Significance: Phosphatidylethanolamine (PE)-linked arachidonic acid (AA) and adrenic acid (AdA) are well-known substrates for lipid peroxidation, which are indispensable for ferroptosis, an iron-dependent regulated necrosis. However, how cells differentially regulate the intracellular pools of AA and AdA is not fully understood. Here, elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) are differentially expressed in gastric cancer cells, discriminating the cellular susceptibility to ferroptosis. Biochemical and lipidomics analyses support the hypothesis that ELOVL5 and FADS1 are required to maintain intracellular levels of AA and AdA and promote ferroptosis. Our study highlights the biosynthesis of AA and AdA by ELOVL5 and FADS1 as a critical checkpoint in the ferroptosis pathway.

Ischaemic heart disease (IHD) is the leading cause of death worldwide. Although myocardial cell death plays a significant role in myocardial infarction (MI), its underlying mechanism remains to be elucidated. To understand the progression of MI and identify potential therapeutic targets, we performed tandem mass tag (TMT)-based quantitative proteomic analysis using an MI mouse model. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) revealed that the glutathione metabolic pathway and reactive oxygen species (ROS) pathway were significantly downregulated during MI. In particular, glutathione peroxidase 4 (GPX4), which protects cells from ferroptosis (an iron-dependent programme of regulated necrosis), was downregulated in the early and middle stages of MI. RNA-seq and qRT-PCR analyses suggested that GPX4 downregulation occurred at the transcriptional level. Depletion or inhibition of GPX4 using specific siRNA or the chemical inhibitor RSL3, respectively, resulted in the accumulation of lipid peroxide, leading to cell death by ferroptosis in H9c2 cardiomyoblasts. Although neonatal rat ventricular myocytes (NRVMs) were less sensitive to GPX4 inhibition than H9c2 cells, NRVMs rapidly underwent ferroptosis in response to GPX4 inhibition under cysteine deprivation. Our study suggests that downregulation of GPX4 during MI contributes to ferroptotic cell death in cardiomyocytes upon metabolic stress such as cysteine deprivation.

: Mitochondria play a key role in maintaining energy homeostasis in metabolic tissues, including adipose tissues. The two main types of adipose tissues are the white adipose tissue (WAT) and the brown adipose tissue (BAT). WAT primarily stores excess energy, whereas BAT is predominantly responsible for energy expenditure by non-shivering thermogenesis through the mitochondria. WAT in response to appropriate stimuli such as cold exposure and β-adrenergic agonist undergoes browning wherein it acts as BAT, which is characterized by the presence of a higher number of mitochondria. Mitochondrial dysfunction in adipocytes has been reported to have strong correlation with metabolic diseases, including obesity and type 2 diabetes. Dysfunction of mitochondria results in detrimental effects on adipocyte differentiation, lipid metabolism, insulin sensitivity, oxidative capacity, and thermogenesis, which consequently lead to metabolic diseases. Recent studies have shown that mitochondrial function can be improved by using thiazolidinedione, mitochondria-targeted antioxidants, and dietary natural compounds; by performing exercise; and by controlling caloric restriction, thereby maintaining the metabolic homeostasis by inducing adaptive thermogenesis of BAT and browning of WAT. In this review, we focus on and summarize the molecular regulation involved in the improvement of mitochondrial function in adipose tissues so that strategies can be developed to treat metabolic diseases.

Liver plays a major role in maintaining glucose homeostasis in mammals. Under fasting conditions, hepatic glucose production is critical as a source of fuel to maintain the basic functions in other tissues, including skeletal muscle, red blood cells, and the brain. Fasting hormones glucagon and cortisol play major roles during the process, in part by activating the transcription of key enzyme genes in the gluconeogenesis such as phosphoenol pyruvate carboxykinase (PEPCK) and glucose 6 phosphatase catalytic subunit (G6Pase). Conversely, gluconeogenic transcription is repressed by pancreatic insulin under feeding conditions, which effectively inhibits transcriptional activator complexes by either promoting post-translational modifications or activating transcriptional inhibitors in the liver, resulting in the reduction of hepatic glucose output. The transcriptional regulatory machineries have been highlighted as targets for type 2 diabetes drugs to control glycemia, so understanding of the complex regulatory mechanisms for transcription circuits for hepatic gluconeogenesis is critical in the potential development of therapeutic tools for the treatment of this disease. In this review, the current understanding regarding the roles of two key transcriptional activators, CREB and FoxO1, in the regulation of hepatic gluconeogenic program is discussed. [BMB Reports 2013; 46(12): 567-574]

Obesity and type II diabetes are characterized by insulin resistance in peripheral tissues. A high caloric intake combined with a sedentary lifestyle is the leading cause of these conditions. Whole-body insulin resistance and its improvement are the result of the combined actions of each insulin-sensitive organ. Among the fundamental molecular mechanisms by which each organ is able to communicate and engage in cross-talk are cytokines or peptides which stem from secretory organs. Recently, it was reported that several cytokines or peptides are secreted from muscle (myokines), adipose tissue (adipokines) and liver (hepatokines) in response to certain nutrition and/or physical activity conditions. Cytokines exert autocrine, paracrine or endocrine effects for the maintenance of energy homeostasis. The present review is focused on the relationship and cross-talk amongst muscle, adipose tissue and the liver as secretory organs in metabolic diseases.

Obesity is one of the main risk factors for type 2 diabetes mellitus (T2DM). It is closely related to metabolic disturbances in the adipose tissue that primarily functions as a fat reservoir. For this reason, adipose tissue is considered as the primary site for initiation and aggravation of obesity and T2DM. As a key endocrine organ, the adipose tissue communicates with other organs, such as the brain, liver, muscle, and pancreas, for the maintenance of energy homeostasis. Two different types of adipose tissues—the white adipose tissue (WAT) and brown adipose tissue (BAT)—secrete bioactive peptides and proteins, known as “adipokines” and “batokines,” respectively. Some of them have beneficial anti-inflammatory effects, while others have harmful inflammatory effects. Recently, “exosomal microRNAs (miRNAs)” were identified as novel adipokines, as adipose tissue-derived exosomal miRNAs can affect other organs. In the present review, we discuss the role of adipose-derived secretory factors—adipokines, batokines, and exosomal miRNA—in obesity and T2DM. It will provide new insights into the pathophysiological mechanisms involved in disturbances of adipose-derived factors and will support the development of adipose-derived factors as potential therapeutic targets for obesity and T2DM.