Molecular Psychiatry ( IF 9.6 ) Pub Date : 2024-09-05 , DOI: 10.1038/s41380-024-02737-9
Sadia Saeed 1, 2, 3 , Amélie Bonnefond 1, 2, 3 , Philippe Froguel 1, 2, 3
Obesity represents an escalating global health burden with profound medical and economic impacts. The conventional perspective on obesity revolves around its classification as a “pure” metabolic disorder, marked by an imbalance between calorie consumption and energy expenditure. Present knowledge, however, recognizes the intricate interaction of rare or frequent genetic factors that favor the development of obesity, together with the emergence of neurodevelopmental and mental abnormalities, phenotypes that are modulated by environmental factors such as lifestyle. Thirty years of human genetic research has unveiled >20 genes, causing severe early-onset monogenic obesity and ~1000 loci associated with common polygenic obesity, most of those expressed in the brain, depicting obesity as a neurological and mental condition. Therefore, obesity’s association with brain function should be better recognized. In this context, this review seeks to broaden the current perspective by elucidating the genetic determinants that contribute to both obesity and neurodevelopmental and mental dysfunctions. We conduct a detailed examination of recent genetic findings, correlating them with clinical and behavioral phenotypes associated with obesity. This includes how polygenic obesity, influenced by a myriad of genetic variants, impacts brain regions associated with addiction and reward, differentiating it from monogenic forms. The continuum between non-syndromic and syndromic monogenic obesity, with evidence from neurodevelopmental and cognitive assessments, is also addressed. Current therapeutic approaches that target these genetic mechanisms, yielding improved clinical outcomes and cognitive advantages, are discussed. To sum up, this review corroborates the genetic underpinnings of obesity, affirming its classification as a neurological disorder that may have broader implications for neurodevelopmental and mental conditions. It highlights the promising intersection of genetics, genomics, and neurobiology as a foundation for developing tailored medical approaches to treat obesity and its related neurological aspects.
中文翻译:
肥胖:通过遗传和基因组学角度探索其与大脑功能的联系
肥胖代表着不断升级的全球健康负担,具有深远的医疗和经济影响。对肥胖的传统观点围绕着将其归类为“纯粹”代谢紊乱,其特点是卡路里消耗和能量消耗之间的不平衡。然而,目前的知识认识到有利于肥胖发展的罕见或频繁遗传因素之间的复杂相互作用,以及神经发育和精神异常的出现,这些表型受生活方式等环境因素的调节。三十年的人类基因研究揭示了 >20 基因,导致严重的早发性单基因肥胖和 ~1000 个与常见多基因肥胖相关的基因座,其中大部分在大脑中表达,将肥胖描述为一种神经和精神状况。因此,应该更好地认识到肥胖与大脑功能的关联。在此背景下,本综述旨在通过阐明导致肥胖、神经发育和精神功能障碍的遗传决定因素来拓宽当前的观点。我们对最近的遗传发现进行了详细检查,将它们与肥胖相关的临床和行为表型相关联。这包括受无数遗传变异影响的多基因肥胖如何影响与成瘾和奖励相关的大脑区域,从而将其与单基因形式区分开来。还讨论了非综合征性和综合征性单基因肥胖之间的连续体,以及来自神经发育和认知评估的证据。讨论了当前针对这些遗传机制的治疗方法,从而改善了临床结果和认知优势。 综上所述,本综述证实了肥胖的遗传基础,确认了其被归类为一种神经系统疾病,可能对神经发育和精神状况具有更广泛的影响。它强调了遗传学、基因组学和神经生物学的有前途的交叉点,作为开发定制医学方法来治疗肥胖及其相关神经学方面的基础。