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. 2019 Jun 5:12:87-93.
doi: 10.2147/TACG.S199092. eCollection 2019.

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

Ihuoma Eneli  1   2 , Jinyu Xu  1 , Matthew Webster  3 , Amy McCagg  3 , Lex Van Der Ploeg  3 , Alastair S Garfield  3 , Elizabeth Estrada  4
Affiliations

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

Ihuoma Eneli et al. Appl Clin Genet. .

Abstract

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.

Keywords: Alström syndrome; Bardet-Biedl syndrome; LEPR; PCSK1; POMC; severe obesity.

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Conflict of interest statement

Lex Van Der Ploeg, Alastair S Garfield, Matthew Webster, and Amy McCagg are employees of Rhythm Pharmaceuticals, Inc. Elizabeth Estrada is a consultant for and reports personal fees from Rhythm Pharmaceuticals, Inc. Jinyu Xu is a research coordinator for the TEMPO registry and reports grants from Rhythm Pharmaceuticals Inc. Ihuoma Eneli has received funding from Rhythm Pharmaceuticals, Inc. Ihuoma Eneli also reports grants from National Institute for Health, PCORI, Rhythm Pharmaceuticals, Nestle, and also received a contract for consulting for the American Academy of Pediatrics, during the conduct of the study. Lex Van Der Ploeg has a patent Rhythm IP licensed. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
The MC4R signaling pathway plays a vital role in regulating appetite and energy balance. Briefly, LEP binds to LEPR on POMC neurons in the arcuate nucleus of the hypothalamus. This triggers a signaling cascade in which the POMC precursor polypeptide is processed by enzymes, including PCSK1, into neuropeptides, which include α- and β-MSH. These neuropeptides can activate MC4R to promote satiety, energy expenditure, and weight loss. Mutations in this pathway can result in rare genetic disorders of obesity. Individuals enrolled in the TEMPO registry must have homozygous, compound heterozygous, heterozygous, or composite heterozygous mutations in one of several genes upstream or downstream of MC4R. aOnly if there is no evidence of clinical syndromic features, likely heterozygous individuals only. Abbreviations: AgRP, agouti-related protein; ARC, arcuate nucleus; LEP, leptin; LEPR, leptin receptor; MC4R, melanocortin-4 receptor; MSH, melanocyte-stimulating hormone; NPY, neuropeptide Y; PCSK1, pro-protein convertase subtilisin/kexin type 1; POMC, proopiomelanocortin; PVN, paraventricular nucleus.
Figure 2
Figure 2
TEMPO registry study design.
See this image and copyright information in PMC

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