Archives of Metabolic Syndrome
Open AccessRare Neurogenetic Signatures in Brain Circuits: A Novel Axis in Metabolic Syndrome Susceptibility
Authors: Anvi Rana.
Abstract
Metabolic syndrome (MetS), a cluster of conditions including central obesity, insulin resistance, dyslipidemia, and hypertension imposes a large burden on global health, yet substantial phenotypic variability persists across individuals with similar lifestyle exposures. While common polygenic risk variants and environmental factors are well characterized, the contribution of rare, high-impact genetic variants affecting neurocircuitry that governs energy homeostasis has not been systematically explored. In this article, we review evidence implicating rare functional variants in central neuroregulatory genes (notably MC4R, BDNF/TrkB, and LEPR) in human and animal models of obesity, hyperphagia, insulin resistance, and other metabolic perturbations. We show these genes are expressed in key brain regions including hypothalamic nuclei and reward pathways that integrate peripheral metabolic signals to regulate appetite, energy expenditure, and glucose/lipid homeostasis. Based on this evidence, we propose the “Gene-Brain-Metabolic Axis” framework, in which rare neurogenetic variants disrupt central neural circuits, increasing susceptibility to MetS independent of environmental risk. Recognizing this axis may (1) explain a portion of unexplained inter-individual heterogeneity in MetS, (2) inform precision-screening strategies, and (3) suggest novel central nervous system targeted therapies (e.g., receptor agonists or neurotrophic modulation). We highlight key gaps and call for integrated studies combining genetics, neuroimaging, metabolic phenotyping, and behavioral assessment.
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