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Small non coding RNAs in adipocyte biology and obesity
Abstract
Obesity has reached epidemic proportions world-wide and constitutes a substantial risk factor for hypertension, type 2 diabetes, cardiovascular diseases and certain cancers. So far, regulation of energy intake by dietary and pharmacological treatments has met limited success. The main interest of current research is focused on understanding the role of different pathways involved in adipose tissue function and modulation of its mass. Whole-genome sequencing studies revealed that the majority of the human genome is transcribed, with thousands of non-protein-coding RNAs (ncRNA), which comprise small and long ncRNAs. ncRNAs regulate gene expression at the transcriptional and post-transcriptional level. Numerous studies described the involvement of ncRNAs in the pathogenesis of many diseases including obesity and associated metabolic disorders. ncRNAs represent potential diagnostic biomarkers and promising therapeutic targets. In this review, we focused on small ncRNAs involved in the formation and function of adipocytes and obesity.
... Killick et al., 2022;Kim et al., 2022). Several studies have investigated the function of snoRNAs in CMDs, including diabetes mellitus, lipid metabolism abnormalities, and doxorubicin cardiotoxicity (Michel et al., 2011;Amri and Scheideler, 2017;Schaffer, 2020). The first of these studies found that the loss of three snoRNAs (U32a, U33 and U35a) from the ribosomal protein L13a (RpL13a) locus conferred in vitro resistance to lipotoxic and oxidative stress and prevented the in vivo propagation of oxidative stress (Michel et al., 2011). ...
Cardiovascular diseases (CVDs) are the leading cause of mortality and disability worldwide. Numerous studies have demonstrated that non-coding RNAs (ncRNAs) play a primary role in CVD development. Therefore, studies on the mechanisms of ncRNAs are essential for further efforts to prevent and treat CVDs. Small nucleolar RNAs (snoRNAs) are a novel species of non-conventional ncRNAs that guide post-transcriptional modifications and the subsequent maturation of small nuclear RNA and ribosomal RNA. Evidently, snoRNAs are extensively expressed in human tissues and may regulate different illnesses. Particularly, as the next-generation sequencing techniques have progressed, snoRNAs have been shown to be differentially expressed in CVDs, suggesting that they may play a role in the occurrence and progression of cardiac illnesses. However, the molecular processes and signaling pathways underlying the function of snoRNAs remain unidentified. Therefore, it is of great value to comprehensively investigate the association between snoRNAs and CVDs. The aim of this review was to collate existing literature on the biogenesis, characteristics, and potential regulatory mechanisms of snoRNAs. In particular, we present a scientific update on these snoRNAs and their relevance to CVDs in an effort to cast new light on the functions of snoRNAs in the clinical diagnosis of CVDs.
... Given the findings of this study and the diseases and functions identified as modified by obesity and aging in ASCs, this could be useful in a similar way to screen individual donor ASCs derived from subcutaneous adipose tissue for risk of disease or dysfunction, similar to how markers of epigenetic age are being used. 61 Non-coding RNA plays a critical role in biological regulation, obesity, 62 in the beneficial effect of caloric restriction, 3 in identifying disease sub-phenotypes, [63][64][65] and in the modification of the epigenetic landscape. 66 Reducing the complexity of differential expression data using WGCNA extracted clusters of highly co-expressed genes and ncRNA biotypes related to age, diet, or bodyweight at sacrifice. ...
The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA‐ and targeted bisulfite‐sequencing in murine ASCs from lean and obese mice at 5‐ and 12‐months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs. YL and AO vs. YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Furthermore, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs. YL), and of the effects of obesity in young animals (YO vs. YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging‐ and obesity‐associated pathologies.
... ECAT also had the largest number of snoRNA that were differentially expressed compared to the other adipose depots, although their specific function in ECAT is unknown. Functionally, snoRNA are well-conserved, housekeeping molecules that maintain ribosomal maturation and translation (Wajahat et al., 2021) and several snoRNAs play a role in metabolism in adipose tissue (Amri and Scheideler, 2017;Schaffer, 2020). ECAT and SAT had the greatest number of differentially expressed miRNA compared to the other adipose depots. ...
Inappropriate developmental exposure to steroids is linked to metabolic disorders. Prenatal testosterone excess or bisphenol A (BPA, an environmental estrogen mimic) leads to insulin resistance and adipocyte disruptions in female lambs. Adipocytes are key regulators of insulin sensitivity and tissue-specific differences in insulin sensitivity, coupled with adipose depot-specific changes in key mRNAs, were previously observed with prenatal steroid exposure. We hypothesized that depot-specific changes in the non-coding RNA (ncRNA) - regulators of gene expression would account for the direction of changes seen in mRNAs. Non-coding RNA (lncRNA, miRNA, snoRNA, snRNA) from various adipose depots of prenatal testosterone and BPA-treated animals were sequenced. Adipose depot-specific changes in the ncRNA that are consistent with the depot-specific mRNA expression in terms of directionality of changes and functional implications in insulin resistance, adipocyte differentiation and cardiac hypertrophy were found. Importantly, the adipose depot-specific ncRNA changes were model-specific and mutually exclusive, suggestive of different regulatory entry points in this regulation.
... Given the findings of this study and the diseases and functions identified as modified by obesity and aging in ASCs, this could be useful in a similar way to screen individual donor ASCs derived from subcutaneous adipose tissue for risk of disease or dysfunction, similar to how markers of epigenetic age are being used. 61 Non-codingRNA play a critical role in biological regulation, obesity, 62 in the beneficial effect of caloric restriction, 3 in identifying disease sub-phenotypes, [63][64][65] and in the modification of the epigenetic landscape. 66 Reducing the complexity of differential expression data using WGCNA extracted clusters of highly co-expressed genes and ncRNA biotypes related to age, diet, or bodyweight at sacrifice. ...
The epigenome of stem cells occupies a critical interface between genes and environment, serving to regulate expression through modification by intrinsic and extrinsic factors. We hypothesized that aging and obesity, which represent major risk factors for a variety of diseases, synergistically modify the epigenome of adult adipose stem cells (ASCs). Using integrated RNA- and targeted bisulfite-sequencing in murine ASCs from lean and obese mice at 5- and 12-months of age, we identified global DNA hypomethylation with either aging or obesity, and a synergistic effect of aging combined with obesity. The transcriptome of ASCs in lean mice was relatively stable to the effects of age, but this was not true in obese mice. Functional pathway analyses identified a subset of genes with critical roles in progenitors and in diseases of obesity and aging. Specifically, Mapt, Nr3c2, App, and Ctnnb1 emerged as potential hypomethylated upstream regulators in both aging and obesity (AL vs YL and AO vs YO), and App, Ctnnb1, Hipk2, Id2, and Tp53 exhibited additional effects of aging in obese animals. Further, Foxo3 and Ccnd1 were potential hypermethylated upstream regulators of healthy aging (AL vs YL), and of the effects of obesity in young animals (YO vs YL), suggesting that these factors could play a role in accelerated aging with obesity. Finally, we identified candidate driver genes that appeared recurrently in all analyses and comparisons undertaken. Further mechanistic studies are needed to validate the roles of these genes capable of priming ASCs for dysfunction in aging- and obesity-associated pathologies.
... The desired strategy should ideally combine an increased therapeutic efficacy with reduced systemic side-effects. Small non-coding RNAs have been demonstrated to carry strong therapeutic potential for obesity and metabolic syndromes [7] and several research groups have investigated the expression of microRNAs in adipose tissue between lean and obese subjects [8]. Therefore microRNAs, as part of a therapeutic strategy, hold promise, although their delivery continues to be a major challenge for this research field. ...
Obesity is a metabolic chronic disease whose prevalence is strongly growing in the last years, reaching pandemic proportions. Nowadays weight loss, achieved through lifestyle changes, is the first line therapeutic objective, although great inter-individual variabilities influence response to treatment, suggesting the involvement of epigenetic factors. In this contest, there is increasing recognition of the role of small RNA molecules, particularly microRNAs in the epigenetic regulation of genes involved in adipose tissue and glucose metabolism and several microRNAs have been found to be dysregulated in obesity and metabolic diseases. The development of novel personalized therapeutic strategies using microRNAs bears promise. However, the application of naked microRNAs has been hampered by their low specificity and sensitivity. In a recent issue of Theranostics, Kumar et al. explored the possibility of microRNA delivery through ginger-derived nanoparticles (GDNPs) as an alternative therapeutic approach for obesity treatment. The results reported by Kumar et al., addressing non-coding RNAs and edible plant derived nanoparticles, open new perspectives for the application of this innovative and safe delivery system in the clinical practice for the treatment of obesity and other metabolic disorders.
... The desired strategy should ideally combine an increased therapeutic efficacy with reduced systemic side-effects. Small non-coding RNAs have been demonstrated to carry strong therapeutic potential for obesity and metabolic syndromes [7] and several research groups have investigated the expression of microRNAs in adipose tissue between lean and obese subjects [8]. Therefore microRNAs, as part of a therapeutic strategy, hold promise, although their delivery continues to be a major challenge for this research field. ...
... For instance, multiple associations and validation studies have demonstrated that small nucleolar RNAs are associated with food intake and body weight in patients with Prader-Willi syndrome. 63 Similarly, micro-RNAs have been associated with metabolic pathways involved in adipogenesis and adipocyte differentiation. 64 RNA sequencing allows the quantification of gene expression and provides a better understanding of cellular functions. ...
Obesity is a multifactorial disease with a variable and underwhelming weight loss response to current treatment approaches. Precision medicine proposes a new paradigm to improve disease classification based on the premise of human heterogeneity, with the ultimate goal of maximizing treatment effectiveness, tolerability, and safety. Recent advances in high-throughput biochemical assays have contributed to the partial characterization of obesity's pathophysiology, as well as to the understanding of the role that intrinsic and environmental factors, and their interaction, play in its development and progression. These data have led to the development of biological markers that either are being or will be incorporated into strategies to develop personalized lines of treatment for obesity. There are currently many ongoing initiatives aimed at this; however, much needs to be resolved before precision obesity medicine becomes common practice. This review aims to provide a perspective on the currently available data of high-throughput technologies to treat obesity.
... For example, the adipocytic expression of miR-26a increases from E18 to D3 (Figures 2 and 3). MiR-26a is known to target a number of metabolic and adipogenic genes (reviewed [30]). Activins are members of the TGF-β superfamily which are highly expressed in adipose tissue [31]. ...
As the chick transitions from embryonic to post-hatching life, its metabolism must quickly undergo a dramatic switch in its major energy source. The chick embryo derives most of its energy from the yolk, a lipid-rich/carbohydrate-poor source. Upon hatching, the chick’s metabolism must then be able to utilize a lipid-poor/carbohydrate-rich source (feed) as its main form of energy. We recently found that a number of hepatically-expressed microRNAs (miRNAs) help facilitate this shift in metabolic processes in the chick liver, the main site of lipogenesis. While adipose tissue was initially thought to mainly serve as a lipid storage site, it is now known to carry many metabolic, endocrine, and immunological functions. Therefore, it would be expected that adipose tissue is also an important factor in the metabolic switch. To that end, we used next generation sequencing (NGS) and real-time quantitative PCR (RT-qPCR) to generate miRNome and transcriptome signatures of the adipose tissue during the transition from late embryonic to early post-hatch development. As adipose tissue is well known to produce inflammatory and other immune factors, we used SPF white leghorns to generate the initial miRNome and transcriptome signatures to minimize complications from external factors (e.g., pathogenic infections) and ensure the identification of bona fide switch-associated miRNAs and transcripts. We then examined their expression signatures in the adipose tissue of broilers (Ross 708). Using E18 embryos as representative of pre-switching metabolism and D3 chicks as a representative of post-switching metabolism, we identified a group of miRNAs which work concordantly to regulate a diverse but interconnected group of developmental, immune and metabolic processes in the adipose tissue during the metabolic switch. Network mapping suggests that during the first days post-hatch, despite the consumption of feed, the chick is still heavily reliant upon adipose tissue lipid stores for energy production, and is not yet efficiently using their new energy source for de novo lipid storage. A number of core master regulatory pathways including, circadian rhythm transcriptional regulation and growth hormone (GH) signaling, likely work in concert with miRNAs to maintain an essential balance between adipogenic, lipolytic, developmental, and immunological processes in the adipose tissue during the metabolic switch.
... The phenotypic change in WAT into more energetically active cells indicates the involvement of gene expression regulation, in which internal or external regulators of WAT physiology must modify the chromatin structure or the DNA promoter methylation pattern of the target genes [74,187,188]. Recently, modifications of noncoding RNAs have been shown to act as an additional level of gene expression control [189,190]. Notably, a number of regulators function by modifying four transcriptional or coregulator factors: PPARγ, CCAAT enhancer binding protein beta (C/EBPβ), PPARγ co-activator-1α (PGC1α) and PRDM16. PPARγ and C/EBPβ act as transcription factors and directly bind DNA [191,192]. ...
Adipose tissue is the largest endocrine organ in humans and has an important influence on many physiological processes throughout life. An increasing number of studies have described the different phenotypic characteristics of fat cells in adults. Perhaps one of the most important properties of fat cells is their ability to adapt to different environmental and nutritional conditions. Hypothalamic neural circuits receive peripheral signals from temperature, physical activity or nutrients and stimulate the metabolism of white fat cells. During this process, changes in lipid inclusion occur, and the number of mitochondria increases, giving these cells functional properties similar to those of brown fat cells. Recently, beige fat cells have been studied for their potential role in the regulation of obesity and insulin resistance. In this context, it is important to understand the embryonic origin of beige adipocytes, the response of adipocyte to environmental changes or modifications within the body and their ability to transdifferentiate to elucidate the roles of these cells for their potential use in therapeutic strategies for obesity and metabolic diseases. In this review, we discuss the origins of the different fat cells and the possible therapeutic properties of beige fat cells.
... Internal or external regulators of WAT physiology must modify the chromatin structure or the DNA promoter methylation pattern of the target genes [106][107][108] . Recently, other modifications of non-coding RNAs have shown an additional degree of controlling gene expression 109,110 . It should be noted that regulators act by modification of four transcriptional or coregulator factors: PPARγ, CCAAT Enhancer Binding Protein Beta (C/EBPβ), PPARγ co-activator-1α (PGC1α) and PRDM16. ...
Adipose tissue is the most abundant endocrine organ in humans with an important influence on many events throughout life. Many studies that highlight the different phenotypic characteristics of fat cells in adults are becoming more frequent. Perhaps, one of the most important properties of fat cells is their flexibility to adapt to different environmental and nutritional conditions. White adipocytes can receive hormonal stimuli from other tissues and differentiate into cells with a greater thermogenic potential. In this process, lipid inclusion changes and the number of mito-chondria increases, leading to functional characteristics similar to those of brown adipocytes. Recently, beige fat cells have been studied in the attempt to elucidate their role in the regulation of obesity and insulin resistance. Therefore, understanding the beige adipocyte embryonic origin and the ability of these cells to transdifferentiate is a major research challenge, with the aim of elucidating the role of these cells as a possible therapeutic strategy for obesity and metabolic diseases. In this manuscript, we will focus on the origins of the different fat cells and the possible therapeutic properties of beige fat cells.
... Our results showed that transfected ssc-miR-204 mimics Many factors contribute to obesity, including epigenetic, genomic, and environmental factors. Epigenetic factors, including histone modifications, 27 noncoding RNA activity, 28 and DNA methylation, 29 are involved in gene regulation. miRNAs have been shown to be involved in a variety of biological functions. ...
MicroRNAs (miRNAs) take part in a variety of biological processes by regulating target genes. Transforming growth factor β receptor 1 (TGFBR1) and TGFBR2 are crucial members of the TGF‐β family and are serine/threonine kinase receptors. The aim of this study was to explore the functions of ssc‐miR‐204 in porcine preadipocyte differentiation and apoptosis with regard to the TGFβ/Smad pathway. We identified miRNAs predicted to target TGFBR1 and TGFBR2 using a database and selected ssc‐miR‐204 as a candidate miRNA. ssc‐miR‐204 overexpression dramatically reduced the levels of TGFBR1 and TGFBR2. However, after transfection with ssc‐miR‐204 inhibitor, TGFBR1 and TGFBR2 levels were dramatically increased. ssc‐miR‐204 overexpression dramatically promoted porcine preadipocyte differentiation and apoptosis. After transfection with ssc‐miR‐204 inhibitor, porcine preadipocyte differentiation and apoptosis were dramatically inhibited. After transfection with ssc‐miR‐204 mimics, Smad2, Smad3, Smad4, p‐Smad2, and p‐Smad3 protein levels significantly decreased, and adipogenesis was regulated by inhibiting the TGF‐β/Smad3 signaling pathway. Taken together, these results verified that ssc‐miR‐204 regulates porcine preadipocyte differentiation and apoptosis by targeting TGFBR1 and TGFBR2. Collectively, our results indicate that ssc‐miR‐204 is a negative regulator that targets transforming growth factor β receptor 1 (TGFBR1) and TGFBR2 in the TGF‐β signaling pathway to promote preadipocyte differentiation and apoptosis. A better understanding of ssc‐miR‐204 in the context of preadipocytes will be beneficial for human medical research.
... The role of miRNAs in obesity has not been clearly defined. Studies on experimental models and in silico analysis suggest miRNAs could play a regulatory role in many biological processes associated with obesity, including insulin signalling pathway and lipid or carbohydrate metabolism (McGregor and Choi 2011, Peng et al. 2014, Amri and Scheideler 2017. miRNAs are implicated too in the hyperactivation of the renin-angiotensin-aldosterone system, endothelial dysfunction and phenotypic change in smooth muscle cells, alterations observed in patients with systemic arterial hypertension (Improta Caria et al. 2018). ...
Context. Differential expression profiles of microRNAs have been reported in human obesity suggesting a miRNAs role in the development of obesity and associated disorders.
Objective. To review circulating microRNAs (c-miRNAs) dysregulated in human obesity and to predict their possible target genes.
Methods. We performed a systematic review on PubMed database (PROSPERO, CRD42017077742) for original works on c-miRNAs and human obesity and recorded c-miRNAs with differential expression profiles. Potential target genes and metabolic pathways for dysregulated miRNAs with at least two independent reports were searched using bioinformatic tools.
Results. Twenty-two c-miRNAs are overexpressed, nine underexpressed and two c-miRNAs dysregulated in both directions in people with obesity compared to lean controls. Bioinformatic analyses suggest these c-miRNAs target on genes associated with fatty acid metabolism and PI3k/Akt pathway.
Conclusion: Literature records 33 c-miRNAs confirmedly dysregulated in human obesity. Their predicted target genes are involved in pathways that could explain the development of obesity and its comorbidities. Further research will clarify the role of these miRNAs on metabolic diseases and their usefulness for the prognosis, prevention and treatment of obesity.
... MicroRNAs (miRNAs) are endogenous noncoding small RNAs that are 18-25 nt in length. Over the past decade, numerous miRNAs have been identified in humans and animals [9][10][11][12]. These control growth and development in various cells via post-transcriptional regulation of target genes. ...
An increasing number of studies have demonstrated that some microRNAs participate in the regulation of growth and development of adipocytes. The present study shows that microRNA-425-5p (miR-425) is a novel strong regulator of adipogenesis and adipolysis in adipocytes. Forced expression of miR-425 in mice promoted body fat accumulation and the development of obesity due to high-fat intake, whereas silencing miR-425 prevented mice from being obese. Mechanically, the expression of miR-425 is controlled by PPARγ during the adipogenesis process in adipocytes. MiR-425 overexpression resulted in a reduction in the proliferation of 3t3-L1 pre-adipocytes but significantly accelerated cellular adipogenic differentiation. Mapk14, a negative regulator of adipogenesis, was predicted and confirmed as a real target gene of miR-425. Moreover, knocking down miR-425 remarkably intensified intracellular lipolysis and promoted lipid oxidation, which is related to the activation of AMPK, a monitor for intracellular energy balance. MiR-425 activated AMPK not only by decreasing cellular ATP concentrations but also by targeting the gene of Cab39, which is an upstream co-activator of AMPK. The findings of the present study suggest that miR-425 could control adipogenesis and adipolysis in adipocytes by simultaneously triggering multidirectional targets.
... Recently, researchers mainly focused on the role of secretions and basal role of the adipocytes and adipose tissue in tumor occurrence and development, including insulin resistance, chronic inflammation and inflammatory cytokines, adipokines, and sex hormones [30,31]. It has been reported that small non-coding RNAs are involved in the functions of adipocytes in breast cancers [31,32]. ...
Excessive adiposity has long been proved to be associated with greater incidence and mortality of breast cancer in post-menopausal women. However, the effects and underlying mechanisms of human adipocytes on breast cancer cells remain largely unknown. In recent years, several reports have revealed the oncogenic role of long non-coding RNA PVT1 in breast cancer. Here, we aimed to investigate the role and underlying mechanisms of PVT1 in triple-negative breast cancer (TNBC) cells cultured with mature adipogenic medium. At first, we successfully induced adipogenic differentiation from human adipose-derived mesenchymal stem cells and collected the mature adipogenic medium to mimic excessive adiposity. Our results demonstrated that the mature adipogenic medium promoted the epithelial-mesenchymal transition, enhanced the cell viability and migration potential of TNBC cells. In addition, we proved that mature adipogenic medium affected the PVT1 expression and inhibition of the PVT1 disturbed the role of mature adipogenic medium in TNBC cells. Finally, we illustrated that repression of p21 restored the phenotype caused by PVT1 knockdown in TNBC cells treated with mature adipogenic medium. Taken together, our results demonstrated that PVT1 affected the role of mature adipogenic medium in TNBC cells via modulating p21 expression.
... 2 Obesity is currently one of the most serious public health issues in the world (1). Obesity is considered as a chronic, multifactorial disease characterized by excess body fat that accumulates when there is a positive energetic balance, i.e., when energy consumption (food intake) overcomes energy expenditure (2), and represents one of the most important risk factors for diseases such as type 2 diabetes (T2D), cardiovascular diseases and several types of cancerthe leading causes of mortality and morbidity worldwide (3). ...
Obesity leads to changes in miRNA expression in adipose tissue and this modulation is linked to the pathophysiology of the disease. Green tea (GT) is a natural source of polyphenols that have been shown to confer health benefits, particularly preventing metabolic diseases. Here we investigated if the beneficial effects of GT in obesity results from changes in the miRNA profile in white adipose tissue. GT treatment (500 mg/ body weight/12 weeks) increased energy expenditure of high fat diet-fed mice (16 weeks), leading to reduced weight gain, decreased adiposity, reduced inflammation and improved insulin sensitivity. These phenotypes were associated with a decrease in the expression of miR-335 in the adipose tissue. miR-335 was up-regulated by TNF-α in adipocytes and in turn down-regulated genes involved in insulin signaling and lipid metabolism. On the other hand, GT inhibited TNF-α effect. In conclusion miR-335 serves as a link between inflammation and impaired metabolism in adipose tissue, providing an important mechanistic insight into the molecular basis underlying GT action during obesity.
White adipose tissue (WAT) serves as the primary site for energy storage and endocrine regulation in mammals, while brown adipose tissue (BAT) is specialized for thermogenesis and energy expenditure. The conversion of white adipocytes to brown-like fat cells, known as browning, has emerged as a promising therapeutic strategy for reversing obesity and its associated co-morbidities. Noncoding RNAs (ncRNAs) are a class of transcripts that do not encode proteins but exert regulatory functions on gene expression at various levels. Recent studies have shed light on the involvement of ncRNAs in adipose tissue development, differentiation, and function. In this review, we aim to summarize the current understanding of ncRNAs in adipose biology, with a focus on their role and intricate mechanisms in WAT browning. Also, we discuss the potential applications and challenges of ncRNA-based therapies for overweight and its metabolic disorders, so as to combat the obesity epidemic in the future.
The proliferation and differentiation of preadipocytes is an important factor determining bovine fat development, which is closely related to the feed conversion ratio, carcass traits, and beef quality. The purpose of this study was to identify the effects of candidate circRNA and miRNA on the proliferation and differentiation of bovine preadipocytes in order to provide basic materials for molecular breeding in cattle. circRNA sequencing was performed on bovine adipocyte samples at different differentiation time points, and a total of 1830 differentially expressed circRNAs were identified. Among them, circBDP1, derived from the bovine BDP1 gene, has potential binding sites for miR-204 (known as a regulator of bovine fat development) and miR-181b, which gives us a hint that circBDP1 may regulate bovine fat development by adsorbing miR-204 and miR-181b. Here, our results revealed that circBDP1 overexpression promoted the proliferation and differentiation of bovine preadipocytes. The miRNA profile of bovine adipocytes at different differentiation time points was also analyzed using the small RNA sequencing method, and a total of 89 differentially expressed miRNAs were identified, including miR-204 and miR-181b. As expected, dual-luciferase reporter results showed that circBDP1 competitively adsorbed miR-181b and miR-204. Overexpression and interference of miR-181b in bovine preadipocytes and 3T3-L1 showed that miR-181b promoted the proliferation and differentiation of preadipocytes. Further results displayed that miR-181b and miR-204 simultaneously targeted the SIRT1 gene, and miR-204 also targeted the 3' UTR region of the TRARG1 gene. In summary, this study found that miR-181b and miR-204 were involved in fat development by targeting SIRT1 and TRARG1. The results of this study will lay a foundation for the research of fat development and beef cattle industry.
The precision medicine approach can be used in endocrinology, which provides improved clinical outcomes and cost-effectiveness in the healthcare system. The new technologies of genotyping have significantly increased genetic understanding, providing an interesting opportunity to use genetic information to predispose disease and to subclassify the patients whom have the greatest benefit of therapies. Precision diabetes medicine consists of the following components: precision diagnosis, precision therapeutics, precision prevention, precision treatment, precision prognostics, and precision monitoring. The treatment of metastatic or advanced thyroid cancer has undergone a substantial change. It evolved from a one-size-fits-all approach to cytotoxic chemotherapy for these patients to an age of personalized targeted therapy based on tumor type and genomic profile. In this chapter, we present a review of precision medicine approach in endocrinology.KeywordsEndocrinologyPrecision medicineDiabetesOsteoporosisThyroid cancerPharmacogenomics
Background
Obesity is increasing rapidly affecting half billion adult's population. Pathophysiology of obesity involves low grade inflammation sustained by Toll like receptor 2 (TLR-2) the innate immune adapters. This study was conducted for detection and association of TLR-2 gene mutations with obesity.
Methods
In this case-control study 228 individuals with obesity and 228 controls were enrolled based on Body Mass Index (BMI) ≥25 and 18-24 kg/m² respectively. The variations in TLR-2 gene were detected by Sanger sequencing. These identified TLR-2 variants were further analyzed in silico for change in miRNA binding and mRNA strucutre.
Results
Four novel single base substitutions (153688371 T >C, 153702295 T >C, 153703504 T >C and 153705074 C >A) were identified in exon 3 and 4 of TLR-2 gene affecting splice site and poly-A tail. The genotypic and allelic frequencies of the variants were strongly associated with increasing obesity susceptibility. Only variant 153703504 T >C was significantly associated with preobesity. Despite variations in gene sequence, no change in miRNA binding except for variant 153688371 T >C of Exon 3 where a novel binding site for hsa-miR-4523 was created. Furthermore, mRNA stability and secondary structure were also compromised in identified variants.
Conclusion
All detected variants of TLR-2 gene were significantly associated with and posed risk for development of obesity. Furthermore, in silico analysis revealed generation of new miRNA (hsa-miR-4523) binding site and change in mRNA structure/stability which needs to be further investigated for possible role in altering TLR-2 gene regulation/expression in obesity.
Despite the increasing prevalence of obesity and diabetes, there is no efficient treatment to combat these epidemics. The adipose organ is the main site for energy storage and plays a pivotal role in whole body lipid metabolism and energy homeostasis, including remodeling and dysfunction of adipocytes and adipose tissues in obesity and diabetes.
Thus, restoring and balancing metabolic functions in the adipose organ is in demand. MiRNAs represent a novel class of drugs and drug targets, as they are heavily involved in the regulation of many cellular and metabolic processes and diseases, likewise in adipocytes.
In this review, we summarize key regulatory activities of miRNAs in the adipose organ, discuss various miRNA replacement and inhibition strategies, promising delivery systems for miRNAs and reflect the future of novel miRNA-based therapeutics to target adipose tissues with the ultimate goal to combat metabolic disorders.
Intramuscular fat is positively related to meat quality including tenderness, flavor, and juiciness. Long noncoding RNA (LncRNA) plays a vital role in regulating adipogenesis. However, it is largely unknown about lncRNAs associated with porcine intramuscular adipocyte adipogenesis. In the present study, we focus on a novel LncRNA, which is named lncIMF2, associated with adipogenesis by our previous RNA-sequence analysis and bioinformatics analysis. We demonstrated LncIMF2 knockdown inhibited the proliferation of porcine intramuscular adipocytes while expression of cell cycle-related genes was decreased. Besides, we found LncIMF2 knockdown inhibited expression of adipogenic differentiation marker genes including PPARγ (Peroxisome proliferator-activated reporter gamma) and ATGL (Adipose triglyceride lipase). Similarly, overexpression of LncIMF2 promotes proliferation and differentiation of porcine intramuscular preadipocytes. Moreover, we proved that IncIMF2 acts as a molecular sponge for MicroRNA-217 (miR-217), which has been found associated with adipogenesis, thereby affecting the expression of the miR-217 target gene. Collectively, our findings will contribute to a deeper understanding of the role of LncRNA in pig IMF deposition for the improvement of meat quality.
MicroRNAs (miRNAs) are important modulators of thermogenic brown adipose tissue (BAT). They have been involved in its differentiation and hence its functioning. While different regulators of the miRNA machinery have been shown to be essential for BAT differentiation, little is known about their implication in BAT activation. The aim of this work was to evaluate the role of AGO2, the chief miRNA mediator, in BAT activation.
We took advantage of two non-genetic models of BAT activation to analyze the miRNA machinery and miRNA expression in BAT. We used principal component analysis (PCA) to obtain an overview of miRNA expression according to the BAT activation state. In vitro, we examined AGO2 expression during brown adipocyte differentiation and activation. Finally, we downregulated AGO2 to reveal its potential role in the thermogenic function of brown adipocytes.
PCA analysis allowed to cluster animals on their miRNA signature in active BAT. Moreover, hierarchical clustering showed a positive correlation between global upregulation of miRNA expression and active BAT. Consistently, the miRNA machinery, particularly AGO2, was upregulated in vivo in active BAT and in vitro in mature brown adipocytes. Finally, the partial loss-of-function of AGO2 in mature brown adipocytes is sufficient to lead to a diminished expression of UCP1 associated to a decreased uncoupled respiration.
Therefore, our study shows the potential contribution of AGO2 in BAT activation. Since BAT is a calorie-burning tissue these data have a translational potential in terms of therapeutic target in the field of altered fuel homeostasis associated to obesity and diabetes.
Brown adipose tissue (BAT) has been suggested to play an important role in lipid and glucose metabolism in rodents and possibly also in humans. In the current study, we used genetic and correlation analyses in the BXH/HXB recombinant inbred (RI) strains, derived from Brown Norway (BN) and spontaneously hypertensive rats (SHR), to identify genetic determinants of BAT function. Linkage analyses revealed a quantitative trait locus (QTL) associated with interscapular BAT mass on chromosome 4 and two closely linked QTLs associated with glucose oxidation and glucose incorporation into BAT lipids on chromosome 2. Using weighted gene co-expression network analysis (WGCNA) we identified 1,147 gene co-expression modules in the BAT from BXH/HXB rats and mapped their module eigengene QTLs. Through an unsupervised analysis, we identified modules related to BAT relative mass and function. The Coral4.1 co-expression module is associated with BAT relative mass (includes Cd36 highly connected gene) and the Darkseagreen co-expression module is associated with glucose incorporation into BAT lipids (includes Hiat1, Fmo5 and Sort1 highly connected transcripts). Because multiple statistical criteria were used to identify candidate modules, significance thresholds for individual tests were not adjusted for multiple comparisons across modules. In summary, a systems genetic analysis using genomic and quantitative transcriptomic and physiologic information has produced confirmation of several known genetic factors and significant insight into novel genetic components functioning in BAT and possibly contributing to traits characteristic of the metabolic syndrome.
Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.
Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin.
Electronic supplementary material
The online version of this article (doi:10.1186/s13041-016-0277-4) contains supplementary material, which is available to authorized users.
Adaptive thermogenesis is an important component of energy expenditure. Brown adipocytes are best known for their ability to convert chemical energy into heat. Beige cells are brown-like adipocytes that arise in white adipose tissue in response to certain environmental cues to dissipate heat and improve metabolic homeostasis. A large body of intrinsic factors and external signals are critical for the function of beige adipocytes. In this review, we discuss recent advances in our understanding of neuronal, hormonal, and metabolic regulation of the development and activation of beige adipocytes, with a focus on the regulation of beige adipocytes by other organs, tissues, and cells. Understanding the cellular and molecular mechanisms of inter-organ regulation of adipose tissue browning may provide an avenue for combating obesity and associated diseases.
Genetic variants in the fat mass- and obesity-associated gene Fto are linked to the onset of obesity in humans. The causal role of the FTO protein in obesity is supported by evidence obtained from transgenic mice; however, the underlying molecular pathways pertaining to the role of FTO in obesity have yet to be established. In this study, we investigate the Fto gene in mouse brown adipose tissue and in the browning process of white adipose tissue. We analyze distinct structural and molecular factors in brown and white fat depots of Fto-deficient mice under normal and obesogenic conditions. We report significant alterations in the morphology of adipose tissue depots and the expression of mRNA and microRNA related to brown adipogenesis and metabolism in Fto-deficient mice. Furthermore, we show that high-fat feeding does not attenuate the browning process of Fto-deficient white adipose tissue as observed in wild-type tissue, suggesting a triggering effect of the FTO pathways by the dietary environment.
Growing evidence demonstrates the important role of microRNAs (miRs) in regulating adipogenesis, obesity and insulin resistance. The miR-200b/a/429 cluster has been functionally characterized in mammalian reproduction; however, the potential role of the miR-200 family in adipocytes is poorly understood. The aim of our study was to investigate the physiological function of miR-200b/a/429 in the regulation of whole-body metabolism in terms of the activities and targets of this cluster in adipocytes. We generated adipocyte-specific miR-200b/a/429 knockout (ASKO) mice using a Cre-loxP system in which Cre expression was driven by the aP2 promoter. The ASKO and wild type (WT) littermate were fed a chow diet (CD) or high-fat-diet (HFD), and changes in body composition, metabolic parameters, energy homeostasis, glucose tolerance and insulin sensitivity were analyzed. The miR-200b/a/429 putative target genes were predicted and validated via luciferase reporter assays. We found that the HFD-fed ASKO mice gradually gained more body weight than the WT mice due to the increased adiposity. Decreased glucose tolerance and insulin sensitivity were also observed in the HFD-fed ASKO mice. Notably, the down-regulation of lipolysis-related genes and the decreased response to CL-316,243 stimulation in the HFD-fed ASKO mice suggested that these animals exhibited impaired lipolysis. In addition, the HFD-fed ASKO mice displayed impaired energy expenditure, indicating that the miR-200b/a/429 cluster is essential for developing adaptive responses to stressors such as HFD. For the first time, our studies demonstrated the essential role of miR-200b/a/429 in adipocytes in the regulation of HFD-induced whole-body metabolic changes.
Many human diseases have been attributed to mutation in the protein coding regions of the human genome. The protein coding portion of the human genome, however, is very small compared with the non-coding portion of the genome. As such, there are a disproportionate number of diseases attributed to the coding compared with the non-coding portion of the genome. It is now clear that the non-coding portion of the genome produces many functional non-coding RNAs and these RNAs are slowly being linked to human diseases. Here we discuss examples where mutation in classical non-coding RNAs have been attributed to human disease and identify the future potential for the non-coding portion of the genome in disease biology.
* CHH, : cartilage-hair hypoplasia; DC, : dyskeratosis congenital; MELAS, : mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF, : myoclonic epilepsy with ragged red fibres; MOPD1, : microcephalic osteodysplastic primordial dwarfism type 1; MRP, : mitochondrial RNA processing; mt-tRNA, : mitochondrial tRNA; pre-mRNA, : pre-messenger RNA; PWS, : Prader–Willi syndrome; snoRNA, : small nucleolar RNA; SNP, : single nucleotide polymorphism; snRNA, : small nuclear RNA; snRNP, : small nuclear ribonucleoprotein particle; TERC, : telomerase RNA component; TERT, : telomerase reverse transcriptase
Background/objectives:
Brown adipose tissue (BAT) is a potential therapeutic target against obesity and diabetes through thermogenesis and substrate disposal with cold exposure. The role of BAT in energy metabolism under thermoneutral conditions, however, remains controversial. We assessed the contribution of BAT to energy expenditure (EE), particularly diet-induced thermogenesis (DIT), and substrate utilization in human adults.
Methods:
In this cross-sectional study, BAT activity was evaluated in 21 men using (18)F-fluoro-2-deoxy-D-glucose positron emission tomography combined with computed tomography ((18)F-FDG-PET/CT) after cold exposure (19 °C). The subjects were divided into BAT-positive (n=13) and BAT-negative (n=8) groups according to the (18)F-FDG-PET/CT findings. Twenty-four hour EE, DIT, and respiratory quotient were measured using a whole-room indirect calorimeter at 27 °C.
Results:
Body composition, blood metabolites, and 24-h EE did not differ between groups. DIT (%), calculated as DIT divided by total energy intake, however, was significantly higher in the BAT-positive group (BAT-positive: 9.7±2.5%, BAT-negative: 6.5±4.0%, P=0.03). The 24-h respiratory quotient was significantly lower (P=0.03) in the BAT-positive group (0.860±0.028) than in the BAT-negative group (0.889±0.024).
Conclusion:
DIT and fat utilization were higher in BAT-positive subjects compared to BAT-negative subjects, suggesting that BAT has a physiologic role in energy metabolism.International Journal of Obesity accepted article preview online, 19 July 2016. doi:10.1038/ijo.2016.124.
Objective:
MicroRNA (miR)-34a regulates inflammatory pathways, and increased transcripts have been observed in serum and subcutaneous adipose of subjects who have obesity and type 2 diabetes. Therefore, the role of miR-34a in adipose tissue inflammation and lipid metabolism in murine diet-induced obesity was investigated.
Methods:
Wild-type (WT) and miR-34a(-/-) mice were fed chow or high-fat diet (HFD) for 24 weeks. WT and miR-34a(-/-) bone marrow-derived macrophages were cultured in vitro with macrophage colony-stimulating factor (M-CSF). Brown and white preadipocytes were cultured from the stromal vascular fraction (SVF) of intrascapular brown and epididymal white adipose tissue (eWAT), with rosiglitazone.
Results:
HFD-fed miR-34a(-/-) mice were significantly heavier with a greater increase in eWAT weight than WT. miR-34a(-/-) eWAT had a smaller adipocyte area, which significantly increased with HFD. miR-34a(-/-) eWAT showed basal increases in Cd36, Hmgcr, Lxrα, Pgc1α, and Fasn. miR-34a(-/-) intrascapular brown adipose tissue had basal reductions in c/ebpα and c/ebpβ, with in vitro miR-34a(-/-) white adipocytes showing increased lipid content. An F4/80(high) macrophage population was present in HFD miR-34a(-/-) eWAT, with increased IL-10 transcripts and serum IL-5 protein. Finally, miR-34a(-/-) bone marrow-derived macrophages showed an ablated CXCL1 response to tumor necrosis factor-α.
Conclusions:
These findings suggest a multifactorial role of miR-34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways.
In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes (brown like adipocytes found within white adipose tissue) has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with a Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.
In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed “brite” (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation.
Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. _In vitro_, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. _In vivo_, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis.
Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
Aging increases the risk of type 2 diabetes, and this can be prevented by dietary restriction (DR). We have previously shown that DR inhibits the downregulation of miRNAs and their processing enzymes - mainly Dicer - that occurs with aging in mouse white adipose tissue (WAT). Here we used fat-specific Dicer knockout mice (AdicerKO) to understand the contributions of adipose tissue Dicer to the metabolic effects of aging and DR. Metabolomic data uncovered a clear distinction between the serum metabolite profiles of Lox control and AdicerKO mice, with a notable elevation of branched-chain amino acids (BCAA) in AdicerKO. These profiles were associated with reduced oxidative metabolism and increased lactate in WAT of AdicerKO mice and were accompanied by structural and functional changes in mitochondria, particularly under DR. AdicerKO mice displayed increased mTORC1 activation in WAT and skeletal muscle, where Dicer expression is not affected. This was accompanied by accelerated age-associated insulin resistance and premature mortality. Moreover, DR-induced insulin sensitivity was abrogated in AdicerKO mice. This was reverted by rapamycin injection, demonstrating that insulin resistance in AdicerKO mice is caused by mTORC1 hyperactivation. Our study evidences a DR-modulated role for WAT Dicer in controlling metabolism and insulin resistance.
Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that guide the post-transcriptional processing of other non-coding
RNAs (mostly ribosomal RNAs), but have also been implicated in processes ranging from microRNA-dependent gene silencing to
alternative splicing. In order to construct an up-to-date catalog of human snoRNAs we have combined data from various databases,
de novo prediction and extensive literature review. In total, we list more than 750 curated genomic loci that give rise to
snoRNA and snoRNA-like genes. Utilizing small RNA-seq data from the ENCODE project, our study characterizes the plasticity
of snoRNA expression identifying both constitutively as well as cell type specific expressed snoRNAs. Especially, the comparison
of malignant to non-malignant tissues and cell types shows a dramatic perturbation of the snoRNA expression profile. Finally,
we developed a high-throughput variant of the reverse-transcriptase-based method for identifying 2′-O-methyl modifications
in RNAs termed RimSeq. Using the data from this and other high-throughput protocols together with previously reported modification
sites and state-of-the-art target prediction methods we re-estimate the snoRNA target RNA interaction network. Our current
results assign a reliable modification site to 83% of the canonical snoRNAs, leaving only 76 snoRNA sequences as orphan.
Brown adipose tissue (BAT) dissipates energy and its activity correlates with leanness in human adults. 18 F-fluorodeoxyglucose (18 F-FDG) positron emission tomography coupled with computer tomography (PET/CT) is still the standard for measuring BAT activity, but exposes subjects to ionizing radiation. To study BAT function in large human cohorts, novel diagnostic tools are needed. Here we show that brown adipocytes release exosomes and that BAT activation increases exosome release. Profiling miRNAs in exosomes released from brown adipocytes, and in exosomes isolated from mouse serum, we show that levels of miRNAs change after BAT activation in vitro and in vivo. One of these exosomal miRNAs, miR-92a, is also present in human serum exosomes. Importantly, serum concentrations of exosomal miR-92a inversely correlate with human BAT activity measured by 18 F-FDG PET/CT in two unique and independent cohorts comprising 41 healthy individuals. Thus, exosomal miR-92a represents a potential serum biomarker for BAT activity in mice and humans.
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological process. They act as intracellular mediators that are necessary for various biological processes. MicroRNAs targeting pathways of human disease provide a new and potential powerful candidate for therapeutic intervention against various pathological conditions. Even though, the information about miRNA biology has significantly enriched but we still do not completely understand the mechanism of miRNA gene regulation. Various groups across the globe and pharmaceutical companies are conducting research and developments to explore miRNA based therapy and build a whole new area of miroRNA therapeutics. Consequently, few miRNAs have entered the preclinical and clinical stage and soon might be available in the market for use in humans.
MicroRNAs (miRNAs) have within the past decade emerged as key regulators of metabolic homeostasis. Major tissues in intermediary metabolism important during development of the metabolic syndrome, such as β-cells, liver, skeletal and heart muscle as well as adipose tissue have all been shown to be affected by miRNAs. In the pancreatic β-cell a number of miRNAs are important in maintaining the balance between differentiation and proliferation (miR-200 and miR-29 families) and insulin exocytosis in the differentiated state is controlled by miR-7, miR-375 and miR-335. MiR-33a and -33b play crucial roles in cholesterol and lipid metabolism, whereas miR-103 and -107 regulates hepatic insulin sensitivity. In muscle tissue a defined number of miRNAs (miR-1, miR-133, mir-206) control myofiber type switch and induce myogenic differentiation programs. Similarly, in adipose tissue a defined number of miRNAs control white to brown adipocyte conversion or differention (miR-365, miR-133, miR-455). The discovery of circulating miRNAs in exosomes emphasizes their importance as both endocrine signaling molecules and potentially disease markers. Their dysregulation in metabolic diseases, such as obesity, type 2 diabetes and atherosclerosis stresses their potential as therapeutic targets. This review emphasizes current ideas and controversies within miRNA research in metabolism. This article is protected by copyright. All rights reserved.
Background: MicroRNAs (miRNAs) are small non-coding RNAs involved in the modulation of gene expression and in the control of numerous cell functions. Alterations of miRNA patterns frequently occur in cancer and metabolic disorders, including obesity. Recent studies showed remarkable stability of miRNAs in both plasma and serum making them suitable as potential circulating biomarkers for a variety of diseases and conditions.
The aim of this study was to assess the profile of circulating miRNAs expressed in plasma samples of overweight or obese (OW/Ob) and normal weight (NW) pre-pubertal children from a European cohort (www.ifamilystudy.eu). The project, aimed to assess the determinants of eating behaviour in children and adolescents of eight European countries, is built on the IDEFICS cohort (www.ideficsstudy.eu), established in 2006. Among the participants of the IFamily Italian Cohort, ten OW/Ob (age 10.7±1.5 yrs, BMI 31.6±4.3 Kg/m2), and ten NW (age 10.5±2.7 yrs, BMI 16.4±1.7 Kg/m2) children were selected for the study. Gene arrays were employed to differentially screen the expression of 372 miRNAs in pooled plasma samples. De-regulated miRNAs (p<0.05) were further validated using a RT-qPCR approach.
Results: Using a significance threshold of p<0.05 and a fold-change threshold of ± 4.0, we identified eight out of 372 total screened miRNAs that differed between the OW/Ob and NW groups. After subsequent validation by RT-qPCR, three specific circulating miRNAs were statistically confirmed (p-value < 0.05): OW/Ob was significantly associated with a two-fold upregulation of miR-31-5p, a three-fold upregulation of miR-2355-5p and a 0.5-fold downregulation of miR-206. The molecular functions of the plasma miRNAs that were most differentially expressed as well as their expected mRNA targets were predicted by bioinformatics tools.
Conclusions: The early detection of circulating miRNA profile may be a promising strategy to identify obese children who may suffer from metabolic abnormalities.
Obesity has been linked to many health problems, such as diabetes. However, there is no drug that effectively treats obesity. Here, we reveal that miR-378 transgenic mice display reduced fat mass, enhanced lipolysis, and increased energy expenditure. Notably, administering AgomiR-378 prevents and ameliorates obesity in mice. We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism. This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1. Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. Thus, miR-378 may serve as a promising agent for preventing and treating obesity in humans.
New therapeutic and preventative strategies are needed to address the growing obesity epidemic. In animal models, brown adipose tissue activation and the associated heat produced contribute to countering obesity and the accompanying metabolic abnormalities. Adult humans also have functional brown fat. Here, we present and discuss the concepts of murine and human white adipose tissue plasticity and the transdifferentiation of white adipocytes into brown adipocytes. Human visceral adipocytes - which are crucial contributors to the burden of obesity and its complications - are particularly susceptible to such transdifferentiation. Therefore, we propose that this process should be a focus of anti-obesity research. Approved drugs that have browning properties as well as future drugs that target molecular pathways involved in white-to-brown visceral adipocyte transdifferentiation may provide new avenues for obesity therapy.
Long noncoding RNAs (lncRNAs) are an emerging class of regulators involved in a myriad of biological processes. Recent studies have revealed that many lncRNAs play pivotal roles in regulating adipocyte development. Due to the prevalence of obesity and the serious effects of adiposity on human health and society development, it is necessary to summarize functions and recent advances of lncRNAs in adipogenesis. In this review, we highlight functional lncRNAs contributed to the regulation of adipogenesis, discussing their potential use as therapeutic targets to combat human obesity.
Obesity is a growing epidemic in developed countries. Obese individuals are susceptible to comorbidities, including cardiovascular disease and metabolic disorder. Increasing the ability of adipose tissue to expend excess energy could improve protection from obesity. One promising target is microRNA (miR)-155-5p. We demonstrate that deletion of miR-155 (-5p and -3p) in female mice prevents diet-induced obesity. Body weight gain did not differ between wild-type (WT) and miR-155 knockout (KO) mice fed control diet (CD); however, miR-155 KO mice fed high-fat diet (HFD) gained 56% less body weight and 74% less gonadal white adipose tissue (WAT) than WT mice. Enhanced WAT thermogenic potential, brown adipose tissue differentiation, and/or insulin sensitivity might underlie this obesity resistance. Indeed, miR-155 KO mice on HFD had 21% higher heat release than WT HFD mice. Compared to WT adipocytes, miR-155 KO adipocytes upregulated brown (Ucp1, Cidea, Pparg) and white (Fabp4, Pnpla2, AdipoQ, Fasn) adipogenic genes, and glucose metabolism genes (Glut4, Irs1). miR-155 deletion abrogated HFD-induced adipocyte hypertrophy and WAT inflammation. Therefore, miR-155 deletion increases adipogenic, insulin sensitivity, and energy uncoupling machinery, while limiting inflammation in WAT, which together could restrict HFD-induced fat accumulation. Our results identify miR-155 as a novel candidate target for improving obesity resistance.
Activation of brown adipose tissue (BAT) controls energy homeostasis in rodents and humans and has emerged as an innovative strategy for the treatment of obesity and type 2 diabetes mellitus. Here we show that ageing- and obesity-associated dysfunction of brown fat coincides with global microRNA downregulation due to reduced expression of the microRNA-processing node Dicer1. Consequently, heterozygosity of Dicer1 in BAT aggravated diet-induced-obesity (DIO)-evoked deterioration of glucose metabolism. Analyses of differential microRNA expression during preadipocyte commitment and mouse models of progeria, longevity and DIO identified miR-328 as a regulator of BAT differentiation. Reducing miR-328 blocked preadipocyte commitment, whereas miR-328 overexpression instigated BAT differentiation and impaired muscle progenitor commitment-partly through silencing of the β-secretase Bace1. Loss of Bace1 enhanced brown preadipocyte specification in vitro and was overexpressed in BAT of obese and progeroid mice. In vivo Bace1 inhibition delayed DIO-induced weight gain and improved glucose tolerance and insulin sensitivity. These experiments reveal Dicer1-miR-328-Bace1 signalling as a determinant of BAT function, and highlight the potential of Bace1 inhibition as a therapeutic approach to improve not only neurodegenerative diseases but also ageing- and obesity-associated impairments of BAT function.
White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol-regulatory element-binding proteins, SREBP-2 and SREBP-1 respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting
in-vitro
adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding
in-vivo
assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human pre-adipocytes, along with
SREBP-1
. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired pre-adipocyte proliferation, and reduced lipid droplet formation and the induction of PPARγ target genes during differentiation. These effects may be mediated by targeting of HMGA2, CDK6 and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.
Offspring affected by sperm small RNAs
Paternal dietary conditions in mammals influence the metabolic phenotypes of offspring. Although prior work suggests the involvement of epigenetic pathways, the mechanisms remains unclear. Two studies now show that altered paternal diet affects the level of small RNAs in mouse sperm. Chen et al. injected sperm transfer RNA (tRNA) fragments from males that had been kept on a high-fat diet into normal oocytes. The progeny displayed metabolic disorders and concomitant alteration of genes in metabolic pathways. Sharma et al. observed the biogenesis and function of small tRNA-derived fragments during sperm maturation. Further understanding of the mechanisms by which progeny are affected by parental exposure may affect human diseases such as diet-induced metabolic disorders.
Science , this issue p. 397 , p. 391
Offspring affected by sperm small RNAs
Paternal dietary conditions in mammals influence the metabolic phenotypes of offspring. Although prior work suggests the involvement of epigenetic pathways, the mechanisms remains unclear. Two studies now show that altered paternal diet affects the level of small RNAs in mouse sperm. Chen et al. injected sperm transfer RNA (tRNA) fragments from males that had been kept on a high-fat diet into normal oocytes. The progeny displayed metabolic disorders and concomitant alteration of genes in metabolic pathways. Sharma et al. observed the biogenesis and function of small tRNA-derived fragments during sperm maturation. Further understanding of the mechanisms by which progeny are affected by parental exposure may affect human diseases such as diet-induced metabolic disorders.
Science , this issue p. 397 , p. 391
BACKGROUND: Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP).
METHODS: Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest.
RESULTS: After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters.
CONCLUSIONS: These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes.
Late-onset hypogonadism (LOH), defined as a combination of low serum testosterone (T) levels in combination with clinical signs and symptoms of androgen deficiency in ageing men, is nowadays a well-characterized disease. Testosterone therapy in males affected by hypogonadism leads to a significant decrease of fat mass. In humans, the exact molecular mechanism of T effects on inhibition of adipogenesis is still unknown. We hypothesized that specific microRNAs could be regulated by androgens which might cause an inhibition of adipogenic differentiation. To confirm this hypothesis, human mesenchymal stem cells and a preadipocyte cell line were differentiated into mature adipocytes and in parallel treated with testosterone and dihydrotestosterone. The expression level of miR-375 was upregulated during adipogenic differentiation and downregulated after androgen treatment. Furthermore, we could show that after androgen treatment the decreased expression of miR-375 led to increased expression levels of adiponectin receptor 2 (ADIPOR2) compared to untreated adipocytes. Moreover, inhibition of miR-375 also mediated a decreased adipogenic differentiation and increased ADIPOR2 expression levels. In summary, we identified miR-375 as an androgen regulated microRNA, which could play an important role for understanding the mechanism of the increase in visceral fat mass and the associated insulin resistance caused by testosterone deficiency.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation.
MicroRNAs (miRNA) are small non-coding RNAs involved in the modulation of gene expression and in the control of cell functions. Alterations of miRNA pattern often occur in cancer and metabolic disorders, including obesity. Recent studies showed remarkable stability of miRNAs in both plasma and serum making miRNAs potential circulating biomarkers for a variety of diseases.
The aim of this pilot study is to evaluate whether circulating miRNAs were differentially expressed in plasma samples of overweight/obese (OW/Ob) and normal weight (NW) children belonging to the Italian cohort of the IFamily project (www.ifamilystudy.eu).
The IFamily project, aimed to assess the determinants of eating behaviour in children and adolescents of eight European countries, is built on the Idefics cohort (www.ideficsstudy.eu), established in 2006. Among the participants of the Italian cohort of the IFamily project, ten OW/Ob (age 11.2±1.5 yrs, BMI 28.2±1.5 Kg/m2), and ten NW (age 11.9±1.7 yrs, BMI 16.4±1.7 Kg/m2) children were selected for the pilot study. MiScript miRNA PCR Array Human Serum/Plasma panels were employed to screen and compare the expression of 384 miRNAs in pooled plasma samples from the two groups. Validation of selected miRNAs was carried out using RT-qPCR. The validation study showed that five specific circulating miRNAs were significantly deregulated in prepubertal OW/Ob children.
Our preliminary results indicate that circulating miRNAs are significantly deregulated in OW/Ob children. The planned completion of the miRNAs studies in selected samples of the eight European countries participating to the IFamily project will allow to confirm miRNA profiling as a promising strategy to identify children who may suffer from metabolic abnormalities during growth.
Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.
The elucidation of the molecular mechanism of adipocyte differentiation in mesenchymal stem cells is of essential importance for the development of treatments for metabolic diseases, such as obesity and diabetes.
The expression levels of miR-342-3p and carboxy-terminal binding protein 2 (CtBP2) were regulated by oligonucleotide transfection. Adipogenic differentiation was induced by adipogenic medium containing indomethacin, dexamethasone and 3-isobutyl-1-methylxanthine on day 12, as determined by Oil Red O staining and triglyceride concentration assay to assess intracellular lipid accumulation. The induction of adipocyte-specific transcription factors and markers was detected by qRT-PCR and western blot. The regulation of CtBP2 expression by miR-342-3p was determined by western blot, qRT-PCR, luciferase reporter assay, ChIP assay and functional experiments.
We revealed that miR-342-3p was enriched in the adipose tissue of obese mice, and its expression was significantly elevated during adipogenic differentiation in both human mesenchymal stem cells (hMSCs) and 3T3L1 cells. Using gain- and loss-of-function assays, we demonstrated that the overexpression of miR-342-3p markedly promoted the differentiation of hMSCs into an adipogenic lineage. Adipogenesis was significantly blocked by miR-342-3p downregulation. We identified and validated that CtBP2 was a direct target of miR-342-3p in this process. The effects of the inhibition of CtBP2 were similar to those of miR-342-5p overexpression on adipogenic differentiation, promoting the release of C/EBPα from CtBP2 binding.
miR-342-3p is a powerful enhancer of the adipogenesis of human adipose-derived MSCs that acts by inhibiting CtBP2 and releasing the key adipogenic regulator C/EBPα from CtBP2 binding, subsequently activating the expression of adipogenic transcription factors and markers. © 2015 S. Karger AG, Basel.
Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader-Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.
Although brown adipose tissue in infants and young children is important for regulation of energy expenditure, there has been considerable debate on whether brown adipose tissue normally exists in adult humans and has physiologic relevance in this population. In the last decade, radiologic studies in adults have identified areas of adipose tissue with high 18F-fluorodeoxyglucose (18F-FDG) uptake, putatively identified as brown fat. This radiologic study assessed the presence of physiologically significant brown adipose tissue among 1972 adult patients who had 3640 consecutive 18F-FDG positron-emission tomographic and computed tomographic whole-body scans between 2003 and 2006. Brown adipose tissue was defined as areas of tissue that were more than 4 mm in diameter, had the CT density of adipose tissue, and had maximal standardized uptake values of 18F-FDG of at least 2.0 gm per mL. A sample of 204 date-matched patients without brown adipose tissue served as the control group. Using these criteria, positron-emission tomographic and computed tomographic scans identified brown adipose tissue in 106 of the 1972 patients (5.4%). The most common location for substantial amounts of brown adipose tissue was the region extending from the anterior neck to supraclavicular region. Immunohistochemical staining for uncoupling protein 1 in this region confirmed the identity of immunopositive, multilocular adipocytes as brown adipose tissue. More brown adipose tissue was detected in women (7.5% [76/1013]) than in men (3.1% [30/959]); the female:male ratio was 2.4:1.0 (P 64) (P 64 years) (P for trend = 0.007). These findings show that functional brown adipose tissue is prevalent in adult humans, and significantly more frequently in women. The inverse correlation of body mass index with the amount of brown adipose tissue, especially in older patients, suggests to the investigators a possible role of brown adipose tissue in protecting against obesity.
Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.
Objective:
Exosomes from obese adipose contain dysregulated microRNAs linked to insulin signaling, as compared with lean controls, providing a direct connection between adiposity and insulin resistance. This study tested the hypotheses that gastric bypass surgery and its subsequent weight loss would normalize adipocyte-derived exosomal microRNAs associated with insulin signaling and the associated metabolome related to glucose homeostasis.
Methods:
African American female subjects with obesity (N = 6; age: 38.5 ± 6.8 years; BMI: 51.2 ± 8.8 kg/m(2) ) were tested before and 1 year after surgery. Insulin resistance (HOMA), serum metabolomics, and global microRNA profiles of circulating adipocyte-derived exosomes were evaluated via ANCOVA and correlational analyses.
Results:
One year postsurgery, patients showed decreased BMI (-18.6 ± 5.1 kg/m(2) ; P < 0.001), ameliorated insulin resistance (HOMA: 1.94 ± 0.6 presurgery, 0.49 ± 0.1 postsurgery; P < 0.001), and altered metabolites including branched chain amino acids (BCAA). Biological pathway analysis of predicted mRNA targets of 168 surgery-responsive microRNAs (P < 0.05) identified the insulin signaling pathway (P = 1.27E-10; 52/138 elements), among others, in the data set. The insulin signaling pathway was also a target of 10 microRNAs correlated to changes in HOMA (P < 0.05; r > 0.4), and 48 microRNAs correlated to changes in BCAA levels.
Conclusions:
These data indicate that circulating adipocyte-derived exosomes are modified following gastric bypass surgery and correlate to improved postsurgery insulin resistance.
Small RNAs have the potential to store a secondary layer of labile biological information in the form of modified nucleotides. Emerging evidence has shown that small RNAs including microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and tRNA-derived small RNAs (tsRNAs) harbor a diversity of RNA modifications. These findings highlight the importance of RNA modifications in the modulation of basic properties such as RNA stability and other complex physiological processes involved in stress responses, metabolism, immunity, and epigenetic inheritance of environmentally acquired traits, among others. High-resolution, high-throughput methods for detecting, mapping and screening these small RNA modifications now provide opportunities to uncover their diagnostic potential as sensitive disease markers.
Metabolic homeostasis emerges from the complex, multidirectional crosstalk between key metabolic tissues including adipose tissue, liver, and skeletal muscle. This crosstalk, traditionally mediated by hormones and metabolites, becomes dysregulated in human diseases such as obesity and diabetes. Extracellular vesicles (EVs; including exosomes) are circulating, cell-derived nanoparticles containing proteins and nucleic acids that interact with and modify local and distant cellular targets. Accumulating evidence, reviewed herein, supports a role for extracellular vesicles in obesity-associated metabolic disturbance, particularly the local and systemic inflammation characteristic of adipose and hepatic stress. As the practical and conceptual challenges facing the field are tackled, this emerging and versatile mode of intercellular communication may afford valuable insights and therapeutic opportunities in combatting these major threats to modern human health.
Germline deletion of the Prader-Willi syndrome (PWS) candidate gene Snord116 in mice leads to some classical symptoms of human PWS, notably reductions in body weight, linear growth and bone mass. However, Snord116 deficient mice (Snord116(-/-)) do not develop an obese phenotype despite their increased food intake and the underlying mechanism for that is unknown. We tested the phenotypes of germline Snord116(-/-) as well as neuropeptide Y (NPY) neuron specific Snord116(lox/lox)/NPY(cre/+) mice at 30°C, the thermoneutral temperature of mice, and compared these to previous reports studies conducted at normal room temperature. Snord116(-/-) mice at 30°C still weighed less than wild type but had increased body weight gain. Importantly, food intake and energy expenditure were no longer different at 30°C, and the reduced bone mass and nasal-anal length observed in Snord116(-/-) mice at room temperature were also normalized. Mechanistically, the thermoneutral condition led to the correction of the mRNA expression of NPY and pro-opiomelanocortin (POMC), which were both previously observed to be significantly up-regulated at room temperature. Importantly, almost identical phenotypes and NPY/POMC mRNA expression alterations were also observed in Snord116(lox/lox)/NPY(cre/+) mice, which lack the Snord116 gene only in NPY neurons. These data illustrate that mild cold stress is a critical factor preventing the development of obesity in Snord116(-/-) mice via the NPY system. Our study highlights that the function of Snord116 in the hypothalamus may be to enhance energy expenditure, likely via the NPY system, and also indicates that Snord116 function in mice is strongly dependent on environmental conditions such as cold exposure.
MicroRNAs (miRNAs) are small non-coding RNA molecules consisting of approximately 20 to 22 nucleotides. They play a very important role in the regulation of gene expression. miRNAs can be found in different species and a variety of organs and tissues including adipose tissue. There are two types of adipose tissue in mammals: White adipose tissue (WAT) is the largest energy storage, whereas brown adipose tissue (BAT) dissipates energy to maintain body temperature. BAT was first identified in hibernating animals and newborns as a defense against cold. Later on, it was also discovered in human adults, suggesting its potential role in energy balance and metabolism. Moreover, “brown-like” adipocytes present in WAT depots, so called beige or brite (brown-in-white) cells, were discovered by several groups. In recent years, miRNAs were found to have important regulatory function during brown fat differentiation, brown fat activation and white fat “browning”. In this review, we focus on the regulation of brown and beige fat by miRNAs including the role in their differentiation and function, providing evidence for their therapeutic potential in metabolic diseases.
We report a 20 year follow up on a Caucasian female, now 26 years of age, with Prader-Willi syndrome (PWS) harboring an atypical 15q11-q13 submicroscopic deletion of 100–200 kb in size first detected in 1996 involving the imprinting center, SNRPN gene and surrounding region. PWS is a rare complex disorder caused by the loss of paternally expressed genes in the 15q11-q13 region. With high resolution chromosomal microarray and methylation – specific MLPA analysis, we updated the genetic findings on our patient and found a 209,819bp deletion including the SNURF-SNRPN gene complex which includes the imprinting center and the SNORD116 region. We compared with four other similarly reported individuals in the literature with atypical submicroscopic deletions within this region but without imprinting center involvement to better characterize the specific genetic lesions causing PWS clinical findings. Clinically, our patient met the diagnostic criteria of PWS including infantile hypotonia, a poor suck with feeding difficulties, global developmental delays and later food foraging, childhood obesity, small hands and skin picking. Small atypical deletions of comparable sizes were seen in the 15q11-q13 region in all five cases and similar behavioral/physical characteristics were found despite an imprinting defect in our patient. These results further support an overlapping critical deletion region involving the non-coding snoRNA SNORD116 in common in the five individuals playing a key role in contributing to the PWS phenotype.
Brown adipose tissue (BAT) is the main site of adaptive thermogenesis and experimental studies have associated BAT activity with protection against obesity and metabolic diseases, such as type 2 diabetes mellitus and dyslipidaemia. Active BAT is present in adult humans and its activity is impaired in patients with obesity. The ability of BAT to protect against chronic metabolic disease has traditionally been attributed to its capacity to utilize glucose and lipids for thermogenesis. However, BAT might also have a secretory role, which could contribute to the systemic consequences of BAT activity. Several BAT-derived molecules that act in a paracrine or autocrine manner have been identified. Most of these factors promote hypertrophy and hyperplasia of BAT, vascularization, innervation and blood flow, processes that are all associated with BAT recruitment when thermogenic activity is enhanced. Additionally, BAT can release regulatory molecules that act on other tissues and organs. This secretory capacity of BAT is thought to be involved in the beneficial effects of BAT transplantation in rodents. Fibroblast growth factor 21, IL-6 and neuregulin 4 are among the first BAT-derived endocrine factors to be identified. In this Review, we discuss the current understanding of the regulatory molecules (the so-called brown adipokines or batokines) that are released by BAT that influence systemic metabolism and convey the beneficial metabolic effects of BAT activation. The identification of such adipokines might also direct drug discovery approaches for managing obesity and its associated chronic metabolic diseases.
The worldwide epidemic of obesity and type 2 diabetes has greatly increased interest in the biology and physiology of adipose tissues. Adipose (fat) cells are specialized for the storage of energy in the form of triglycerides, but research in the last few decades has shown that fat cells also play a critical role in sensing and responding to changes in systemic energy balance. White fat cells secrete important hormone-like molecules such as leptin, adiponectin, and adipsin to influence processes such as food intake, insulin sensitivity, and insulin secretion. Brown fat, on the other hand, dissipates chemical energy in the form of heat, thereby defending against hypothermia, obesity, and diabetes. It is now appreciated that there are two distinct types of thermogenic fat cells, termed brown and beige adipocytes. In addition to these distinct properties of fat cells, adipocytes exist within adipose tissue, where they are in dynamic communication with immune cells and closely influenced by innervation and blood supply. This review is intended to serve as an introduction to adipose cell biology and to familiarize the reader with how these cell types play a role in metabolic disease and, perhaps, as targets for therapeutic development.
Incidence of diabetes and other metabolic disorders is increasing worldwide, with almost half the cases remaining undiagnosed. This is cause for concern as poor management of glucose or lipid levels causes tissue damage that may result in micro- or macrovascular complications. Current methods of diagnosing metabolic disorders do not provide any clues on disease aetiology or their posterior evolution and incidence of complications, which are the main cause of disease-associated morbidity. Circulating microRNAs found in blood change with the physiological condition of the organism and may help to: (1) identify people at risk of developing metabolic disease, (2) diagnose diabetes or other metabolic disorders on the basis of their aetiology, (3) predict the development of complications, and (4) monitor response to treatment. Results published to date show promise in this direction but technical issues must still be honed in order to warrant their application in the clinical practice.
Obesity is a major public health problem conferring substantial excess risk for Type 2 diabetes (T2D). The role of microRNAs (miRNAs) in obesity and adipose tissue is not clearly defined. We hypothesize that circulating miRNA expression profiles vary according to differences in body mass index (BMI) and T2D and circulating miRNAs may reflect adipose tissue expression. Compared to healthy, lean individuals, circulating miR-100 was significantly lower in obese normoglycemic subjects and subjects with T2D. In visceral adipose tissue, expression of miR-100 was lower from obese subjects with T2D compared to obese subjects without T2D. miR-100 expression was significantly lower after adipogenic induction in human visceral, subcutaneous adipocytes and 3T3-L1 adipocytes. miR-100 reduced expression of mammalian target of rapamycin (mTOR) and Insulin Growth Factor Receptor (IGFR) directly. Differentiation of 3T3-L1 was accelerated by inhibition of miR-100 and reduced by miR-100 mimic transfection. Our data provide the first evidence of an association of circulating miR-100 with obesity and diabetes. Additionally, our in-vitro findings, and the miR-100 expression patterns in site-specific adipose tissue suggest miR-100 to modulate IGFR, mTOR and mediate adipogenesis.
The emergence of a worldwide obesity epidemic has dramatically increased the prevalence of insulin resistance and metabolic syndrome, predisposing individuals to a greater risk for the development of non-alcoholic fatty liver disease, type II diabetes and atherosclerotic cardiovascular diseases. Current available pharmacological interventions combined with diet and exercise-based managements are still poorly effective for weight management, likely in part due to an incomplete understanding of regulatory mechanisms and pathways contributing to the systemic metabolic abnormalities under disturbed energy homeostasis. MicroRNAs, small non-coding RNAs that regulate posttranscriptional gene expression, have been increasingly described to influence shifts in metabolic pathways under various obesity-related disease settings. This review discusses the recent discoveries of the mechanistic role that microRNAs play in regulating metabolic functions in liver and adipose tissues involved in obesity associated disorders, and briefly discusses the potential candidates that are being pursued as viable therapeutic targets.
Childhood obesity is an increasing health challenge related to increased risk of chronic diseases. microRNAs (miRNAs) are noncoding short RNA molecules regulating multiple biological processes linked to obesity.
We aimed at evaluating the association between circulating miRNA levels and lipid metabolism in obese and non-obese children and adolescents.
By constituting study group, 45 obese children and adolescents were recruited. To perform comparisons with study group, 41 lean controls were matched for age and sex. Using real-time quantitative PCR analysis, circulating miRNAs were evaluated in both groups.
Circulating miR-335 (P < 0.001), miR-143 (P = 0.001) and miR-758 (P = 0.006) in obese children were significantly lower than those of controls. However, circulating miR-27 (P = 0.032), miR-378 (P < 0.001) and miR-370 (P = 0.045) in obese children were significantly higher, compared with those of controls. In addition, circulating miR-33 in obese children was higher than those of controls, but no significant difference was present (P = 0.687).
Our findings showed that a significant association is present between circulating miR-370, miR-33, miR-378, miR-27, miR-335, miR-143 and miR-758 values, and childhood obesity. Low levels of miR-335, miR-143 and miR-758, and high levels of miR-27, miR-378, miR-33 and miR-370 may have been responsible for elevated triglycerides and low-density lipoprotein (LDL-C) levels, and low level of high-density lipoprotein (HDL-C) in obese subjects. Therefore, miRNAs may be a good novel biomarker for childhood obesity.
© 2015 World Obesity.
Previous evidence has indicated that the microRNA-125b (miR-125b) family plays important roles in the regulation of cancer cell growth, development, differentiation, and apoptosis. However, whether they contribute to the process of adipocyte differentiation remains unclear. In the present study, we revealed that the expression level of miR-125b-5p, a member of miR-125b family, was dramatically up-regulated during differentiation of 3T3-L1 preadipocyte into mature adipocyte. Supplement of miR-125b-5p into 3T3-L1 cells promoted adipogenic differentiation as evidenced by increased lipid droplets and mRNA levels of adipocyte-specific molecular markers, including peroxisome proliferators-activated receptor γ, CCAAT/enhancer-binding protein α, fatty acid-binding protein 4, and lipoprotein lipase, and by triglyceride accumulation. CCK-8 assay showed that miR-125b-5p supplementation significantly inhibited cell proliferation. Flow cytometry analysis showed that miR-125b-5p impaired G1/S phase transition as well as the mRNA and protein expression of G1/S-related genes, such as Cyclin D2, Cyclin D3, and CDK4. Nevertheless, it had no effect on apoptosis. Additionally, by target gene prediction, we demonstrated that smad4 may be a potential target of miR-125b-5p in mouse 3T3-L1 preadipocytes, accounting for some of miR-125b-5p's functions. Taken together, these data indicated that miR-125b-5p may serve as an important positive regulator in adipocyte differentiation, at least partially through down-regulating smad4.
© The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
In this work, the normal (0 ) and oblique (30 and 45 ) ballistic impact behavior of glass fiber-reinforced aluminum laminates (fiber metal laminate, FMLs) impacted by a rigid cylindrical projectile (with a flat nose) has been investigated from an experimental point of view. The ballistic impact tests were conducted on the FMLs using a one-stage gas gun at different impact angels, i.e. 0 , 30 and 45. A high-speed camera was used to capture and record the experimental images and data during the impacting process. Different failure patterns were observed in the FMLs under oblique and normal impact, with the differences concentrated on the initial crack (in the back surface) and plugging damage (in both the front and back surface). The angular change in direction of the projectile during perforation was only observed during oblique impact tests while the maximum value of the angular change was observed when the impact velocity was close to its ballistic limit velocity. In addition, the angular change decreases with increasing impact velocity and is almost constant when the value of vi/v50 reaches a critical value. It can also be observed from the impact test results (both normal and oblique impacts) that FMLs exhibited the lowest ballistic limit velocity when the impact angle was close to 30. In particular, normal impact shows a higher ballistic limit velocity than that of oblique impact while the ballistic limit velocity at impact angle 45 is slightly higher than that at 30.
A rapid growth in the overweight and obese population in the last few decades suggest that the current diet, exercise, awareness or drug strategies are still not effectively restraining the obesity epidemic. Obesity results from increased energy intake, and the body's energy balance shifts towards energy abundance. Therefore, current research is focused on developing new strategies aimed at increasing energy expenditure. As a result, brown adipose tissue (BAT) is receiving tremendous attention since the major function of BAT is to dissipate energy as heat. For example, mouse models that have increased BAT activity or increased numbers of brown-like adipocytes within the white adipose tissue (WAT) are lean and protected from obesity. Alternatively, mouse models that lack BAT activity are more susceptible to age and diet-induced obesity. However, a significant loss of BAT mass during the natural growth process in humans has created enormous challenges in effectively utilizing this tissue to increase energy expenditure. New strategies are primarily focused on expanding the BAT mass and/or activating the existing BAT. In this regard, recent finding that expression of early B cell factor-2 (Ebf2) reprograms the white pre-adipocytes into brown adipocytes is a significant break-through in developing BAT-mediated strategies to treat obesity. Here we review the major biological functions of WAT and BAT, which play critical but opposing roles in the energy spectrum, energy storage versus energy expenditure, and we evaluate whether activation and/or expansion of BAT is practically achievable to treat obesity in humans. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.