Molecular Insight into the Interaction between Epigenetics and Leptin in Metabolic Disorders

Abstract

Nowadays, it is well-known that the deregulation of epigenetic machinery is a common biological event leading to the development and progression of metabolic disorders. Moreover, the expression level and actions of leptin, a vast adipocytokine regulating energy metabolism, appear to be strongly associated with epigenetics. Therefore, the aim of this review was to summarize the current knowledge of the epigenetic regulation of leptin as well as the leptin-induced epigenetic modifications in metabolic disorders and associated phenomena. The collected data indicated that the deregulation of leptin expression and secretion that occurs during the course of metabolic diseases is underlain by a variation in the level of promoter methylation, the occurrence of histone modifications, along with miRNA interference. Furthermore, leptin was proven to epigenetically regulate several miRNAs and affect the activity of the histone deacetylases. These epigenetic modifications were observed in obesity, gestational diabetes, metabolic syndrome and concerned various molecular processes like glucose metabolism, insulin sensitivity, liver fibrosis, obesity-related carcinogenesis, adipogenesis or fetal/early postnatal programming. Moreover, the circulating miRNA profiles were associated with the plasma leptin level in metabolic syndrome, and miRNAs were found to be involved in hypothalamic leptin sensitivity. In summary, the evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.

c‐Jun acts downstream of PI3K/AKT signaling to mediate the effect of leptin on methionine adenosyltransferase 2B in hepatic stellate cells in vitro and in vivo

“…Indeed, our in vivo results showed that knockdown of MAT2B attenuated leptin‐induced liver fibrosis in the ob/ob mouse model. Notably, leptin affected epigenetic changes which develop in numerous tissues during metabolic disorders [19] and influenced global DNA methylation in inguinal adipocytes in ob/ob C57BL/6J mice [21]. Our previous results also demonstrated the inductive effect of leptin on Mat2a [33], suggesting that leptin regulated not only Mat2b but also Mat2a in HSCs.…”

“…The progress of HSC activation requires global reprogramming of gene expression, and epigenetic regulation of gene expression is associated with HSC activation [18]. Leptin was revealed to affect epigenetic modifications in metabolic disorders [19]. Our previous results showed that leptin downregulated miR‐122 in HSCs in ob/ob mice [20].…”

mir-101-3p Downregulation Promotes Fibrogenesis by Facilitating Hepatic Stellate Cell Transdifferentiation During Insulin Resistance

“…Firstly, we examined the miRNA signature in InsR+/− HSCs, which are characterized by an impaired insulin signaling, by analyzing the whole transcriptome, revealing 36 differentially expressed miRNAs compared to wt cells. These deregulated miRNAs were mainly involved in cell proliferation and cancer onset, probably profiling a peculiar pattern of miRNA expression that may orchestrate liver damage progression towards fibrosis and cancer development in IR conditions [4,24,25,26,27].…”

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress

“…It is perceived as an immunological organ and it releases polypeptides (adipo-/cytokines) as well as metabolites capable of exerting systemic actions, including body weight/energy balance, appetite regulation, glucose homeostasis, insulin signaling, and blood pressure control [65,66]. The first known adipocyte hormone, leptin, whose genetic absence causes massive obesity, suppresses appetite, while other hormones, like adiponectin, have just the opposite effect [67,68]. Adiponectin increases sensitivity of cells to insulin as well as pancreatic β-cells survival and functionality.…”