Resilience to obesity in carriers of monogenic obesity mutations - a study on the underlying mechanisms

肥胖是慢性病的主要危险因素。除了我们肥胖的生活方式，人们天生的 生理/代谢，由他们的基因组编码，是决定为什么有些人的另一个主要因素， 比其他人更容易发胖。对动物模型和人类的遗传学研究表明， 是调节体重的关键因素特别是构成瘦素-黑皮质素途径的基因具有 重复与肥胖有关;即LEP，LEPR，POMC，MC 4 R，PCSK 1和SH 2B 1的突变 经常被报道会导致早发性严重肥胖，可能是通过影响食欲、饥饿感、饱腹感， 此外，在肥胖/BMI的GWAS中已经鉴定了相同基因附近的常见变体。 在最近的一项大规模外显子组范围的研究中，我们发现MC 4 R中的无义突变（Tyr 35 Ter）是 与携带者体重增加约15磅相关。MC 4 R Tyr 35 Ter在20多年前被鉴定为高- 影响导致严重早发性肥胖的单基因突变。深入的功能分析表明， 35 Ter导致MC 4 R功能完全丧失。然而，在英国生物银行的66名突变携带者中， （N~ 500，000），9人（14%）体重正常，从未超重，超过了他们的遗传几率。 这一观察激发了我们对研究瘦素-黑皮质素基因中所有突变的兴趣。 途径，据报道导致肥胖。通过对正常体重携带者与肥胖携带者的深入比较， 目的是揭示补偿机制（遗传的，非遗传的），防止体重增加，尚未针对 预防和治疗。然而，迄今为止报道的作为肥胖“原因”的突变已经在2005年被确定。 小规模的病例偏倚人群，以及他们在人群水平上对肥胖的影响从未被研究过。 估计。由于突变是罕见的，严格确定其影响需要非常大的人群。 可访问来自> 220，000个个体的测序数据和来自约500，000个个体的基因型数据 （Mount Sinai BioMe Biobank，TOPMed Program，UK Biobank），我们处于独特的位置，（目标1）确定 已建立的单基因肥胖基因（LEP、LEPR、POMC、MC 4 R、PCSK 1、SH 2B 1）突变的影响 通过估计他们的肥胖率和评估他们对肥胖的影响。目标2：确定特征 利用表型/基因型数据， 已经在BioMe、TOPMed和英国生物库中提供。目标3A：更深入地了解 通过对从BioMe生物库中召回的60名参与者进行极深的表型分析， 评估能量摄入、能量消耗、生活方式和其他行为。目标3B：调查参与者的 iPSC衍生的下丘脑神经元的信号特征和等位基因特异性表达。 虽然传统上，肥胖研究的重点是肥胖的个人和机制，导致体重 因此，我们提出了一个范式转变。通过研究正常体重突变携带者和保护 为了防止他们体重增加，我们的目标是揭示普通人群中治疗和预防的新目标。

Obesity is a major risk factor for chronic disease. Besides our obesogenic lifestyle, people’s innate physiology/metabolism, encoded by their genomes, is another major factor that determines why some people gain weight more easily than others. Genetic studies in animal models and humans, have shown that the brain is a key player in body weight regulation. In particular genes that constitute the leptin-melanocortin pathway have been repeatedly implicated in obesity; i.e. mutations in LEP, LEPR, POMC, MC4R, PCSK1 and SH2B1 have been frequently reported to cause early-onset severe obesity, likely through influencing appetite, hunger, satiety, reward, etc. In addition, common variants near the same genes have been identified in GWAS for obesity/BMI. In a recent, large-scale exome-wide study, we showed that a nonsense mutation (Tyr35Ter) in MC4R was associated with a ~15lbs higher body weight in carriers. MC4R Tyr35Ter was identified >20 years ago as a high- impact monogenic mutation that causes severe early-onset obesity. In-depth functional analyses showed that 35Ter results in a complete loss of function of MC4R. Yet, of the 66 mutation carriers in the UK Biobank (N~500,000), nine (14%) were of normal weight and had never been overweight, beating their genetic odds. This observation sparked our interest in investigating all mutations in genes of the leptin-melanocortin pathway, reported to cause obesity. By in-depth comparison of normal weight carriers with obese carriers, we aim the reveal compensatory mechanisms (genetic, non-genetic) that prevent weight gain, not yet targeted for prevention and treatment. However, mutations reported so far as the “cause” of obesity have been identified in small-scale case-biased populations, and their penetrance and effect on obesity at a population-level has never been estimated. As mutations are rare, determining their impact with rigor requires extremely large populations. With access to sequencing data from >220,000 individuals and genotype data from ~500,000 individuals (Mount Sinai BioMe Biobank, TOPMed Program, UK Biobank), we are uniquely positioned to (Aim 1) determine the impact of mutations in established monogenic obesity genes (LEP, LEPR, POMC, MC4R, PCSK1, SH2B1) through estimating their penetrance and assess their effect on obesity. Aim 2: To determine the characteristics that protect normal weight carriers of high-impact mutations from gaining weight, using phenotype/genotype data already available in BioMe, TOPMed, and UK Biobank. Aim 3A: To gain deeper insight in the underlying mechanisms by performing extremely deep-phenotyping in 60 participants recalled from the BioMe Biobank to assess energy intake, energy expenditure, lifestyle and other behaviors. Aim 3B: To investigate participants’ iPSC-derived hypothalamic neurons for signaling characteristics and allele-specific expression. While traditionally, obesity research focuses on obese individuals and on the mechanisms that cause weight gain, we propose a paradigm shift. By studying normal weight mutation carriers and the mechanisms that protect them from gaining weight, we aim to reveal new targets for treatment and prevention in the general population.