Saeed Sadia, Bonnefond Amélie, Froguel Philippe
INSERM UMR 1283, CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Lille, France.
University of Lille, Lille University Hospital, Lille, France.
Mol Psychiatry. 2025 Feb;30(2):651-658. doi: 10.1038/s41380-024-02737-9. Epub 2024 Sep 5.
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.
肥胖是一个不断升级的全球健康负担，具有深远的医学和经济影响。传统上对肥胖的看法主要围绕将其归类为一种“纯粹”的代谢紊乱，其特征是卡路里摄入与能量消耗之间的不平衡。然而，目前的知识认识到，罕见或常见的遗传因素与肥胖发展之间存在复杂的相互作用，同时还出现了神经发育和精神异常，这些表型受到生活方式等环境因素的调节。三十年的人类遗传学研究已经发现了20多个导致严重早发性单基因肥胖的基因，以及约1000个与常见多基因肥胖相关的基因座，其中大多数在大脑中表达，将肥胖描述为一种神经和精神疾病。因此，应该更好地认识肥胖与脑功能之间的关联。在此背景下，本综述旨在通过阐明导致肥胖以及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。我们对最近的遗传研究结果进行了详细检查，并将它们与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脑区，以及它与单基因形式的区别。还讨论了非综合征性和综合征性单基因肥胖之间的连续性，并提供了神经发育和认知评估的证据。本文还讨论了针对这些遗传机制的当前治疗方法，这些方法产生了改善的临床结果和认知优势。总之，本综述证实了肥胖的遗传基础，肯定了将其归类为一种神经疾病，这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之间有前景的交叉点，作为开发定制医疗方法来治疗肥胖及其相关神经方面的基础。
