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

Project Information

DOPA-Kiss

Grant agreement ID: 101096793

DOI

10.3030/101096793

EC signature date 14 June 2023

Start date 1 September 2023

End date 31 August 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 499 995,00

EU contribution

€ 2 499 995,00

Coordinated by

UNIVERSIDAD DE CORDOBA
Spain

Periodic Reporting for period 1 - DOPA-Kiss (Dissecting the Brain Basis of Obesity-Induced Pubertal Alterations: A View to a Kiss)

Reporting period: 2023-09-01 to 2026-02-28

Summary of the context and overall objectives of the project

Obesity is a major health problem that has reached pandemic proportions. Particularly worrying is the condition of childhood obesity, whose prevalence is escalating alarmingly, with 20% of children and adolescents being obese. Puberty is a key maturational phenomenon influenced by metabolic and nutritional cues. Early obesity is bound to pubertal alterations, whose prevalence is rising, via as yet largely unknown mechanisms, with sex differences being detected. Kiss1 neurons in the hypothalamus have been identified as essential elements for the brain control of puberty. However, the molecular mechanisms whereby different populations of Kiss1 neurons control puberty and contribute to its modulation by metabolic cues need to be fully elucidated.
Despite recent progress, the fundamental question of how do body weight and nutritional cues control puberty in normal and pathological conditions remains unsolved, and the neuroendocrine and molecular mechanisms whereby obesity alters pubertal timing are largely unknown. Elucidation of these essential aspects of pubertal control is highly relevant in terms of translational medicine, not only because of the importance of puberty on its own, but also due to the impact of disordered puberty on later health, with discernible adverse outcomes, including higher risk of cardiometabolic diseases.
The overarching hypothesis of DOPA-Kiss is that early obesogenic conditions drive pubertal alterations in both sexes, via potentially different mechanisms, occurring at the hypothalamus and converging on Kiss1 neurons and/or related pathways. To cover this goal, DOPA-Kiss1 is deploying a workplan organized into three collaborative WPs that will shed light into the intricate mechanisms whereby early obesity alters pubertal timing.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

DOPA-Kiss was initiated in 01/09/2023. The workplan has been conducted as originally planned, it being implemented in three connected work packages (WP), which have all progressed efficiently. The sections below show the work performed and main achievements for each WP.

WP1: Characterization of the hypothalamic metabolomic landscape and transcriptomic profiles of Kiss1 neuronal populations at pubertal maturation and conditions of early-onset obesity using multi-omic techniques.
Models of early-onset obesity with alterations of pubertal timing have been developed in female rats and in male and female mice, and we have completed large-scale lipidomic analyses of the mediobasal hypothalamus in the female rat model. We have generated suitable mouse lines to allow separation of Kiss1 neurons in models of early-onset obesity, implemented in juvenile and pubertal male and female mice, both under normal nutrition and obesity. We have conducted RNAseq analyses of these neuronal populations followed by in depth bioinformatic analyses. Finally, we have carried out initial spatial transcriptomic analyses in hypothalamic tissue sections form juvenile and peripubertal female mice, under control nutrition or obesity, and are optimizing protocols for bioinformatic analysis of these large datasets.

WP2: Characterization of novel mechanisms of metabolic and nutrient sensing in Kiss1 neurons and related pathways, as major determinants for obesity-induced perturbed puberty.
We have completed a study addressing the role of novel lipid sensing mechanisms at the hypothalamus in the control of puberty and its alterations in conditions of early obesity. This study is being complemented with additional analyses addressing the role of hypothalamic ER stress in the control of puberty and its perturbations in early obesity. Altogether, these data point out changes in the expression profiles of components of lipid sensing pathways and their contribution to the control of puberty in conditions of normal nutrition and obesity. Changes in ER stress are likely involved also in pubertal alterations bound to obesity, in a mechanism converging at the hypothalamic arcuate nucleus and potentially involving Kiss1 neurons.

WP3: Dissection of the molecular basis of the metabolic control of puberty by applying genome editing of Kiss1 neurons in vivo, using conventional and CRISPR-Cas9 based functional genomics.
Progression of WP3 is subordinated to that of WP1-2. Yet, we have already conducted activities for in vivo gene editing/ablation of suspected key factors in pubertal control, paving the way for additional analyses during the next 3 years. As most salient result so far, we have used functional genomics in the context of our studies to address the putative roles of kisspeptin signaling in key non-neuronal cells involved in pubertal control, namely, astrocytes. These analyses, which have been published recently, documented for the first time the putative role of kisspeptin actions in astrocytes as component for female pubertal acceleration in conditions of early obesity.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

While DOPA-Kiss has not yet reached its equator, and hence it is expected that major achievements and eventual breakthroughs may come during the latest stages of its implementation, some of the outputs so far can be determinant to substantially advance our understanding on how puberty is controlled and perturbed by conditions of early obesity.

1. Our studies on hypothalamic lipid sensing and ER stress are the first to document the relevance of these signalling pathways and fundamental biological process in the regulation of puberty, and how obesity can substantially alter pubertal maturation. This advancement is both conceptual and (eventually) translational, since specific targets, such as ER stress at the ARC or brain TGR5 signalling, are potentially actionable and thus may define the basis for putative interventions to prevent or reverse pubertal alterations linked to infantile obesity.

2. Our studies on a novel signalling pathway of kisspeptins in astrocytes, via its canonical receptor, have illuminated a new complementary route for auto-regulation of kisspeptin actions on the reproductive axis. While this study is wider than the focus of DOPA-Kiss, studies conducted in the context of puberty and early obesity, under the umbrella of this project, have set the contention that activation of kisspeptin actions in astrocytes might be instrumental for female pubertal acceleration in conditions of early obesity. This finding was somewhat unexpected, given our concurrent findings on the roles of Kiss1r on prostaglandin synthesis machinery in astrocytes, and clearly illustrate the complexity of this tripartite regulatory hub (Kiss1-astrocyte-GnRH) in the control of puberty and fertility.