Dissecting the Brain Basis of Obesity-Induced Pubertal Alterations: A View to a Kiss

Child obesity is a worrying condition, affecting 20% adolescents.

Among its comorbidities, early obesity is linked to disturbed puberty, which is more evident in girls, but bound to adverse health outcomes in both sexes. Yet, how our brain decodes nutritional info to finely control puberty remains unsolved. Genetic data suggest obesity is largely an hypothalamic disease.

Puberty is also hypothalamic-driven and governed by complex neuronal circuits.

Among them, Kiss1 neurons have emerged as key elements in the brain control of puberty and its metabolic regulation, likely in cooperation with other central signaling systems, as POMC/melanocortins.

Yet, the mechanisms whereby early obesity impacts on different Kiss1 neuronal populations and pubertal timing are ill-defined.

The global aim of DOPA-Kiss is to unveil the brain basis of obesity-induced pubertal alterations in both sexes, with a major focus on Kiss1 neurons.

An integral research plan will be implemented based on (i) Multidimensional integration of omics data, including hypothalamic global and spatial metabolomics, as well as transcriptomic and epigenomic profiling of Kiss1 neuronal subpopulations during pubertal maturation in conditions of obesity; (ii) Analysis of the molecular mechanisms for nutrient & metabolic sensing at the hypothalamus, and particularly in Kiss1 neurons; and (iii) Functional genomic dissection of key metabolic pathways in Kiss1 neurons using Cre/LoxP- & CRISPR-based genome editing in vivo.

Sex differences in the impact of early obesity on subsets of Kiss1 neurons and puberty, and, when relevant, parallel changes in POMC neurons, will be explored. Putative human correlates of our experimental data will be scrutinized using public databases.

DOPA-Kiss will not only surface unsolved aspects of the metabolic control of puberty, but will reveal also groundbreaking info on pathophysiological mechanisms and putative targets of intervention in conditions of altered puberty due to early obesity.