Overweight-induced Hypogonadism as major factor for the generation and/or perpetuation of Metabolic Co-morbidities of Obesity: Contribution of Epigenetic Regulatory Mechanisms. (ReprObesity)
Obesity is a global health problem whose prevalence is increasing substantially due to lifestyle changes. This complex medical condition is frequently linked to serious metabolic complications and deregulation of hormonal axes, which lead to perturbed homeostasis in conditions of overweight. Different studies have suggested that obesity is often associated to hypogonadism, a reproductive disorder that might also promote metabolic alterations, thus setting a vicious circle in the generation/perpetuation of obesity co-morbidities. While the targets and molecular mechanisms underlying this phenomenon are still unknown, emerging evidence from experimental models of metabolic stress linked to hypogonadism strongly suggests the potential role of perturbations of hypothalamic Kiss1/NKB neurons. Likewise, the recently identified involvement of epigenetics in the control of Kiss1 expression at puberty, a crucial stage in sexual development that is metabolically gated, suggests also the contribution of these regulatory mechanisms to this phenomenon. In this context, this project aims to elucidate the pathophysiological relevance of epigenetic regulatory mechanisms in obesity-induced hypogonadism and their influence in the generation/ maintenance of the metabolic complications of overweight. To this end, we will characterize the time-course of alterations of key hormonal and epigenetic factors in preclinical models of obesity and will evaluate the contribution of epigenetic modifications in deregulation of hypothalamic Kiss1/NKB neurons in conditions of overweight. In addition, we will analyse the potential role of gonadal steroids in this phenomenon. This project will help to identify the molecular targets and epigenetic mechanisms responsible for the metabolic perturbations linked to obesity-induced hypogonadism, and will aid to define better tools for the treatment of these complications.
The GENERAL OBJECTIVE of this project is to elucidate the pathophysiological relevance of epigenetic regulatory mechanisms in obesity-induced hypogonadism and its influence in the generation/maintenance of the metabolic complications of overweight. Special attention will be paid to characterize the role of epigenetic mechanisms in the control of hypothalamic Kiss1/NKB neurons, as essential integrators of metabolism and reproduction, and the involvement of sex steroids, as key metabolic modifiers, in the development/progression of obesity and its associated metabolic diseases, including insulin resistance and T2DM.
Specific Objective-1 (SO-1): To define the time-course of major alterations in endocrine, neuroendocrine and epigenetic profiles in pre-clinical models of obesity, with special attention to the impact of changes in circulating levels of gonadal steroids on endocrine/epigenetic responses to obesogenic insults causing metabolic deregulation.
Specific Objective-2 (SO-2): To evaluate the role of epigenetic modifications in the control of hypothalamic Kiss1 and NKB expression, and their eventual contribution to the development of obesity-induced hypogonadism and its metabolic co-morbidities.
Specific Objective-3 (SO-3): To address the specific contribution of epigenetic modifications in Kiss1 neurons to the development of obesity-induced hypogonadism and its metabolic co-morbidities by combining genetically manipulated mouse models (Kiss1-CreGFP) and virally mediated gene delivery systems (Adeno-associated viral vectors -AAV-).
- Panel of early endocrine and neuroendocrine markers of the development of obesity-induced hypogonadism and its metabolic co morbidities.
- Report on changes of hypothalamic expression and neuroanatomical distribution of key epigenetic factors during development of obesity induced hypogonadism and its metabolic co-morbidities.
- Report on the epigenetic landscape of Kiss1/NKB genes in the hypothalamus during the development of obesityinduced hypogonadism and its metabolic co-morbidities.
- Report on the impact of pharmacological manipulation of methylation/acetylation in vivo on the state of hypogonadotropic hypogonadism associated to obesity and its metabolic co-morbidities.
- Report on the expression profile of relevant epigenetic factors in hypothalamic Kiss1 neurons during the development of obesity induced hypogonadism and its metabolic co-morbidities.
- Report on the impact of the overexpression of specific epigenetic factors in hypothalamic Kiss1 neurons on the state of hypogonadotropic hypogonadism associated to obesity and its metabolic co-morbidities.
- Generation of SOP in the host group for novel techniques/laboratory procedures included in the proposal.
- Paper(s) draft(s) for publication.
The Project enhance the future career prospects of the researcher after the fellowship in the following impacts:
- to improve of professional profile by increase of scientific skills,to up-to-date methodological approaches for investigating the basis for the close interaction between metabolic homeostasis and gonadal function;
- to establish a collaboration network beyond the host institution and provide international visibility and strength of network capacity;
- to increase of European R&I visibility;
- to define new strategies to palliate the increasing incidence of reproductive disorders putatively associated to metabolic causes in EU.
Balance Energético y Función Reproductora
Code PAIDI: BIO-310
Manuel José Tena Sempere. Coordinator.
Universidad de Córdoba
Budget of Andalusian group: € 158,121,60€