The miRNA Interactome in Metabolic Homeostasis

Abstract

Global expression analyses demonstrate that alterations in miRNA levels correlate with various metabolic diseases. miRNAs regulate central metabolic pathways and thus play vital roles in maintaining organismal energy balance and metabolic homeostasis. Here we highlight novel sequencing technologies used to comprehensively define the target spectrum of miRNAs in metabolic disease that complement recent literature reporting physiologic roles for miRNAs in the regulation of glucose and lipid metabolism in peripheral tissues of animal models of metabolic dysfunction. These emerging technologies help decipher the complexity of the miRNA interactome and enrich our understanding of how miRNAs mediate physiologic effects by targeting a spectrum of gene transcripts simultaneously. miRNA-based therapeutics emerge as a viable strategy for treating metabolic diseases.

Keywords: adipose tissue; insulin; lipid metabolism; miRNA; sequencing.

Figure 1. miRNAs target the insulin pathway at multiple levels

miRNA targeting of insulin signaling occurs centrally at the beta cell and peripherally in target tissues. Several miRNAs, such as the miR-141/200c family and the DLK1-MEG3 cluster, directly regulate cellular response to stress and are active in facilitating (miR-141/200c) or disrupting (DLK1-MEG3 cluster) beta cell apoptosis in response to metabolic stress. miR-375 is important for beta cell proliferation and maintenance of beta cell mass while miR-7 regulates innsulin granule release by inhibiting the SNARE complex. Peripherally, miRNAs are capable of disrupting insulin signaling at almost every point along its axis. miR-103/107 disrupt caveolae formation, impacting insulin receptor and insulin-like growth factor receptor expression at the membrane. The let-7 miRNA family directly targets high-level insulin signaling by reducing insulin receptor (IR) and insulin receptor substrate (IRS) expression. Hnf1b, a transcription factor important for maintaining insulin signaling, is targeted by miR-802. Finally, miR-143 inhibits insulin activity by targeting effector genes downstream of AKT such as ORP8.

KEY FIGURE, Figure 2. miRNAs exert physiologic function by targeting multiple genes and gene networks

Though miRNA research often focuses on defining a few important targets of specific miRNAs that are relevant to the system or pathology in question, it is understood that the majority of miRNA targeting remains undescribed. In order to illustrate the number of potential targeting and co-targeting interactions that may occur in any given system, we defined targets of metabolically relevant miRNAs miR-33a, let-7 and miR-143 from all available human AGO-CLIP datasets. Individual miRNA-target interactions are illustrated as individual links. Targets of a single miRNA are illustrated as light grey links, co-targeted genes of miR-143 and let-7 are illustrated as green links, co-targets of miR-33 and miR-143 are illustrated as blue links, co-targets of miR-33 and let-7 are illustrated as orange links, and co-targets of all three genes are illustrated as purple links. Critical metabolic target genes are labeled in red. This figure demonstrates the possible breadth and complexity of miRNA targeting, as well as the ability of miRNAs to form complex, redundant, co-targeting networks.