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Molecular and cellular bases of alterations in signaling cross-talk in relation to adipose and metabolic dysfunction

Grant number: 17/26509-8
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): March 12, 2018
Effective date (End): January 24, 2019
Field of knowledge:Health Sciences - Nutrition
Principal Investigator:Anderson Marliere Navarro
Grantee:Mariana Palma Guimarães
Supervisor abroad: Marta Giralt Oms
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Universitat de Barcelona (UB), Spain  
Associated to the scholarship:16/19155-2 - Influence of brown adipose tissue in energy metabolism of people living with HIV and AIDS, BP.DR

Abstract

Intoduction: The use of antiretroviral therapy (ART) has reduced the mortality of HIV infection. However, its use implies accumulation of toxic side effects that, together with other pathophysiological mechanisms related to immune activation, chronic inflammation and aging, result in the associated comorbidities such as lipodystrophy and metabolic syndrome. It is known that adipose tissue is one of the target organs of the deleterious effects of HIV and ART. Studies with adipose tissue biopsy of HIV-infected people indicate alterations in adipogenesis, adipokine secretion, mitochondrial dysfunction and inflammatory processes resulting from the effects produced by viral proteins (Vpr, Tat) and by the release of proinflammatory cytokines (TNF±, IL- 6). These alterations affect the cross-talk of tissues involved in energy homeostasis and metabolism, thus contributing to the onset of pathologies associated with the metabolic syndrome. It is possible that the HIV and ART also influence brown and beige adipose tissue. One of the batokines (citocines from brown adipose tissue) expressed exclusively in brown and beige adipose tissue is FGF21. The superfamily of fibroblast growth factors FGF19, FGF21 and FGF23 act as hormonal factors and are involved in many aspects of metabolic regulation. Objective: To elucidate the contribution of alterations in endocrine FGF systems to changes in adipose tissue and metabolic syndrome associated with HIV infection. Methods: Serum samples from HIV seropositive patients and healthy controls, matched for age, sex and BMI, will be evaluated for biochemical analyzes of endocrine FGFs, adipokines and inflammatory cytokines. Experimental studies will also be conducted in vitro and in vivo. For the in vitro study, the human adipocyte SGBS line (with specific white and brown adipocyte differentiation protocols) treated with different antiretroviral classes will be used to evaluate the differential effects of agents associated with viral infection and ART in endocrine FGF response and adipocyte differentiation and function. For the in vivo study, the HIV-Tg26 transgenic mouse model, treated with ART with higher toxicity potential, will be used to evaluate the effects of HIV proteins and ART on the biology of the endocrine FGF system and its relationship with metabolic changes and adipose homeostasis (white and brown adipose tissues, and browning phenomena). For the studies will be carried out: biochemical analysis through the Multiplex and ELISA system; obtaining RNA and DNA by the affinity microcolumn system; analysis of gene expression by RT-PCR; protein level analysis by Western blot; cell viability analyzes; morphometric and histological analyzes of adipose tissue. Statistical analyzes will be performed and the level of statistical significance will be P<0.05.