RESUMO

In obesity, high levels of TNF-α in the bone marrow microenvironment induce the bone marrow-mesenchymal stem cells (BM-MSCs) towards a pro-adipogenic phenotype. Here, we investigated the effect of obesity on the migratory potential of BM-MSCs and their fate towards the adipose tissues. BM-MSCs were isolated from male C57Bl/06 mice with high-fat diet-induced obesity. The migratory potential of the BM-MSCs, their presence in the subcutaneous (SAT) and the visceral adipose tissues (VAT), and the possible mechanisms involved were investigated. Obesity did not affect MSC content in the bone marrow but increased the frequency of MSCs in blood, SAT, and VAT. In these animals, the SAT adipocytes presented a larger area, without any changes in adipokine production or the Sdf-1α gene expression. In contrast, in VAT, obesity increased leptin and IL-10 levels but did not modify the size of the adipocytes. The BM-MSCs from obese animals presented increased spontaneous migratory activity. Despite the augmented expression of Cxcr4, these cells exhibited decreased migratory response towards SDF-1α, compared to that of BM-MSCs from lean mice. The PI3K-AKT pathway activation seems to mediate the migration of BM-MSCs from lean mice, but not from obese mice. Additionally, we observed an increase in the spontaneous migration of BM-MSCs from lean mice when they were co-cultured with BM-HCs from obese animals, suggesting a paracrine effect. We concluded that obesity increased the migratory potential of the BM-MSCs and induced their accumulation in VAT, which may represent an adaptive mechanism in response to chronic nutrient overload.

Assuntos

Gordura Intra-Abdominal/patologia , Células-Tronco Mesenquimais/patologia , Obesidade/patologia , Animais , Composição Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Glucose/metabolismo , Homeostase/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Comunicação Parácrina/efeitos dos fármacos , Receptores CXCR4/metabolismo , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/patologia , Fator de Necrose Tumoral alfa/farmacologia

RESUMO

BACKGROUND: In 1957, Francis Crick drew a linear diagram on a blackboard. This diagram is often called the "central dogma." Subsequently, the relationships between different steps of the "central dogma" have been shown to be considerably complex, mostly because of the emerging world of small molecules. It is noteworthy that metabolites can be generated from the diet through gut microbiome metabolism, serve as substrates for epigenetic modifications, destabilize DNA quadruplexes, and follow Lamarckian inheritance. Small molecules were once considered the missing link in the "central dogma"; however, recently they have acquired a central role, and their general perception as downstream products has become reductionist. Metabolomics is a large-scale analysis of metabolites, and this emerging field has been shown to be the closest omics associated with the phenotype and concomitantly, the basis for all omics. AIM OF REVIEW: Herein, we propose a broad updated perspective for the flux of information diagram centered in metabolomics, including the influence of other factors, such as epigenomics, diet, nutrition, and the gut- microbiome. KEY SCIENTIFIC CONCEPTS OF REVIEW: Metabolites are the beginning and the end of the flux of information.

Assuntos

Metabolômica , Dieta , Microbioma Gastrointestinal

RESUMO

During tumor development, the spleen acts as an extra-medullar reservoir of LY6Chi inflammatory monocytes, which can migrate toward tumor to differentiate into tumor-associated macrophage (TAMs), renewing the TAM population. In the tumor microenvironment, pro-inflammatory macrophages (M1) acquire anti-inflammatory and pro-tumor (M2) characteristics favoring tumor development. We previously demonstrated that lipoxins, a family of pro-resolving lipid mediators, restored in vitro the cytotoxic M1-like properties of TAMs. Objective: In this study, we have investigated in vivo the cellular mechanisms underlying the anti-tumor property of lipoxins. Methods: Fourteen days after inducing B16-F10 melanoma tumors, mice received one single dose of ATL-1 (1 µg/i.v.), a lipoxin A4 analog. After further 7 days, blood and bone-marrow were collected, tumors and spleens were removed, and TAMs and blood monocytes were isolated. Results: While the population of LY6Chi monocytes was increased in non-treated tumor-bearing mice, the treatment with ATL-1 diminished the population of LY6Chi monocytes in spleen, blood and bone marrow, decreasing macrophage infiltration into the tumor and reducing the M2 markers expression on TAMs. Importantly, those effects were accompanied by an impairment of tumor growth and improved survival of tumor-bearing mice. The data evidence the anti-tumor mechanism of ATL-1, by decreasing the availability of TAM-precursor monocytes and changing TAMs profile in vivo, impairing tumor progression. ATL-1 may become a new tool in cancer control.