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Orientadores: Marcelo Alves da Silva Mori, Renato Vicentini dos Santos Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia Resumo: A obesidade é uma doença epidêmica com graves complicações à saúde. O recrutamento de adipócitos beges no tecido adiposo branco - um fenômeno denominado browning - resulta em uma termogênese induzida e gasto energético aumentado, representando uma intervenção promissora no combate à obesidade e doenças relacionadas. Dados da literatura sugerem que algumas células imunes residentes no tecido adiposo, quando estimuladas pelo frio, por exemplo, podem promover o recrutamento de adipócitos beges. Os miRNAs também foram implicados na regulação da adipogênese e na manutenção da identidade funcional dos adipócitos marrons / beges. Camundongos AdicerKO com nocauteamento adipócito-específico da enzima DICER - uma enzima responsável pelo processamento de miRNA ¿apresentam um fenótipo de lipodistrofia parcial associado à redução de marcadores de adipócitos marrons / beges e resistência à insulina. Diante dessas observações, o objetivo desse estudo foi investigar como a presença de DICER em adipócitos maduros pode modular o perfil inflamatório local do tecido adiposo e, consequentemente, a diferenciação de adipócitos beges. Nossos dados mostraram que a falta de DICER em adipócitos altera a população de macrófagos M1 residentes no tecido adiposo subcutâneo de camundongos AdicerKO jovens, resultando em um ambiente pró-inflamatório antes de qualquer outra alteração fisiopatológica ou morfológica no tecido adiposo. Consistentemente, demonstramos que a ausência de DICER em adipócitos altera o metabolismo energético e a biossíntese de diversos lipídeos que podem estar contribuindo para a reprogramação de macrófagos e o aumento da produção da citocina pró-inflamatória IL-1?. Fortalecendo essa comunicação entre macrófagos e adipócitos, observamos em um sistema de co-cultura que macrófagos limitam a indução de Ucp1 em adipócitos beges, aparentemente via DICER. Esse fenômeno pode indicar um novo mecanismo pelo qual DICER em adipócitos medeiam a inflamação de indivíduos com doenças metabólicas, como obesidade e diabetes Abstract: Obesity is an epidemic disease with severe health complications. The recruitment of beige adipocytes into white adipose tissue - a phenomenon called browning - results in induced thermogenesis and increased energy expenditure, representing a promising intervention to treat the disease and its complications. Published data suggest that some immune cells residing in adipose tissue, when stimulated by cold, for example, can promote the recruitment of beige adipocytes. The miRNAs were also implicated in the regulation of adipogenesis and maintenance of brown/beige adipocytes. AdicerKO mice, DICER knockout specific in adipocytes - an enzyme responsible for miRNA processing - have a partial lipodystrophy phenotype associated with the reduction of brown/beige adipocyte markers and insulin resistance. Consistent with these observations, the objective of this study is to track possible molecules capable of establishing such communications. Our data indicate that the absence of DICER in adipocytes alters the macrophages resident population in subcutaneous adipose tissue of young mice, resulting in a proinflammatory environment before any other pathophysiological or morphological alterations in adipose tissue. Consistently, we showed that the lack of DICER in adipocytes alters energy metabolism and the biosynthesis of several lipids that may contribute to reprogramming macrophages to enhance the production of IL-1?, a proinflammatory cytokine. We observed in a co-culture system that macrophages limit the Ucp1 induction in beiges adipocytes, possibly via DICER, establishing the communication between macrophages and adipocytes. This phenomenon may indicate a new mechanism of DICER in adipocytes mediating inflammation in individuals with metabolic diseases, such as obesity and diabetes Doutorado Imunologia Doutora em Genética e Biologia Molecular FAPESP 2016/12294-7; 2019/10592-9 CAPES 001

Agradecimentos: The authors are thankful to Dr. Iscia Lopes-Cendes for providing facilities in her laboratory. The authors are grateful to FAPESP (Grants 2009/16150-6 and 2017/04377-2), CNPq and CAPES for the funding of this research. INFABiC is co-funded by FAPESP (Grant 2014/50938-8) and CNPq (Grant 465699/2014-6) Abstract: Environmental and nutritional factors, including fatty acids (FA), are associated with prostatitis, benign prostate hyperplasia and prostate cancer. We hypothesized that different FA in normolipidic diets (7%) affect prostate physiology, increasing the susceptibility to prostate disorders. Thus, we fed male C57/BL6 mice with normolipidic diets based on linseed oil, soybean oil or lard (varying saturated and unsaturated FA contents and omega-3/omega-6 ratios) for 12 or 32 weeks after weaning and examined structural and functional parameters of the ventral prostate (VP) in the systemic metabolic context. Mongolian gerbils were included because they present a metabolic detour for low water consumption (i.e., oxidize FA to produce metabolic water). A linseed oil-based diet (LO, 67.4% PUFAs, omega-3/omega-6 = 3.70) resulted in a thermogenic profile, while a soybean oil-based diet (SO, 52.7% PUFAs, omega-3/omega-6 = 0.11) increased body growth and adiposity. Mice fed lard (PF, 13.1% PUFA, omega-3/omega-6 = 0.07) depicted a biphasic growth, resulting in decreased adiposity in adulthood. SO and PF resulted in hepatic steatosis and steatohepatitis, respectively. PF and SO increased prostate epithelial volume, and lard resulted in epithelial hyperplasia. Animals in the LO group had smaller prostates with predominant atrophic epithelia and inflammatory loci. Inflammatory cells were frequent in the VP of PF mice (predominantly stromal) and LO mice (predominantly luminal). RNAseq after 12 weeks revealed good predictors of a later-onset inflammation. The transcriptome unveiled ontologies related to ER stress after 32 weeks on PF diets. In conclusion, different FA qualities result in different metabolic phenotypes and differentially impact prostate size, epithelial volume, inflammation and gene expression FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPES Aberto

Agradecimentos: The study was supported by grants from the São Paulo Research Foundation (2013/07607-8) and Conselho Nacional de Pesquisa e Desenvolvimento Cientifico. INFABIC is co-funded by Fundação de Amparo a Pesquisa do Estado de São Paulo (FAPESP) (08/57906-3) and Conselho Nacional de Desenvolvimento Cientifico e Tecnológico (CNPq) (573913/2008-0) Abstract: Inflammation is the most relevant mechanism linking obesity with insulin-resistance and metabolic disease. It impacts the structure and function of tissues and organs involved in metabolism, such as the liver, pancreatic islets and the hypothalamus. Brown adipose tissue has emerged as an important component of whole body energy homeostasis, controlling caloric expenditure through the regulation of non-shivering thermogenesis. However, little is known about the impact of systemic inflammation on the structure and function of brown adipose tissue. The relations between IL10 and mitochondria structure/function and also with thermogenesis were evaluated by bioinformatics using human and rodent data. Real-time PCR, immunoblot, fluorescence and transmission electron microscopy were employed to determine the effect of IL10 in the brown adipose tissue of wild type and IL10 knockout mice. IL10 knockout mice, a model of systemic inflammation, present severe structural abnormalities of brown adipose tissue mitochondria, which are round-shaped with loss of cristae structure and increased fragmentation. IL10 deficiency leads to newborn cold intolerance and impaired UCP1-dependent brown adipose tissue mitochondrial respiration. The reduction of systemic inflammation with an anti-TNFa monoclonal antibody partially rescued the structural but not the functional abnormalities of brown adipose tissue mitochondria. Using bioinformatics analyses we show that in both humans and mice, IL10 transcripts correlate with mitochondrial lipid metabolism and caspase gene expression. IL10 and systemic inflammation play a central role in the regulation of brown adipose tissue by controlling mitochondrial structure and function Obesity CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP Aberto