SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner.

Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.

Extracellular miRNAs in redox signaling: Health, disease and potential therapies.

Extracellular microRNAs (miRNAs) have emerged as important mediators of cell-to-cell communication and intertissue crosstalk. MiRNAs are produced by virtually all types of eukaryotic cells and can be selectively packaged and released to the extracellular medium, where they may reach distal cells to regulate gene expression cell non-autonomously. By doing so, miRNAs participate in integrative physiology. Oxidative stress affects miRNA expression, while miRNAs control redox signaling. Disruption in miRNA expression, processing or release to the extracellular compartment are associated with aging and a number of chronic diseases, such as obesity, type 2 diabetes, neurodegenerative diseases and cancer, all of them being conditions related to oxidative stress. Here we discuss the interplay between redox balance and miRNA function and secretion as a determinant of health and disease states, reviewing the findings that support this notion and highlighting novel and yet understudied venues of research in the field.

Lipid droplets: platforms with multiple functions in cancer hallmarks.

Lipid droplets (also known as lipid bodies) are lipid-rich, cytoplasmic organelles that play important roles in cell signaling, lipid metabolism, membrane trafficking, and the production of inflammatory mediators. Lipid droplet biogenesis is a regulated process, and accumulation of these organelles within leukocytes, epithelial cells, hepatocytes, and other nonadipocyte cells is a frequently observed phenotype in several physiologic or pathogenic situations and is thoroughly described during inflammatory conditions. Moreover, in recent years, several studies have described an increase in intracellular lipid accumulation in different neoplastic processes, although it is not clear whether lipid droplet accumulation is directly involved in the establishment of these different types of malignancies. This review discusses current evidence related to the biogenesis, composition and functions of lipid droplets related to the hallmarks of cancer: inflammation, cell metabolism, increased proliferation, escape from cell death, and hypoxia. Moreover, the potential of lipid droplets as markers of disease and targets for novel anti-inflammatory and antineoplastic therapies will be discussed.

Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation.

Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway-dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-ß production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF-ß production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma.

Mecanismos associados a obesidade e carcinogênesepapel da leptina e corpúsculos lipídicos na regulação do metabolismo lipídico e progressao tumoral

A obesidade é uma condição predisponente ao desenvolvimento de câncer de cólon, esôfago, pulmão, próstata, dentre outros. Um dos maiores desafios no estabelecimento da ligação de obesidade e o risco de câncer tem sido correlacionar a epidemiologia e sua base biológica, ou seja, o mecanismo pelo qual a obesidade leva ao desenvolvimento de câncer. A leptina é uma adipocitocina, produzida e secretada pelo tecido adiposo que possui além dos efeitos em nível central no controle da saciedade, ações na regulação da resposta imune e inflamatória. Temos por hipótese que os níveis elevados de leptina na obesidade ative vias de sinalização envolvidas na regulação da inflamação, metabolismo lipídico e proliferação celular em células epiteliais. Os corpúsculos lipídicos são organelas dinâmicas envolvidas no metabolismo lipídico e inflamação, e o aumento no número destas organelas foi observado no câncer de cólon humano. A mTOR é uma serina/treonina cinase que está relacionada com o estímulo à tradução de proteínas, proliferação celular e progressão tumoral. Nosso objetivo foi, portanto, estudar o papel da leptina na alteração do metabolismo lipídico e progressão tumoral. Células epiteliais intestinais (IEC-6) não-transformadas de rato foram incubadas com leptina por 6h, na presença ou ausência do inibidor de mTOR, rapamicina. O estímulo com leptina induziu aumento na formação de corpúsculos lipídicos em células IEC-6 quando comparadas às células controle após coloração com tetróxido de ósmio ou ORO. O pré-tratamento com rapamicina inibiu significantemente a indução de corpúsculos lipídicos por leptina, sugerindo um papel de mTOR na sinalização induzida por esta adipocina Nós demonstramos que a leptina aumenta a fosforilação de S6K em um mecanismo sensível à rapamicina. Além, disso, a leptina aumenta a proliferação de células epiteliais de forma dependente da via de mTOR, aumentando o número de células na fase S do ciclo celular. Através de proteoma descritivo de corpúsculos lipídicos de células de adenocarcinoma de cólon, verificamos a presença de 370 proteínas, incluindo diversas proteínas importantes no metabolismo lipídico, tradução de proteínas, sinalização e proliferação celular, sugerindo que estas organelas podem ser sítios de tradução de proteínas e sinalização, e poderiam contribuir para o fenótipo hiperproliferativo observado em tumores. Através de fracionamento subcelular e microscopia confocal, validamos que corpúsculos lipídicos de células de adenocarcinoma de cólon são sítios de localização da proteína S6K e mTOR. O estudo da regulação e ativação de mTOR e outras importantes vias durante processos patológicos como o câncer poderá contribuir para o entendimento dos mecanismos básicos de regulação do metabolismo lipídico e transformação celular de células tumorais. Dessa forma, nossos estudos podem contribuir para a identificação de novos alvos terapêuticos para o tratamento do câncer