Article
Biochemistry & Molecular Biology
Ren-Lei Ji, Ya-Xiong Tao
Summary: Two new human MRAP2 splice variants were identified in this study, and the effects of MRAP1 and MRAP2 on MC3R and MC4R were investigated. The results suggest that MRAPs play important roles in the signaling and regulation of neural MC3R and MC4R.
Article
Biochemistry & Molecular Biology
Ren-Lei Ji, Shan-Shan Jiang, Ya-Xiong Tao
Summary: The neural melanocortin receptors (MCRs) and their accessory proteins MRAP1 and MRAP2 play crucial roles in regulating energy homeostasis. This study reveals that MRAP1 and MRAP2s have species-specific effects on canine neural MCRs, providing a better understanding of their regulation.
Article
Cell Biology
Meng Wang, Jing Xu, Xiao-Wei Lei, Cong Zhang, Shang-Yun Liu, Li-Na Jin, Chao Zhang
Summary: This study investigated the interaction between MRAP1 and SSTRs and examined the pharmacological modulation of MRAP1 on mouse SSTR2/SSTR3 and SSTR2/SSTR5 heterodimerization in vitro. The results showed that MRAP1 selectively interacts with SSTR3 and SSTR5 but not SSTR2. Furthermore, MRAP1 binding sites were extensive on SSTR3 and restricted on transmembrane region six and seven of SSTR5. Co-expression of SSTR2/SSTR3 or SSTR2/SSTR5 with MRAP1 enhanced cell growth inhibition.
Article
Endocrinology & Metabolism
Ren-Lei Ji, Lu Huang, Yin Wang, Ting Liu, Si-Yu Fan, Min Tao, Ya-Xiong Tao
Summary: The study explored the expression and signaling of topmouth culter MC3R and its interaction with MRAP2a and MRAP2b. The results showed that culter MC3R exhibited higher expression in the CNS, and could bind and stimulate intracellular cAMP accumulation in a dose-dependent manner. MRAP2a and MRAP2b had different effects on basal cAMP production and cell surface expression of caMC3R, with MRAP2a significantly decreasing these parameters. Additionally, it was suggested that MRAP2a and MRAP2b might play a more important role in regulating MC3R/MC4R signaling during the larval period, while reduced expression of mc3r, mc4r, and pomc might be involved in modulation of MC3R/MC4R in adults.
ENDOCRINE CONNECTIONS
(2021)
Article
Endocrinology & Metabolism
Robert M. Dores, Emilia Chapa
Summary: The co-evolution of MC2R and MRAP1 in chordates has had profound effects on the physiological systems of bony vertebrates, leading to specific ligand selectivity and trafficking properties. However, the effects of this interaction on cartilaginous fishes are less clear. Future studies may shed more light on the differences in ligand activation and trafficking between these two groups of vertebrates.
FRONTIERS IN ENDOCRINOLOGY
(2021)
Letter
Medicine, General & Internal
Kok-Siong Poon, Karen M. Tan
Summary: In an exome-sequencing study, GNAS variants were found in children with severe childhood-onset obesity. These variants affect the signaling of the melanocortin 4 receptor. The authors suggest screening for GNAS variants in children to enable early diagnosis and treatment.
NEW ENGLAND JOURNAL OF MEDICINE
(2022)
Article
Pharmacology & Pharmacy
Nathaniel A. K. Glenn, David B. Finlay, Emma R. Carruthers, Kathleen G. Mountjoy, Christopher S. Walker, Natasha L. Grimsey
Summary: The interactions between RAMPs and MRAPs with GPCRs play a significant role in modulating the expression and signaling of these receptors, particularly in cannabinoid receptors CB1, CB2, GPR18, and GPR55. The binding of CB1, CB2, and GPR55 with MRAPs influences their surface expression, possibly through glycosylation and hetero-oligomerization mechanisms, which potentially leads to physiological and disease-related consequences.
BRITISH JOURNAL OF PHARMACOLOGY
(2023)
Article
Endocrinology & Metabolism
Carl Spana, Robert Jordan, Steven Fischkoff
Summary: The results of two randomized controlled clinical trials demonstrate that agonistic activity of bremelanotide at MC4R may help in reducing caloric intake and promoting weight loss in obese women.
DIABETES OBESITY & METABOLISM
(2022)
Article
Genetics & Heredity
Itzel G. Salazar-Valencia, Hugo Villamil-Ramirez, Francisco Barajas-Olmos, Martha Guevara-Cruz, Luis R. Macias-Kauffer, Humberto Garcia-Ortiz, Omar Hernandez-Vergara, David Alberto Diaz De Sandy-Galan, Paola Leon-Mimila, Federico Centeno-Cruz, Luis E. Gonzalez-Salazar, Rocio Guizar-Heredia, Edgar Pichardo-Ontiveros, Leonor Jacobo-Albavera, Rosalinda Posadas-Sanchez, Gilberto Vargas-Alarcon, Rafael Velazquez-Cruz, Ruth Gutierrez-Aguilar, Carlos Zerrweck, Hector Isaac Rocha-Gonzalez, Juan Gerardo Reyes-Garcia, Miriam Del C. Carrasco-Portugal, Francisco Javier Flores-Murrieta, Armando R. Tovar, Lorena Orozco, Teresa Villarreal-Molina, Samuel Canizales-Quinteros
Summary: The MC4R Ile269Asn mutation is associated with obesity in the Mexican population. Weight loss interventions such as dietary restriction, phentermine, and RYGB have similar effects on mutation carriers and non-carriers. Therefore, these interventions may be effective in the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.
Article
Medicine, General & Internal
Ahmed W. Al-Humadi, Khaled Alabduljabbar, Moath S. Alsaqaaby, Hani Talaee, Carel W. le Roux
Summary: The study aimed to identify associations between clinico-demographical characteristics and genetic mutations associated with obesity. The results revealed that gene mutations associated with obesity are common among patients with a BMI > 40 kg/m(2). However, a patient's BMI, age of onset of obesity, or age of onset of hyperphagia did not provide valuable information in predicting the presence of genetic mutations associated with obesity.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Medicine, General & Internal
Edson Mendes de Oliveira, Julia M. Keogh, Fleur Talbot, Elana Henning, Rachel Ahmed, Aliki Perdikari, Rebecca Bounds, Natalia Wasiluk, Vikram Ayinampudi, Ines Barroso, Jacek Mokrosinski, Deepthi Jyothish, Sharon Lim, Sanjay Gupta, Melanie Kershaw, Cristina Matei, Praveen Partha, Tabitha Randell, Antoinette McAulay, Louise C. Wilson, Tim Cheetham, Elizabeth C. Crowne, Peter Clayton, I. Sadaf Farooqi
Summary: Variants in the GNAS gene have been linked to childhood obesity, showing the importance of genetic factors in this condition. Mutations in GNAS affect GPCR signaling pathways, leading to a wide range of clinical manifestations. Early diagnosis through genetic screening and targeted treatment with melanocortin agonists may improve outcomes for children with severe obesity.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Minseon Kim, Soyeon Jo, Ji-Ho Jeong, Yongae Kim
Summary: This study optimized the expression and isolation of wiim-hMC4R-TM2 proteins under different chemical cleavage reaction times and purification procedures, obtaining proteins with high purity. The structure of wt/m-hMC4R-TM2 protein was studied using solid-state NMR spectroscopy, providing insights into the peptide's behavior in the cell membrane.
PROTEIN AND PEPTIDE LETTERS
(2021)
Article
Multidisciplinary Sciences
Yulong Wei, Parisa Aris, Heba Farookhi, Xuhua Xia
Summary: SARS-CoV-2 can efficiently transmit in humans, and potentially infect other mammals with ACE2 receptors similar to humans. The study suggests that local similarities at key S protein-binding sites in ACE2 receptors are crucial for determining high-risk mammals for SARS-CoV-2 infection.
SCIENTIFIC REPORTS
(2021)
Article
Medicine, Research & Experimental
Adelaide Bernard, Irene Ojeda Naharros, Xinyu Yue, Francois Mifsud, Abbey Blake, Florence Bourgain-Guglielmetti, Jordi Ciprin, Sumei Zhang, Erin McDaid, Kellan Kim, Maxence V. Nachury, Jeremy F. Reiter, Christian Vaisse
Summary: The study reveals the importance of MC4R and MRAP2 in regulating food intake and body weight in humans. MRAP2 plays a critical role in the weight-regulating function of MC4R neurons and the ciliary localization of MC4R. Furthermore, the study suggests that specific accessory proteins are required for GPCR localization to primary cilia, which may not be present in heterologous cell culture systems. The findings also imply that disruption of MC4R ciliary localization may frequently be responsible for inherited forms of obesity.
Review
Biochemistry & Molecular Biology
Susanna Tornroth-Horsefield, Clara Chivasso, Helin Strandberg, Claudia D'Agostino, Carla V. T. O'Neale, Kevin L. Schey, Christine Delporte
Summary: This review provides a comprehensive overview of the current knowledge of AQP interactomes and discusses the molecular basis and functional significance of these protein-protein interactions in health and diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pediatrics
Christopher M. Parry, Li F. Chan, Daniel F. Carr, Daniel B. Hawcutt
Summary: PDGFD is expressed in the human adrenal cell line, H295R, and its expression can be influenced by beclometasone and steroidogenesis agonists/antagonists. This study provides in vitro evidence supporting a potential link between the PDGF and cortisol production pathways, indicating that PDGFD variants may impact an individual's sensitivity to corticosteroid-induced adrenal suppression.
PEDIATRIC RESEARCH
(2023)
Article
Immunology
L. M. Goff, K. Davies, W. M. Zelek, E. Kodosaki, O. Hakim, S. Lockhart, S. O'Rahilly, B. P. Morgan
Summary: Poor metabolic health and obesity in Black African populations contribute to increased susceptibility to disease, including COVID-19. Complement dysregulation has been linked to metabolic health and implicated as a driver of pathology; however, ethnic differences in complement have not been explored.
CLINICAL AND EXPERIMENTAL IMMUNOLOGY
(2023)
Article
Endocrinology & Metabolism
Spyros Vernardis, Vadim Demichev, Oliver Lemke, Nana-Maria Gruening, Christoph Messner, Matt White, Maik Pietzner, Alina Peluso, Tinh-Hai Collet, Elana Henning, Christoph Gille, Archie Campbell, Caroline Hayward, David J. Porteous, Riccardo E. Marioni, Michael Muelleder, Aleksej Zelezniak, Nicholas J. Wareham, Claudia Langenberg, I. Sadaf Farooqi, Markus Ralser
Summary: Humans exhibit profound responses to changes in diet, making it important to study the nutritional responses in depth. This study used high-throughput mass spectrometry to investigate the impact of caloric restriction and a glucose challenge on the plasma proteome, identifying proteins that correlate with metabolome and endocrine changes. The study highlights the role of APOC1 as a dominant nutritional responder and emphasizes the interdependency between acute nutritional response proteins and the endocrine system.
JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
(2023)
Article
Nutrition & Dietetics
Imen Becetti, Esther L. Bwenyi, Ivan E. de Araujo, Jamy Ard, John F. Cryan, Ismaa Sadaf Farooqi, Carrie R. Ferrario, Marci E. Gluck, Laura M. Holsen, Paul J. Kenny, Elizabeth A. Lawson, Bradford B. Lowell, Ellen A. Schur, Takara L. Stanley, Ali Tavakkoli, Steven K. Grinspoon, Vibha Singhal
Summary: Obesity is increasing rapidly, and current strategies for its treatment are limited. Understanding the neurobiology of appetite and energy intake can lead to more effective prevention and treatment. Appetite regulation is complex and influenced by genetic, social, and environmental factors, involving endocrine, gastrointestinal, and neural systems. Research is now yielding potentially effective treatment strategies, as highlighted in the findings presented at the Harvard Nutrition Obesity Symposium.
AMERICAN JOURNAL OF CLINICAL NUTRITION
(2023)
Article
Biochemistry & Molecular Biology
Agatha C. van der Klaauw, Emily Horner, Pehuen Pereyra-Gerber, Utkarsh S. Agrawal, William Foster, Sarah Spencer, Bensi Vergese, Miriam Smith, Elana D. Henning, Isobel A. Ramsay, Jack M. Smith, Stephane J. Guillaume, Hayley M. Sharpe, Iain Hay, Sam Thompson, Silvia H. Innocentin, Lucy Booth, Chris Robertson, Colin McCowan, Steven Kerr, Thomas J. Mulroney, Martin P. O'Reilly, Thevinya P. Gurugama, Lihinya A. Gurugama, Maria Rust, Alex Ferreira, Soraya Ebrahimi, Lourdes Ceron-Gutierrez, Jacopo Scotucci, Barbara J. Kronsteiner, Susanna Dunachie, Paul J. Klenerman, Adrian A. Park, Francesco Rubino, Abigail Lamikanra, Hannah Stark, Nathalie Kingston, Lise Estcourt, Heli Harvala, David A. Roberts, Rainer J. Doffinger, Michelle Linterman, Nicholas Matheson, Aziz Sheikh, I. Sadaf Farooqi, James E. D. Thaventhiran
Summary: Obesity is associated with an increased risk of severe COVID-19 infection and mortality. COVID-19 vaccines may be less effective in individuals with obesity. A study in Scotland found that vaccinated individuals with severe obesity were more likely to experience hospitalization or death from COVID-19. Another study found that individuals with severe obesity had lower levels of neutralizing antibodies after vaccination compared to individuals with a normal BMI, and the decline in antibody levels was faster in people with severe obesity.
Article
Medicine, General & Internal
Jan-Bernd Funcke, Barbara Moepps, Julian Roos, Julia von Schnurbein, Kenneth Verstraete, Elke Froehlich-Reiterer, Katja Kohlsdorf, Adriana Nunziata, Stephanie Brandt, Alexandra Tsirigotaki, Ann Dansercoer, Elisabeth Suppan, Basma Haris, Klaus-Michael Debatin, Savvas N. Savvides, I. Sadaf Farooqi, Khalid Hussain, Peter Gierschik, Pamela Fischer-Posovszky, Martin Wabitsch
Summary: This article describes two novel homozygous leptin variants that caused intense hyperphagia, severe obesity, and high leptin levels in two unrelated children. These variants bind to the leptin receptor but have marginal signaling. In the presence of nonvariant leptin, they act as competitive antagonists. High-dose recombinant leptin treatment was initiated and gradually reduced, resulting in near-normal weight for both patients. Antidrug antibodies developed in the patients, but did not appear to affect efficacy. No severe adverse events were observed.
NEW ENGLAND JOURNAL OF MEDICINE
(2023)
Article
Endocrinology & Metabolism
Valeria Hasenmajer, Rosario Ferrigno, Marianna Minnetti, Bianca Pellegrini, Andrea M. Isidori, Andrea Lenzi, Mariacarolina Salerno, Marco Cappa, Li Chan, Maria Cristina De Martino, Martin O. Savage
Summary: Adrenal insufficiency is a severe endocrine disorder characterized by insufficient secretion of glucocorticoid and/or mineralocorticoid due to impaired adrenal function or inadequate adrenal stimulation. This review focuses on rare genetic causes of primary adrenal insufficiency with isolated glucocorticoid or combined glucocorticoid and mineralocorticoid deficiencies, as well as rare syndromes of isolated mineralocorticoid deficiency. The diagnosis of these rare genetic forms of pediatric adrenal insufficiency is challenging due to their clinical heterogeneity and rarity, and this review aims to provide an overview of their genetic and clinical features, as well as diagnostic and therapeutic approaches.
REVIEWS IN ENDOCRINE & METABOLIC DISORDERS
(2023)
Article
Multidisciplinary Sciences
Fleur Talbot, Claire H. Feetham, Jacek Mokrosinski, Katherine Lawler, Julia M. Keogh, Elana Henning, Edson Mendes de Oliveira, Vikram Ayinampudi, Sadia Saeed, Amelie Bonnefond, Mohammed Arslan, Giles S. H. Yeo, Philippe Froguel, David A. Bechtold, Antony Adamson, Neil Humphreys, Ines Barroso, Simon M. Luckman, I. Sadaf Farooqi
Summary: Loss of function variants in the GPR10 gene are found in people with severe obesity, impairing ligand binding and G protein-dependent signaling. Transgenic mice with one of these variants gain excessive weight due to decreased energy expenditure. Targeting GPR10 may be a potential weight-loss therapy.
NATURE COMMUNICATIONS
(2023)
Editorial Material
Endocrinology & Metabolism
Francesco Rubino, Rachel L. Batterham, Marta Koch, Geltrude Mingrone, Carel W. le Roux, I. Sadaf Farooqi, Nathalie Farpour-Lambert, Edward W. Gregg, David E. Cummings
LANCET DIABETES & ENDOCRINOLOGY
(2023)
Article
Medicine, General & Internal
Natalie B. B. Lister, Louise A. A. Baur, Janine F. F. Felix, Andrew J. J. Hill, Claude Marcus, Thomas Reinehr, Carolyn Summerbell, Martin Wabitsch
Summary: The prevalence of child and adolescent obesity has plateaued at high levels in most high-income countries and is increasing in many low-income and middle-income countries. Obesity arises when a mix of genetic and epigenetic factors, behavioural risk patterns and broader environmental and sociocultural influences affect the two body weight regulation systems. Treatment incorporates a respectful, stigma-free and family-based approach involving multiple components, and addresses dietary, physical activity, sedentary and sleep behaviours. Prevention of obesity requires a whole-system approach and joined-up policy initiatives across government departments.
NATURE REVIEWS DISEASE PRIMERS
(2023)
Article
Public, Environmental & Occupational Health
R. Asaad Baksh, Sarah E. Pape, Li F. Chan, Aisha A. Aslam, Martin C. Gulliford, Andre Strydom
Summary: This study comprehensively estimated the risk of multiple morbidity across the lifespan in people with Down syndrome and identified syndrome-specific health conditions. The results showed that people with Down syndrome had an increased risk of dementia, hypothyroidism, epilepsy, and haematological malignancy, while asthma, cancer, ischaemic heart disease, and hypertension were less frequent. Compared to people with other intellectual disabilities, people with Down syndrome had higher risks of dementia, hypothyroidism, obstructive sleep apnoea, and haematological malignancy, with reduced rates for a third of conditions. The morbidities in Down syndrome could be categorized based on age-related incidence trajectories and clustered into typical syndromic conditions, cardiovascular diseases, autoimmune disorders, and mental health conditions.
LANCET PUBLIC HEALTH
(2023)
Article
Biology
Sadaf Farooqi
Summary: Genetic disruption of the hypothalamic leptin-melanocortin pathway causes severe obesity, while a lack of leptin leads to increased appetite. Studies on obesity and thinness provide insights into weight regulation mechanisms and molecular targets for weight loss therapy.
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
(2023)
Article
Cell Biology
Isabella A. T. M. Ferreira, Colin Y. C. Lee, William S. Foster, Adam Abdullahi, Lisa M. Dratva, Zewen Kelvin Tuong, Benjamin J. Stewart, John R. Ferdinand, Stephane M. Guillaume, Martin O. P. Potts, Marianne Perera, Benjamin A. Krishna, Ana Penalver, Mia Cabantous, Steven A. Kemp, Lourdes Ceron-Gutierrez, Paul Lyons, Kenneth G. C. Smith, John Bradley, Dami A. Collier, Laura E. Mccoy, Agatha van der Klaauw, James E. D. Thaventhiran, I. Sadaf Farooqi, Sarah A. Teichmann, Paul A. Macary, Rainer Doffinger, Mark R. Wills, Michelle A. Linterman, Menna R. Clatworthy, Ravindra K. Gupta
Summary: Elderly individuals have suboptimal immune responses to primary vaccination against COVID-19, but there is no significant difference in neutralizing antibody levels between elderly and younger individuals after receiving a booster dose of mRNA vaccine. This study highlights the differential effects of adenoviral and mRNA vaccine formats on the memory B cell response.
Article
Cell Biology
Ruth Hanssen, Chiara Auwerx, Maarja Joeloo, Elana Henning, Julia Keogh, Rebecca Bounds, Miriam Smith, Helen V. Firth, Zoltan Kutalik, I. Sadaf Farooqi, Alexandre Reymond, Katherine Lawler, M. C. Sadler
Summary: People with 16p11.2 BP2-3 deletions have early and complex obesity and type 2 diabetes (T2D), suggesting a potential benefit from therapies that enhance leptin and insulin signaling.
CELL REPORTS MEDICINE
(2023)
Article
Cell Biology
Lena R. Kaisinger, Katherine A. Kentistou, Stasa Stankovic, Eugene J. Gardner, Felix R. Day, Yajie Zhao, Alexander Morseburg, Christopher J. Carnie, Guido Zagnoli-Vieira, Fabio Puddu, Stephen P. Jackson, Stephen O'Rahilly, I. Sadaf Farooqi, Laura Dearden, Lucas C. Pantaleao, Susan E. Ozanne, Ken K. Ong, John R. B. Perry
Summary: Obesity has a significant heritable component, and recent studies have identified genes that have a large effect on adult BMI. By performing sex-stratified associations in the UK Biobank study, researchers discovered several genes that increase adult BMI in women (DIDO1, PTPRG, and SLC12A5) and in men (SLTM) with large effect sizes. Analyses also implicated rare variants in OBSCN and MADD for childhood adiposity. These findings suggest the involvement of neuron death, apoptosis, and DNA damage response mechanisms in obesity susceptibility across the life-course.
