpoint being the proportion of participants achieving a clinically meaningful reduction in body weight after approximately 52 weeks. Safety and tolerability will be assessed by frequency of adverse events.

CONTEMPORARY CLINICAL TRIALS COMMUNICATIONS (2021)

Review Pharmacology & Pharmacy

Bremelanotide: New Drug Approved for Treating Hypoactive Sexual Desire Disorder

Danielle Mayer et al.

ANNALS OF PHARMACOTHERAPY (2020)

Article Multidisciplinary Sciences

NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons

Linda Engstroem Ruud et al.

NATURE COMMUNICATIONS (2020)

Review Endocrinology & Metabolism

Integrating Hunger with Rival Motivations

Amy K. Sutton et al.

TRENDS IN ENDOCRINOLOGY AND METABOLISM (2020)

Article Medicine, Research & Experimental

Semaglutide lowers body weight in rodents via distributed neural pathways

Sanaz Gabery et al.

JCI INSIGHT (2020)

Review Nutrition & Dietetics

The Ghrelin-AgRP Neuron Nexus in Anorexia Nervosa: Implications for Metabolic and Behavioral Adaptations

Mathieu Mequinion et al.

FRONTIERS IN NUTRITION (2020)

Article Genetics & Heredity

Genetic architecture of human thinness compared to severe obesity

Fernando Riveros-McKay et al.

PLOS GENETICS (2019)

Article Biochemistry & Molecular Biology

Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity

Luca A. Lotta et al.

Review Biochemistry & Molecular Biology

Current Mechanistic and Pharmacodynamic Understanding of Melanocortin-4 Receptor Activation

Shubh Sharma et al.

MOLECULES (2019)

Article Biology

Need-based prioritization of behavior

C. Joseph Burnett et al.

ELIFE (2019)

Article Pharmacology & Pharmacy

Bremelanotide: First Approval

Sohita Dhillon et al.

DRUGS (2019)

Article Obstetrics & Gynecology

Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder Two Randomized Phase 3 Trials

Sheryl A. Kingsberg et al.

OBSTETRICS AND GYNECOLOGY (2019)

Article Biochemistry & Molecular Biology

A Neural Circuit for the Suppression of Pain by a Competing Need State

Amber L. Alhadeff et al.

Article Medicine, Research & Experimental

Motivational valence is determined by striatal melanocortin 4 receptors

Anna Mathia Klawonn et al.

JOURNAL OF CLINICAL INVESTIGATION (2018)

Article Psychology, Clinical

Treatment With a Ghrelin Agonist in Outpatient Women With Anorexia Nervosa: A Randomized Clinical Trial

Pouneh K. Fazeli et al.

JOURNAL OF CLINICAL PSYCHIATRY (2018)

Article Biochemistry & Molecular Biology

MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

Karine Clement et al.

NATURE MEDICINE (2018)

Article Cell Biology

Nucleus of the Solitary Tract Serotonin 5-HT2C Receptors Modulate Food Intake

Giuseppe D'Agostino et al.

CELL METABOLISM (2018)

Article Multidisciplinary Sciences

Regulation of energy rheostasis by the melanocortin-3 receptor

Masoud Ghamari-Langroudi et al.

SCIENCE ADVANCES (2018)

Review Neurosciences

Toward a Wiring Diagram Understanding of Appetite Control

Mark L. Andermann et al.

NEURON (2017)

Article Multidisciplinary Sciences

AgRP to Kiss1 neuron signaling links nutritional state and fertility

Stephanie L. Padilla et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2017)

Article Multidisciplinary Sciences

MRAP2 regulates ghrelin receptor signaling and hunger sensing

Dollada Srisai et al.

NATURE COMMUNICATIONS (2017)

Review Neurosciences

A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling

Andrew A. Butler et al.

FRONTIERS IN NEUROSCIENCE (2017)

Article Endocrinology & Metabolism

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency

Tinh-Hai Collet et al.

MOLECULAR METABOLISM (2017)

Article Biochemistry & Molecular Biology

Regions of MRAP2 required for the inhibition of orexin and prokineticin receptor signaling

Alix A. J. Rouault et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (2017)

Review Biochemistry & Molecular Biology

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Mark D. Ericson et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (2017)

Article Biochemistry & Molecular Biology

Biased signaling at neural melanocortin receptors in regulation of energy homeostasis

Li-Kun Yang et al.

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE (2017)

Review Endocrinology & Metabolism

Liraglutide for weight management: a critical review of the evidence

A. Mehta et al.

OBESITY SCIENCE & PRACTICE (2017)

Review Physiology

GLP-1 and weight loss: unraveling the diverse neural circuitry

Scott E. Kanoski et al.

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY (2016)

Article Pharmacology & Pharmacy

Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist

Jocelyn M. Bischof et al.

BRITISH JOURNAL OF PHARMACOLOGY (2016)

Article Cell Biology

Parabrachial CGRP Neurons Control Meal Termination

Carlos A. Campos et al.

CELL METABOLISM (2016)

Review Neurosciences

Melanocortin-4 receptor-regulated energy homeostasis

Michael J. Krashes et al.

NATURE NEUROSCIENCE (2016)

Article Neurosciences

Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state

Stephanie L. Padilla et al.

NATURE NEUROSCIENCE (2016)

Article Neurosciences

Hunger-Driven Motivational State Competition

C. Joseph Burnett et al.

NEURON (2016)

Article Medicine, General & Internal

Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist

Peter Kuehnen et al.

NEW ENGLAND JOURNAL OF MEDICINE (2016)

Review Biochemistry & Molecular Biology

Neural Control of Energy Balance: Translating Circuits to Therapies

Laurent Gautron et al.

Article Biochemistry & Molecular Biology

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Marcelo O. Dietrich et al.

Article Medicine, Research & Experimental

Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice

Christoffer Clemmensen et al.

EMBO MOLECULAR MEDICINE (2015)

Article Medicine, General & Internal

Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes The SCALE Diabetes Randomized Clinical Trial

Melanie J. Davies et al.

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION (2015)

Article Multidisciplinary Sciences

G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons

Masoud Ghamari-Langroudi et al.

NATURE (2015)

Article Multidisciplinary Sciences

Neurons for hunger and thirst transmit a negative-valence teaching signal

J. Nicholas Betley et al.

NATURE (2015)

Article Neurosciences

A neural basis for melanocortin-4 receptor-regulated appetite

Alastair S. Garfield et al.

NATURE NEUROSCIENCE (2015)

Article Medicine, General & Internal

Afamelanotide for Erythropoietic Protoporphyria

J. G. Langendonk et al.

NEW ENGLAND JOURNAL OF MEDICINE (2015)

Article Medicine, General & Internal

A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management

Xavier Pi-Sunyer et al.

NEW ENGLAND JOURNAL OF MEDICINE (2015)

Review Pharmacology & Pharmacy

Liraglutide: A New Option for the Treatment of Obesity

Wesley A. Nuffer et al.

PHARMACOTHERAPY (2015)

Review Endocrinology & Metabolism

Ghrelin

T. D. Mueller et al.

MOLECULAR METABOLISM (2015)

Article Biochemistry & Molecular Biology

Defect in MAPK Signaling As a Cause for Monogenic Obesity Caused By Inactivating Mutations in the Melanocortin-4 Receptor Gene

Shan He et al.

INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES (2014)

Article Medicine, Research & Experimental

The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss

Anna Secher et al.

JOURNAL OF CLINICAL INVESTIGATION (2014)

Review Endocrinology & Metabolism

Leptin at 20: an overview

Jeffrey Friedman

JOURNAL OF ENDOCRINOLOGY (2014)

Article Neurosciences

Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia

Eric D. Berglund et al.

NATURE NEUROSCIENCE (2014)

Article Multidisciplinary Sciences

MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus

Bhavik P. Shah et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2014)

Article Biochemistry & Molecular Biology

Parallel, Redundant Circuit Organization for Homeostatic Control of Feeding Behavior

J. Nicholas Betley et al.

Review Medicine, General & Internal

Lorcaserin: a novel serotonin 2C agonist for the treatment of obesity

Stefanie C. Nigro et al.

CURRENT MEDICAL RESEARCH AND OPINION (2013)

Article Multidisciplinary Sciences

Developmental Control of the Melanocortin-4 Receptor by MRAP2 Proteins in Zebrafish

Julien A. Sebag et al.

SCIENCE (2013)

Review Neurosciences

Neuronal circuits that regulate feeding behavior and metabolism

Jong-Woo Sohn et al.

TRENDS IN NEUROSCIENCES (2013)

Article Pharmacology & Pharmacy

Naltrexone/Bupropion

Drugs in research & development (2013)

Review Neurosciences

Unraveling the central proopiomelanocortin neural circuits

Aaron J. Mercer et al.

FRONTIERS IN NEUROSCIENCE (2013)

Article Behavioral Sciences

Melanocortin-3 receptors are involved in adaptation to restricted feeding

K. Begriche et al.

GENES BRAIN AND BEHAVIOR (2012)

Article Medicine, Research & Experimental

Obesity-programmed mice are rescued by early genetic intervention

Viviana F. Bumaschny et al.

JOURNAL OF CLINICAL INVESTIGATION (2012)

Article Multidisciplinary Sciences

Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

Byung Kook Lim et al.

NATURE (2012)

Article Multidisciplinary Sciences

Deciphering a neuronal circuit that mediates appetite

Qi Wu et al.

NATURE (2012)

Article Multidisciplinary Sciences

Deconstruction of a neural circuit for hunger

Deniz Atasoy et al.

NATURE (2012)

Article Multidisciplinary Sciences

Melanocortin-3 receptor regulates the normal fasting response

Benjamin J. Renquist et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2012)

Article Chemistry, Multidisciplinary

A small molecule antagonist of ghrelin O-acyltransferase (GOAT)

Amanda L. Garner et al.

CHEMICAL COMMUNICATIONS (2011)

Article Endocrinology & Metabolism

Lorcaserin, A 5-HT2C Receptor Agonist, Reduces Body Weight by Decreasing Energy Intake without Influencing Energy Expenditure

Corby K. Martin et al.

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM (2011)

Article Medicine, Research & Experimental

Rapid, reversible activation of AgRP neurons drives feeding behavior in mice

Michael J. Krashes et al.

JOURNAL OF CLINICAL INVESTIGATION (2011)

Review Endocrinology & Metabolism

The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology

Ya-Xiong Tao

ENDOCRINE REVIEWS (2010)

Review Endocrinology & Metabolism

GOAT: the master switch for the ghrelin system?

Amparo Romero et al.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2010)

Article Neurosciences

A Serotonin and Melanocortin Circuit Mediates D-Fenfluramine Anorexia

Yong Xu et al.

JOURNAL OF NEUROSCIENCE (2010)

Article Medicine, General & Internal

Multicenter, Placebo-Controlled Trial of Lorcaserin for Weight Management.

Steven R. Smith et al.

NEW ENGLAND JOURNAL OF MEDICINE (2010)

Review Geriatrics & Gerontology

Ghrelin and its potential in the treatment of eating/wasting disorders and cachexia

Timo D. Mueller et al.

JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE (2010)

Article Biochemistry & Molecular Biology

Contrave™: novel treatment for obesity

Derek J. Hausenloy

CLINICAL LIPIDOLOGY (2009)

Review Biochemistry & Molecular Biology

The role of the Agouti-Related Protein in energy balance regulation

O. Ilnytska et al.

CELLULAR AND MOLECULAR LIFE SCIENCES (2008)

Article Neurosciences

The Melanocortin-3 Receptor Is Required for Entrainment to Meal Intake

Gregory M. Sutton et al.

JOURNAL OF NEUROSCIENCE (2008)

Article Genetics & Heredity

Common variants near MC4R are associated with fat mass, weight and risk of obesity

Ruth J. F. Loos et al.

NATURE GENETICS (2008)

Article Multidisciplinary Sciences

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Qi Wu et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2008)

Article Urology & Nephrology

Bremelanotide: An overview of preclinical CNS effects on female sexual function

James Pfaus et al.

JOURNAL OF SEXUAL MEDICINE (2007)

Article Biochemistry & Molecular Biology

Creation of a genetic model of obesity in a teleost

Youngsup Song et al.

FASEB JOURNAL (2007)

Article Endocrinology & Metabolism

Melanocortin activation of nucleus of the solitary tract avoids anorectic tachyphylaxis and induces prolonged weight loss

Gang Li et al.

AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM (2007)

Review Endocrinology & Metabolism

Studies on the physiological functions of the melanocortin system

Roger D. Cone

ENDOCRINE REVIEWS (2006)

Article Biochemistry & Molecular Biology

Divergence of melanocortin pathways in the control of food intake and energy expenditure

N Balthasar et al.

Review Biochemistry & Molecular Biology

Agouti-related protein: More than a melanocortin-4 receptor antagonist?

LE Pritchard et al.

PEPTIDES (2005)

Review Biochemistry & Molecular Biology

Involvement of melanocortin-4 receptor in anxiety and depression

S Chaki et al.

PEPTIDES (2005)

Review Neurosciences

Anatomy and regulation of the central melanocortin system

RD Cone

NATURE NEUROSCIENCE (2005)

Article Endocrinology & Metabolism

Differential role of melanocortin receptor subtypes in cachexia

DL Marks et al.

ENDOCRINOLOGY (2003)

Article Medicine, General & Internal

Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene

IS Farooqi et al.

NEW ENGLAND JOURNAL OF MEDICINE (2003)

Article Biochemistry & Molecular Biology

Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations

C Lubrano-Berthelier et al.

HUMAN MOLECULAR GENETICS (2003)

Article Multidisciplinary Sciences

A role for the melanocortin 4 receptor in sexual function

LHT Van der Ploeg et al.

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2002)

Article Multidisciplinary Sciences

Activation of central melanocortin pathways by fenfluramine

LK Heisler et al.

SCIENCE (2002)

Article Endocrinology & Metabolism

The melanocortin receptors: Lessons from knockout models

AA Butler et al.

NEUROPEPTIDES (2002)

Article Multidisciplinary Sciences

A role for ghrelin in the central regulation of feeding

M Nakazato et al.

NATURE (2001)

Article Multidisciplinary Sciences

Ghrelin induces adiposity in rodents

M Tschöp et al.

NATURE (2000)

Article Pharmacology & Pharmacy

Melanocortins and the brain: from effects via receptors to drug targets

RAH Adan et al.

EUROPEAN JOURNAL OF PHARMACOLOGY (2000)

Article Physiology

Long-term orexigenic effects of AgRP-(83-132) involve mechanisms other than melanocortin receptor blockade

MM Hagan et al.

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY (2000)

Article Medicine, Research & Experimental

Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency

IS Farooqi et al.

JOURNAL OF CLINICAL INVESTIGATION (2000)