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Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice.

ABSTRACT: Adipose tissue inflammation is a characteristic of obesity. However, the mechanisms that regulate this inflammatory response and link adipose inflammation to systemic metabolic consequences are not fully understood. In this study, we have taken advantage of the highly restricted coexpression of adipocyte/macrophage fatty acid-binding proteins (FABPs) aP2 (FABP4) and mal1 (FABP5) to examine the contribution of these lipid chaperones in macrophages and adipocytes to local and systemic inflammation and metabolic homeostasis in mice. Deletion of FABPs in adipocytes resulted in reduced expression of inflammatory cytokines in macrophages, whereas the same deletion in macrophages led to enhanced insulin signaling and glucose uptake in adipocytes. Using radiation chimerism through bone marrow transplantation, we generated mice with FABP deficiency in bone marrow and stroma-derived elements in vivo and studied the impact of each cellular target on local and systemic insulin action and glucose metabolism in dietary obesity. The results of these experiments indicated that neither macrophages nor adipocytes individually could account for the total impact of FABPs on systemic metabolism and suggest that interactions between these 2 cell types, particularly in adipose tissue, are critical for the inflammatory basis of metabolic deterioration.

SUBMITTER: Furuhashi M

PROVIDER: S-EPMC2423863 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Expression of Adipocyte/Macrophage Fatty Acid-Binding Protein in Tumor-Associated Macrophages Promotes Breast Cancer Progression.

Project description:Tumor-associated macrophages (TAM) play a critical role in cancer development and progression. However, the heterogeneity of TAM presents a major challenge to identify clinically relevant markers for protumor TAM. Here, we report that expression of adipocyte/macrophage fatty acid-binding protein (A-FABP) in TAM promotes breast cancer progression. Although upregulation of A-FABP was inversely associated with breast cancer survival, deficiency of A-FABP significantly reduced mammary tumor growth and metastasis. Furthermore, the protumor effect of A-FABP was mediated by TAM, in particular, in a subset of TAM with a CD11b+F4/80+MHCII-Ly6C- phenotype. A-FABP expression in TAM facilitated protumor IL6/STAT3 signaling through regulation of the NF?B/miR-29b pathway. Collectively, our results suggest A-FABP as a new functional marker for protumor TAM.Significance: These findings identify A-FABP as a functional marker for protumor macrophages, thus offering a new target for tumor immunotherapy. Cancer Res; 78(9); 2343-55. ©2018 AACR.

| S-EPMC5932212 | biostudies-literature

C1q<sup>+</sup> tumor-associated macrophages contribute to immunosuppression through fatty acid metabolic reprogramming in malignant pleural effusion.

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Macrophage and adipocyte IGF1 maintain adipose tissue homeostasis during metabolic stresses.

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Project description: Not available

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Methyl 3,4,5-trimethoxycinnamate suppresses inflammation in RAW264.7 macrophages and blocks macrophage-adipocyte interaction.

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| S-EPMC7524821 | biostudies-literature

Macrophages in metabolic associated fatty liver disease.

Project description:Metabolic associated fatty liver disease (MAFLD), formerly named non-alcoholic fatty liver disease is the most common liver disorder in many countries. The inflammatory subtype termed steatohepatitis is a driver of disease progression to cirrhosis, hepatocellular carcinoma, liver transplantation, and death, but also to extrahepatic complications including cardiovascular disease, diabetes and chronic kidney disease. The plasticity of macrophages in response to various environmental cues and the fact that they can orchestrate cross talk between different cellular players during disease development and progression render them an ideal target for drug development. This report reviews recent advances in our understanding of macrophage biology during the entire spectrum of MAFLD including steatosis, inflammation, fibrosis, and hepatocellular carcinoma, as well as for the extra-hepatic manifestations of MAFLD. We discuss the underlying molecular mechanisms of macrophage activation and polarization as well as cross talk with other cell types such as hepatocytes, hepatic stellate cells, and adipose tissue. We conclude with a discussion on the potential translational implications and challenges for macrophage based therapeutics for MAFLD.

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Expression of Adipocyte/Macrophage Fatty Acid Binding Protein in Tumor Associated Macrophages Promotes Breast Cancer Progression

Project description:Identification of A-FABP as a new functional marker for pro-tumor associated macrophages.

2018-01-27 | GSE109703 | GEO

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Project description:Brown adipose tissue (BAT) is the primary non-shivering thermogenesis organ in mammals, which plays essential roles in maintaining the body temperature of infants. Although the development of BAT during embryogenesis has been well addressed in rodents, how BAT grows after birth remains unknown. Using mouse interscapular BAT (iBAT) as an example, we studied the cellular and molecular mechanisms that regulate postnatal BAT growth. By analyzing the developmental dynamics of brown adipocytes (BAs), we found that BAs size enlargement partially accounts for iBAT growth. By investigating the BAs cell cycle activities, we confirmed the presence of proliferative BAs in the neonatal mice. Two weeks after birth, most of the BAs exit cell cycle, and the further expansion of the BAT was mainly due to lipogenesis-mediated BAs volume increase. Microscopy and fluorescence-activated cell sorting analyses suggest that most BAs are mononuclear and diploid. Based on the developmental dynamics of brown adipocytes, we propose that the murine iBAT has two different growth phases between birth and weaning: increase of BAs size and number in the first two weeks, and BAs size enlargement thereafter. In summary, our data demonstrate that both lipogenesis and proliferation of BAs contribute to postnatal iBAT growth in mice.

| S-EPMC7683731 | biostudies-literature

Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming.

Project description:Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an in vitro coculture model, it was shown that adipocytes promoted tumor progression, and an intricate metabolic network between PC cells and adipocytes was identified and elucidated. First, the proteome of Panc‑1 PC cells cultured with or without mature adipocytes was identified. This revealed activated hypoxia signaling in cocultured Panc‑1 cells, which was confirmed by the increased expression of factors downstream of hypoxia signaling, such as ANGPTL4 and glycolytic genes, as determined by reverse transcription‑quantitative PCR and western blot analysis. In addition, it was demonstrated that coculture with cancer cells activated STAT3 and induced an insulin‑resistant phenotype in adipocytes. Furthermore, enhanced fatty acid β‑oxidation and increased lipid droplets (LDs) were observed in the cocultured cancer cells. In contrast, downregulated lipid metabolism and a decrease in the size of LDs were found in cocultured adipocytes. Finally, it was shown that the increase in LDs contributed to the increased metastatic capacity of the cocultured PC cells. These data demonstrated that interrupting the mechanisms of lipid uptake from adipocytes in the microenvironment may offer a potential strategy for attenuating PC metastasis.

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