The Impact of Adipose Tissue-Derived miRNAs in Metabolic Syndrome, Obesity, and Cancer

Abstract

Obesity is a multifactorial and complex condition that is characterized by abnormal and excessive white adipose tissue accumulation, which can lead to the development of metabolic diseases, such as type 2 diabetes mellitus, nonalcoholic fatty liver disease, cardiovascular diseases, and several types of cancer. Obesity is characterized by excessive adipose tissue accumulation and associated with alterations in immunity, displaying a chronic low-grade inflammation profile. Adipose tissue is a dynamic and complex endocrine organ composed not only by adipocytes, but several immunological cells, which can secrete hormones, cytokines and many other factors capable of regulating metabolic homeostasis and several critical biological pathways. Remarkably, adipose tissue is a major source of circulating microRNAs (miRNAs), recently described as a novel form of adipokines. Several adipose tissue-derived miRNAs are deeply associated with adipocytes differentiation and have been identified with an essential role in obesity-associated inflammation, insulin resistance, and tumor microenvironment. During obesity, adipose tissue can completely change the profile of the secreted miRNAs, influencing circulating miRNAs and impacting the development of different pathological conditions, such as obesity, metabolic syndrome, and cancer. In this review, we discuss how miRNAs can act as epigenetic regulators affecting adipogenesis, adipocyte differentiation, lipid metabolism, browning of the white adipose tissue, glucose homeostasis, and insulin resistance, impacting deeply obesity and metabolic diseases. Moreover, we characterize how miRNAs can often act as oncogenic and tumor suppressor molecules, significantly modulating cancer establishment and progression. Furthermore, we highlight in this manuscript how adipose tissue-derived miRNAs can function as important new therapeutic targets.

Keywords: miRNA; adipose tissue; cancer; metabolic syndrome; obesity.

Figure 1

Adipose tissue–derived miRNAs modulate inflammation and tumor microenvironment. The adipose tissue produces and secretes several miRNAs that dynamically regulate the tissue homeostasis. These miRNAs can be secreted by both adipose tissue and macrophages, playing a crucial role impacting on inflammatory pathways, angiogenesis, cell growth, cell proliferation, and contributing to tumor development. The lean adipose tissue is characterized by an infiltrate of M2 polarized macrophages and TCD4+ lymphocytes. The secretion of miR-223, suppressing PBX/Knotted 1 Homeobox 1 (Pknox1), is shown to inhibit the activation of pro-inflammatory M1 macrophages, leading to an anti-inflammatory environment. The miR-145 exerts a tumor suppressor role, associated to the inhibition of oncogenic transcriptional factor C-MYC. The transition from lean to obese adipose tissue is characterized by the adipocytes hypertrophy, an increase of blood vessels and pro-inflammatory cell recruitment and polarizing as a common feature of obesity. Regarding the inflammatory recruitment, the infiltration of pro-inflammatory macrophages around the dying adipocytes is strongly present, forming structures known as CLS (crown-like structures), associated with the secretion of multiple inflammatory factors and considered an aggressiveness marker in breast cancer. The miR-21 is depicted being secreted by adipose tissue macrophages, also known as an oncomiR or oncogenic, through PTEN silencing, thus leading to the activation of tumor growth and proliferation pathways. The miR-155 contributes to the activation of the inflammatory response. The miR-222 is associated with angiogenesis, one of the tumor development hallmarks. The oncogenic miR-27a can lead to the inhibition of Forkhead box transcription factor O1 (FOXO1), an antitumoral multifunctional transcription factor, regulating genes linked to cell cycle arrest and apoptosis.

Figure 2

miRNAs processing and releasing by adipocytes and their influence on metabolic syndrome, obesity and cancer. Adipocytes are the main source of circulating miRNAs in mice and human. The process of miRNA maturation begins in the nucleus with the gene transcription by RNA polymerase II or III in pri-miRNA. Following the maturation process, the enzyme DROSHA and its Pasha cofactor leads to the pre-miRNA, which are exported to the cytosol by the Exportin-5 protein, and further processed by Dicer enzyme, leading to the mature miRNA. It is taken into the RISC silencing complex and then become an active post-transcriptional regulator. This may occur by cell free miRNA release, associated with apoptotic body, exosomes, or HDL. miRNAs can act influencing different types of cells. Circulating miRNAs are able to control: (I) the expression of several genes related to adipogenesis, (II) the adipocyte differentiation and lipid metabolism impacting obesity, (III) the expression of membrane proteins responsible for the glucose homeostasis and insulin resistance, (IV) the metabolic diseases development, and (V) the cancer establishment and progression as oncomiR molecules.