Obesity: exploring its connection to brain function through genetic and genomic perspectives

Abstract

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.

Fig. 1. Regulation of energy balance by MC4R signaling in the hypothalamus and associated approved therapeutic agents.

ADCY3 adenylate cyclase 3, AgRP agouti-related peptide, BDNF brain derived neurotrophic factor, GLP1 glucagon like peptide 1, GLP1R glucagon like peptide 1 receptor, KSR2 kinase suppressor of ras 2, LHA lateral hypothalamu, MC4R melanocortin-4 receptor, MRAP2 melanocortin 2 receptor accessory Ppn 2, MSH melanocyte-stimulating hormone, NTS nucleus tractus solitarius, PCSK1 proprotein convertase subtilisin/kexin type 1, POMC proopiomelanocortin, SIM1 SIM BHLH transcription factor 1, TRKB tropomyosin-related kinase B, VMH ventromedial nucleus of the hypothalamus.

Fig. 2. Comparative overview of brain regulation of energy balance in monogenic versus polygenic obesity.

Monogenic obesity is characterized by disruptions in the hypothalamic circuits responsible for appetite control, leading to hyperphagia. Contrastingly, polygenic obesity implicates brain regions such as the substantia nigra and the insula, which are associated with addiction and reward processing.