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The relationship between bone mineral metabolism and autonomic nervous system in obesity

Grant number: 18/17867-0
Support type:Regular Research Grants
Duration: October 01, 2019 - September 30, 2021
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Ita Pfeferman Heilberg
Grantee:Ita Pfeferman Heilberg
Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
Assoc. researchers:Aluízio Barbosa de Carvalho ; Cassia Marta de Toledo Bergamaschi ; Erika Emy Nishi

Abstract

Obesity has become a major public health problem worldwide, because of conferring a higher risk of developing cardiovascular diseases, type 2 diabetes mellitus, metabolic syndrome, arterial hypertension and renal diseases such as nephrolithiasis and glomerulopathies. Moreover, obesity affects the bone mineral metabolism, in an important way. Although increased body weight had been traditionally considered as protective against osteoporosis due to the mechanical loading, recent studies suggest a negative effect of obesity on bone metabolism. The increase in visceral adiposity is associated with activation of the sympathetic autonomic nervous system (ANS). The adipose tissue is an endocrine organ that releases hormones and cytokines, such as leptin, that plays a role in the regulation of bone metabolism throughout the central nervous system. Whereas the peripheral actions of leptin favor the increase of bone mass, its effect at a central level inhibits bone formation throughout serotonergic pathways (brainstem to hypothalamus) and sympathetic tonus of ANS, generated by the hypothalamus. It has been suggested that the sympathetic signaling in the osteoblasts promotes an increase in the expression of the receptor activator of nuclear factor Kappa-B ligand (RANKL), resulting in an increased bone resorption consequent to the osteoclastic stimulation. Recent studies have focused on the importance of some microRNAs (miRs) in the control of bone metabolism. However, the impact of obesity on such miRs expression is still unknown. Considering the controversial beneficial effects of obesity upon bone mass and given the recent concepts that leptin and other adipose tissue-derived hormones are regulated by ANS, the development of an animal model of obesity in order to investigate the pathophysiological mechanisms involved in the relationship between bone metabolism and ANS is warranted. The aims of the present study are to evaluate bone mineral metabolism in an animal model of obesity in male rats treated with high fat diet (60% fat) during 18 weeks. The methodology will include histomorphometric analysis with double-labeled tetracycline to evaluate bone microarchitecture, immuno-histochemistry for expression of bone proteins and qRT-PCR for the analysis of gene expression of cytokines, growth factors and receptors involved in bone mineralization in adipose, renal and bone tissues. Throughout the whole protocol, serum samples will be collected for determination of renal function, calciotropic hormones as well as bone formation and resorption markers. In addition, the expression of several miRs will be quantified in serum and bone samples. The effects of the acute denervation of ANS upon bone mineral metabolism will be assessed. (AU)