The prevalence of metabolic diseases, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD), is steadily increasing. Although many risk factors, such as obesity, insulin resistance, or hyperlipidemia, as well as several metabolic gene programs that contribute to the development of metabolic diseases are known, the underlying molecular mechanisms of these processes are still not fully understood. In recent years, it has become evident that not only protein-coding genes, but also noncoding genes, including a class of noncoding transcripts referred to as long noncoding RNAs (lncRNAs), play key roles in diet-induced metabolic disorders. Here, we provide an overview of selected lncRNA genes whose direct involvement in the development of diet-induced metabolic dysfunctions has been experimentally demonstrated in suitable in vivo mouse models. We further summarize and discuss the associated molecular modes of action for each lncRNA in the respective metabolic disease context. This overview provides examples of lncRNAs with well-established functions in diet-induced metabolic diseases, highlighting the need for appropriate in vivo models and rigorous molecular analyses to assign clear biological functions to lncRNAs.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world, with epidemiological studies indicating a 25% prevalence. NAFLD is considered to be a progressive disease that progresses from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), then to liver fibrosis, and finally to cirrhosis or hepatocellular carcinoma (HCC). Existing research has mostly elucidated the etiology of NAFLD, yet its particular molecular processes remain uncertain. Long non-coding RNAs (LncRNAs) have been linked in a wide range of biological processes in recent years, with the introduction of microarray and high-throughput sequencing technologies, and previous studies have established their tight relationship with several stages of NAFLD development. Existing studies have shown that lncRNAs can regulate the signaling pathways related to hepatic lipid metabolism, NASH, NASH-related fibrosis and HCC. This review aims to provide a basic overview of NAFLD and lncRNAs, summarize and describe the mechanisms of lncRNAs action involved in the development of NAFLD, and provide an outlook on the future of lncRNAs-based therapy for NAFLD.

The adipose organ is involved in many metabolic functions, ranging from the production of endocrine factors to the regulation of thermogenic processes. Aging is a natural process that affects the physiology of the adipose organ, leading to metabolic disorders, thus strongly impacting healthy aging. Cellular senescence modifies many functional aspects of adipose tissue, leading to metabolic alterations through defective adipogenesis, inflammation, and aberrant adipocytokine production, and in turn, it triggers systemic inflammation and senescence, as well as insulin resistance in metabolically active tissues, leading to premature declined physiological features. In the various aging fat depots, senescence involves a multiplicity of cell types, including mature adipocytes and immune, endothelial, and progenitor cells that are aging, highlighting their involvement in the loss of metabolic flexibility, one of the common features of aging-related metabolic disorders. Since mitochondrial stress represents a key trigger of cellular senescence, and senescence leads to the accumulation of abnormal mitochondria with impaired dynamics and hindered homeostasis, this review focuses on the beneficial potential of targeting mitochondria, so that strategies can be developed to manage adipose tissue senescence for the treatment of age-related metabolic disorders.

Insulin resistance (IR), designated as the blunted response of insulin target tissues to physiological level of insulin, plays crucial roles in the development and progression of diabetes, nonalcoholic fatty liver disease (NAFLD) and other diseases. So far, the distinct mechanism(s) of IR still needs further exploration. Long non-coding RNA (lncRNA) is a class of non-protein coding RNA molecules with a length greater than 200 nucleotides. LncRNAs are widely involved in many biological processes including cell differentiation, proliferation, apoptosis and metabolism. More recently, there has been increasing evidence that lncRNAs participated in the pathogenesis of IR, and the dysregulated lncRNA profile played important roles in the pathogenesis of metabolic diseases including obesity, diabetes and NAFLD. For example, the lncRNAs MEG3, H19, MALAT1, GAS5, lncSHGL and several other lncRNAs have been shown to regulate insulin signaling and glucose/lipid metabolism in various tissues. In this review, we briefly introduced the general features of lncRNA and the methods for lncRNA research, and then summarized and discussed the recent advances on the roles and mechanisms of lncRNAs in IR, particularly focused on liver, skeletal muscle and adipose tissues.

The prevalence of a high-energy diet and a sedentary lifestyle has increased the incidence of type 2 diabetes (T2D). T2D is a chronic disease characterized by high blood glucose levels and insulin resistance in peripheral tissues. The pathological mechanism of this disease is not fully clear. Accumulated evidence has shown that noncoding RNAs have an essential regulatory role in the progression of diabetes and its complications. The roles of small noncoding RNAs, such as miRNAs, in T2D, have been extensively investigated, while the function of long noncoding RNAs (lncRNAs) in T2D has been unstudied. It has been reported that lncRNAs in T2D play roles in the regulation of pancreatic function, peripheral glucose homeostasis and vascular inflammation. In addition, lncRNAs carried by small extracellular vesicles (sEV) were shown to mediate communication between organs and participate in diabetes progression. Some sEV lncRNAs derived from stem cells are being developed as potential therapeutic agents for diabetic complications. In this review, we summarize the current knowledge relating to lncRNA biogenesis, the mechanisms of lncRNA sorting into sEV and the regulatory roles of lncRNAs and sEV lncRNAs in diabetes. Knowledge of lncRNAs and sEV lncRNAs in diabetes will aid in the development of new therapeutic drugs for T2D in the future.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of chronic liver disorder worldwide. It represents a spectrum that includes a continuum of different clinical entities ranging from simple steatosis to nonalcoholic steatohepatitis, which can evolve to cirrhosis and in some cases to hepatocellular carcinoma, ultimately leading to liver failure. The pathogenesis of NAFLD and the mechanisms underlying its progression to more pathological stages are not completely understood. Besides genetic factors, evidence indicates that epigenetic mechanisms occurring in response to environmental stimuli also contribute to the disease risk. Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are one of the epigenetic factors that play key regulatory roles in the development of NAFLD. As the field of ncRNAs is rapidly evolving, the present review aims to explore the current state of knowledge on the roles of these RNA species in the pathogenesis of NAFLD, highlight relevant mechanisms by which some ncRNAs can modulate regulatory networks implicated in NAFLD, and discuss key challenges and future directions facing current research in the hopes of developing ncRNAs as next-generation non-invasive diagnostics and therapies in NAFLD and subsequent progression to hepatocellular carcinoma.

Modern lifestyle, genetics, nutritional overload through high-fat diet attributed prevalence and diabetes outcomes with various complications primarily due to obesity in which energy-dense diets frequently affect metabolic health. One possible issue usually associated with elevated chronic fat intake is insulin resistance, and hyperglycaemia constitutes an important function in altering the carbohydrates and lipids metabolism. Similarly, in assessing human susceptibility to weight gain and obesity, genetic variations play a central role, contributing to keen interest in identifying the possible role of epigenetics as a mediator of gene-environmental interactions influencing the production of type 2 diabetes mellitus and its related concerns. Epigenetic modifications associated with the acceptance of a sedentary lifestyle and environmental stress factors in response to energy intake and expenditure imbalances complement genetic alterations and lead to the production and advancement of metabolic disorders such as diabetes and obesity. Methylation of DNA, histone modifications and increases in the expression of non-coding RNAs can result in reduced transcriptional activity of key β-cell genes thus creating insulin resistance. Epigenetics contribute to changes in the expression of the underlying insulin resistance and insufficiency gene networks, along with low-grade obesity-related inflammation, increased ROS generation and DNA damage in multi organs. This review focused on epigenetic mechanisms and metabolic regulations associated with high fat diet (HFD)-induced diabetes mellitus.

The important role of mitochondria in the regulation of white adipose tissue (WAT) remodeling and energy balance is increasingly appreciated. The remarkable heterogeneity of the adipose tissue stroma provides a cellular basis to enable adipose tissue plasticity in response to various metabolic stimuli. Regulating mitochondrial function at the cellular level in adipocytes, in adipose progenitor cells (APCs), and in adipose tissue macrophages (ATMs) has a profound impact on adipose homeostasis. Moreover, mitochondria facilitate the cell-to-cell communication within WAT, as well as the crosstalk with other organs, such as the liver, the heart, and the pancreas. A better understanding of mitochondrial regulation in the diverse adipose tissue cell types allows us to develop more specific and efficient approaches to improve adipose function and achieve improvements in overall metabolic health.

The Long non-coding RNA (lncRNA) expression profile data of ten samples including human Mesenchymal Stem Cell (MSC) adipogenic differentiation 0, 3, and 6 days from the GEO database, and then perform gene ID conversion, BLAST comparison, and annotation marking. Finally, group A (treatment group on day 3 of differentiation and control group on day 0 of differentiation) obtained a total of 1180 mRNA and 185 lncRNA; group B (treatment group on day 6 of differentiation and control group on day 0 of differentiation). A total of 1376 mRNA and 206 lncRNA were obtained. Finally, we processed the differential lncRNAs and mRNAs obtained in the two groups, and obtained 113 shared differential lncRNAs to further predict the targeted miRNA, a total of 815 lncRNA-miRNA pairs. The targeted mRNA was further predicted, and the grouped differential mRNAs were combined to obtain 64 differential mRNAs. In the end, we obtained 216 ceRNAs containing 26 lncRNAs, 27 miRNAs and 64 mRNAs. We found that the mRNAs in the ceRNA network were mainly enriched with 45 Gene Ontology (GO) terms, mainly including glucose homeostasis mechanism and insulin stimulation response. 69 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were mainly enriched. It mainly includes many pathways related to lipid metabolism such as Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), Rap1, cAMP, mitogen-activated protein kinase (MAPK), Ras, hypoxia inducible factor-1 (HIF-1), PI3K-Akt, insulin signaling and so on. In the end, we identified 216 ceRNA regulatory relationships related to obesity research. Our research provides a clearer direction for understanding the molecular mechanism of obesity, the screening and determination of drug targets biomarkers in the future.

Obesity is an evolutionary, chronic, and relapsing disease that consists of a pathological accumulation of adipose tissue able to increase morbidity for high blood pressure, type 2 diabetes, metabolic syndrome, and obstructive sleep apnea in adults, children, and adolescents. Despite intense research over the last 20 years, obesity remains today a disease with a complex and multifactorial etiology. Recently, long non-coding RNAs (lncRNAs) are emerging as interesting new regulators as different lncRNAs have been found to play a role in early and late phases of adipogenesis and to be implicated in obesity-associated complications onset. In this review, we discuss the most recent advances on the role of lncRNAs in adipocyte biology and in obesity-associated complications. Indeed, more and more researchers are focusing on investigating the underlying roles that these molecular modulators could play. Even if a significant number of evidence is correlation-based, with lncRNAs being differentially expressed in a specific disease, recent works are now focused on deeply analyzing how lncRNAs can effectively modulate the disease pathogenesis onset and progression. LncRNAs possibly represent new molecular markers useful in the future for both the early diagnosis and a prompt clinical management of patients with obesity.

Obesity is associated with chronic low-grade inflammation that affects the phenotype of multiple tissues and therefore is implicated in the development and progression of several age-related chronic inflammatory disorders. Importantly, a new family of noncoding RNAs, termed long noncoding RNAs (lncRNAs), have been identified as key regulators of inflammatory signalling pathways that can mediate both pretranscriptional and posttranscriptional gene regulation. Furthermore, several lncRNAs have been identified, which are differentially expressed in multiple tissue types in individuals who are obese or in preclinical models of obesity. In this review, we examine the evidence for the role of several of the most well-studied lncRNAs in the regulation of inflammatory pathways associated with obesity. We highlight the evidence for their differential expression in the obese state and in age-related conditions including insulin resistance, type 2 diabetes (T2D), sarcopenia, osteoarthritis and rheumatoid arthritis, where obesity plays a significant role. Determining the expression and functional role of lncRNAs in mediating obesity-associated chronic inflammation will advance our understanding of the epigenetic regulatory pathways that underlie age-related inflammatory diseases and may also ultimately identify new targets for therapeutic intervention.