Melanocortin 4 Receptor Pathway Dysfunction in Obesity: Patient Stratification Aimed at MC4R Agonist Treatment

Ayers, Kristin L.; Glicksberg, Benjamin S.; Garfield, Alastair S.; Longerich, Simonne; White, Joseph A.; Yang, Pengfei; Du, Lei; Chittenden, Thomas; Gulcher, Jeff; Roy, Sougata; Fiedorek, Fred T.; Gottesdiener, Keith; Cohen, Sarah S.; North, Kari E.; Schadt, Eric E.; Li, Shuyu D.; Chen, Rong; Ploeg, Lex H.T. Van der

doi:10.1210/jc.2018-00258

Cited by 63 publications

(44 citation statements)

References 49 publications

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“…α-and β-MSH bind to melanocortin 3 and melanocortin 4 receptors (MC3R and MC4R) and induce their activity. Mutations in the leptin/melanocortin pathway ( OB, LEPR, POMC, PCK1, MC4R ) are associated with obesity in rodents and humans [27,28].…”

Section: Energy Balancementioning

confidence: 99%

Functional Relationship between Leptin and Nitric Oxide in Metabolism

et al. 2019

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Leptin, the product of the ob gene, was originally described as a satiety factor, playing a crucial role in the control of body weight. Nevertheless, the wide distribution of leptin receptors in peripheral tissues supports that leptin exerts pleiotropic biological effects, consisting of the modulation of numerous processes including thermogenesis, reproduction, angiogenesis, hematopoiesis, osteogenesis, neuroendocrine, and immune functions as well as arterial pressure control. Nitric oxide (NO) is a free radical synthesized from L-arginine by the action of the NO synthase (NOS) enzyme. Three NOS isoforms have been identified: the neuronal NOS (nNOS) and endothelial NOS (eNOS) constitutive isoforms, and the inducible NOS (iNOS). NO mediates multiple biological effects in a variety of physiological systems such as energy balance, blood pressure, reproduction, immune response, or reproduction. Leptin and NO on their own participate in multiple common physiological processes, with a functional relationship between both factors having been identified. The present review describes the functional relationship between leptin and NO in different physiological processes.

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Section: Energy Balancementioning

confidence: 99%

Functional Relationship between Leptin and Nitric Oxide in Metabolism

et al. 2019

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“…Biallelic deficiencies in LEPR, POMC , or PCSK1 are predicted to affect an estimated 12,800 individuals in the United States 14. However, this conservative estimate does not include individuals with heterozygous or composite heterozygous variants; composites have a loss-of-function defect in 2 or more alleles from among 2 or more of the 3 ( POMC, PCSK1 , and LEPR ) MC4R pathway genes.…”

Section: Introductionmentioning

confidence: 99%

<p>Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry</p>

Eneli¹,

Xu²,

Webster

et al. 2019

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Purpose: The hypothalamic melanocortin-4 receptor (MC4R) pathway, a component of the central melanocortin pathway, regulates energy balance and satiety. Rare genetic disorders of obesity may be characterized by impaired MC4R pathway signaling, which results in early-onset severe obesity and insatiable hunger (hyperphagia). The TEMPO registry (NCT03479437) is a voluntary, prospective, open-ended registry of individuals with rare genetic disorders of obesity due to mutations in genes within the MC4R pathway who have early-onset severe obesity. The objective of the TEMPO registry is to evaluate the burden of rare genetic disorders of obesity on individuals, their parents/caregivers, health care providers, and the health care system. Patients and methods: Individuals with rare genetic disorders of obesity (adults aged ≥18 years and children and adolescents aged from 2 to 17 years) will be referred by their health care providers or by a genetic screening study. Individuals must meet age- and sex-specific body mass index values that define the clinical criteria for severe obesity and carry selected variants in MC4R or in one of several genes upstream or downstream of the MC4R. Online surveys will be completed by the individual, parent/caregiver, and health care provider at baseline and annually thereafter and will collect data on demographics, results of genetic testing, medical/family history, disease characteristics, resource utilization, eating habits/hunger episodes, social and emotional impacts, and interest in future clinical trial participation. Conclusions: The TEMPO registry will provide insights into the overall course and disease burden for individuals with rare genetic disorders of obesity. Health care providers may use this resource to improve the identification, diagnosis, and treatment of individuals with rare forms of genetic obesity.

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“…These results have potential clinical relevance, as MC4R agonists that cross the blood-brain barrier have been developed and tested in clinical trials for treatment of patients with proopiomelanocortin gene mutations ( 39 ) and some other genetic forms of severe obesity ( 40 , 41 ). MC4R agonists also appear to have minimal adverse side effects when used to treat premenopausal women with acquired, generalized hypoactive sexual desire disorder ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%