Evaluation of the role of TGF-ß1 and microglia in the hypothalamic inflammatory response induced by saturated fatty acids

Author(s)

Natália Ferreira Mendes

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Enfermagem
• Defense date: 2021-01-15

Examining board members

Eliana Pereira de Araujo; Marcio Alberto Torsoni; Marciane Milanski Ferreira; Andreza Fabro de Bem; Cristiano Mendes da Silva

• Advisor: Eliana Pereira de Araujo

Abstract

Excessive consumption of fat triggers an inflammatory response in the hypothalamus, which depends on the activation of astrocytes and microglia, which release various inflammatory cytokines, growth factors, and chemokines in the hypothalamic parenchyma. When the high-fat diet (HFD) persists for several weeks, peripheral myeloid cells are recruited to the hypothalamus. In this work, (1) we investigate whether the expression of the growth factor TGF-?1 in the hypothalamus affects energy homeostasis, (2) we assess whether microglial activation is involved in the recruitment of peripheral myeloid cells to the hypothalamus, and (3) we analyze the morphology of these cells. For this, we reduced the levels of TGF-?1 in the arcuate hypothalamic nucleus (ARC) of C57BL/6J Unib mice, fed a 14-day HFD, and evaluated several metabolic and inflammatory parameters in these animals. To activate the ARC microglia cells, we used the DREADD technique in CX3CR1-cre mice fed a standard diet. ARC samples from these animals were analyzed by quantitative PCR and the neural tissue by immunofluorescence. We also used CX3CR1GFP/+ CCR2RFP/+ mice to investigate the characteristics of peripheral myeloid cells that migrate to the hypothalamus. As a result, the reduction of TGF-?1 expression in the ARC of mice fed a HFD resulted in reduced body weight and fat mass gain, decreased hypothalamic inflammation, attenuated lipohypertrophy of brown adipose tissue, increased locomotor activity and reduced hepatic steatosis and serum triglyceride levels. The activation of the microglia in the ARC resulted in inflammation and recruitment of peripheral myeloid cells to the hypothalamus, regardless of the fat content in the diet and the activation of other cells. The analysis of the characteristics of the infiltrating cells showed that CCR2 + and CD169 + cells are morphologically distinct after infiltrating the hypothalamic parenchyma. In conclusion, the reduction of TGF-?1 in the ARC attenuates hypothalamic inflammation resulting in an improved energy metabolism. The recruitment of peripheral myeloid cells to the hypothalamic parenchyma depends on the activation of the microglia. These infiltrating cells have morphological differences between them, however, the functions that each cell type plays in the inflammatory response remain unknown (AU)

• FAPESP's process: 16/17810-3 - Evaluation of TGF-b1 function in the hypothalamus of animals with obesity and diabetes induced by high-fat diet
• Grantee: Natália Ferreira Mendes
• Support Opportunities: Scholarships in Brazil - Doctorate