Involvements of long noncoding RNAs in obesity‐associated inflammatory diseases

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


| INTRODUCTION
With the understanding that much of the human genome is transcribed into noncoding transcripts, it comes as no surprise that long noncoding RNAs (lncRNAs) have been linked to multiple diseases including developmental disorders and many cancers. Characterized as noncoding transcripts larger than 200 nucleotides, 1 they are the largest and most heterogeneous group of noncoding RNAs involved in several cellular processes. 2,3 Generally transcribed by RNA polymerase II, lncRNA transcripts undergo splicing events to remove introns and form alternatively spliced isoforms, are 5 0 capped and can even be polyadenylated. LncRNAs can exhibit tissue and cell-specific expression 4,5 and can impact gene regulation at every level, from manipulating epigenetic marks and chromatin folding to transcriptional initiation, activation and silencing, RNA splicing, editing, translation and RNA and protein turnover. 6 The LncRNA and Disease Database (LncRNADisease: http:// www.cuilab.cn/lncrnadisease) has seen entries surge from 63 diseaseassociated lncRNAs to 2,947 experimentally verified diseaseassociated lncRNAs in as little as 5 years. 7 With the development in deep-sequencing technologies, studies have been able to uncover genome-wide mutations associated with disease. Remarkably, Calin et al. found that many ultra-conserved noncoding regions that give rise to ncRNAs harbour mutations in cancers that lead to their dysregulation. 8,9 Currently, the function and mechanism of action of the vast majority of lncRNAs remain unclear. However, there are a small number of well-characterized lncRNAs, which have provided evidence of several mechanisms by which lncRNAs can exert their diverse functions. A strong argument for the physiological importance of lncRNAs as molecular signals lies in their variable expression observed between different cell types and tissues, in response to numerous stimuli and timely expression at specific developmental cues. 10 The process of initiation, elongation or termination at a lncRNA gene alone can suffice to elicit a regulatory response. 10 Additionally, transcripts are thought to recruit chromatin-remodelling complexes to modulate epigenetic regulation leading to either the repression or activation of specific genes. This holds true in the case of the X-inactive specific transcript (XIST), the antisense of insulin growth factor 2 receptor lncRNA and HOX transcript antisense RNA (HOTAIR) known to interact with several histone-modifying complexes. XIST is thought to recruit the PRC2 complex, which is essential for catalysing the repressive histone modification, trimethylation of histone H3 lysine 27 (H3K27me3), leading to X-chromosome inactivation. 11 As such, XIST influences chromatin compaction and silencing of the future inactive X-chromosome. Similarly, HOTAIR is also known to selectively bind components of the PRC2 complex including the histone methyltransferase EZH2. 12 Whereas the 5 0 region of HOTAIR associates with PRC2 proteins, the 3 0 domain also has been found to interact with the histone demethylase complex LSD1/CoREST/REST. 13 Decoy lncRNAs can act as a sponge or 'molecular sink' for RNAbinding proteins or as guides to specifically localize bound proteins to target genes, allowing for greater coordination of transcription factors and chromatin modifiers ( Figure 1A,B). 10 GAS5 is a well-studied decoy lncRNA that competitively binds the DNA-binding domain of the glucocorticoid receptor (GR) supressing the activation of GR target genes ( Figure 1A), 14 whereas MEG3 lncRNA acts as a guide for the PRC2 complex to specific chromatin sites due to a triplex forming GA-rich sequence at MEG3 binding sites that enable an RNA-DNA triplex formation ( Figure 1B). 15 Similarly, CCDC26 lncRNA regulates global DNA methylation in myeloid cells by coordinating the subcellular locations of DNA-methyltransferase 1 (DNMT1). 16 LncRNAs can also act as scaffolds forming functional ribonucleoprotein complexes providing a platform for the assembly of multiple proteins onto chromatin through sequence complementarity, stem loops, affinity and various tertiary structures ( Figure 1C,D). 17 HOTAIR is cited as such owing to its ability to simultaneously bind the PRC2 and LSD1 complex bridging the two to form the gene suppressive HOTAIR/PRC2/LSD1 complex ( Figure 1C). 10,18 Similarly, lncRNA ROCKI forms a ribonucleic complex at the MARCKS promoter with the endodeoxyribonuclease APEX1, which recruits HDAC1, a histone deacetylase to silence its own transcription ( Figure 1D). 19 These are the key mechanisms by which lncRNAs can epigenetically influence chromatin state and gene regulation. As such, lncRNAs are directly and indirectly significant for coordinating the activation or repression of target genes, and thus, it is important to gain an understanding of these integral regulators in the context of obesity-associated chronic inflammation on age-related conditions (Table 1).

| LncRNAs AND OBESITY
Obesity is the accumulation of excessive body fat, which can severely impact health and currently affects 650 million adults worldwide.
Transcriptional analyses by both next-generation sequencing and microarray have identified several lncRNAs that are differentially expressed in body fat or adipose tissue (AT) in individuals who are obese. The human body consists of the insulating, energy-storing white AT (WAT) and thermogenic brown AT (BAT). Visceral WAT around the intra-abdominal organs and subcutaneous WAT under the skin are fundamental in energy homeostasis, whereas energy-burning and heat-generating BAT is found around the shoulders and ribs. 20 In obesity, BAT undergoes molecular and morphological changes effectively 'whitening' to resemble WAT, thus impacting on metabolic dysfunction and inflammation. 21 Brown fat lncRNA 1 (Blnc1) is a conserved BAT-enriched nuclear lncRNA that acts as a scaffold to form ribonucleoprotein complexes with several transcription factors.
In BAT, Blnc1 interacts with thermogenic transcription factors including EBF2 and ZBTB7B. [21][22][23] Zhao et al. found high expression of Blnc1 in high-fat diet (HFD)-fed obese mice, which on conditional inactivation accelerated BAT whitening, fibrosis and tissue inflammation. 21 Transgenic expression of Blnc1 rescues these effects by silencing pro-inflammatory cytokines interleukin 6 (IL-6) and CCL5 and promoting lipid metabolism through a ribonucleoprotein complex with ZBTB7B. 21 Additionally, Tang et al. find that not only is overexpression of Blnc1 in WAT protective against HFD-induced obesity but through remodelling of mitochondrial biogenesis is able to improve insulin sensitivity. 24 There is increasing interest in the lipid oxidation-mediated thermoregulatory properties of BAT, and understanding the role of lncRNAs in this process may be key in harnessing this potential for therapeutic treatment of obesity. 20,24 RNA-sequencing analysis of human AT has provided a catalogue of over 3,000 lncRNAs, of which approximately 900 were specifically detected in BAT, which in humans is associated with improved metabolic health. Of these BAT-specific lncRNAs, the expression of lnc-dPRM16 was associated with the expression of BAT-selected markers in vivo and its knockdown impaired differentiation of brown adipocytes. 25 Furthermore, BAT H19 expression, which in the mouse decreases with obesity, has been reported to be inversely correlated with body mass index (BMI) in humans. 26 H19 is implicated in several obesity-associated inflammatory conditions. H19 expression is reduced in adipocytes from individuals with obesity, and its overexpression in mice was found to have a protective effect against dietinduced obesity and improved insulin sensitivity in BAT but not WAT tissue. 26 As BAT 'whitening' in obesity impacts on metabolic dysfunction and inflammation, 21 there is increasing interest in the thermoregulatory properties of BAT, and understanding the role of lncRNAs may be key in tackling obesity and obesity-associated conditions.
In abdominal subcutaneous WAT, 1,268 lncRNAs were found to be differentially expressed in children with obesity, compared with age-and gender-matched children without obesity. Of these, the expression level of lncRNA RP11-20G13.3 was positively associated with BMI, waist circumference, waist-to-hip ratio, fasting insulin, lowdensity lipoprotein cholesterol, high-sensitivity C-reactive protein and leptin. On the contrary, the expression level of the lncRNA GYG2P1 was negatively associated with BMI, waist circumference, fasting insulin and triglycerides. 27 In a separate study, lncRNA u001kfc.1 was identified as differentially downregulated in visceral WAT from individuals with obesity, compared with those without, 28 and was predicted to be a potential cis-regulator for phosphatase and tensin or PTEN homolog.
In addition to AT, differential expression of lncRNAs has been reported in the blood of individuals classed as obese, suggesting that the obesity-associated differences in lncRNA expression will affect Expression is negatively associated with BMI, waist circumference, fasting insulin and triglycerides.
Liu et al. 27 lnc-dPrm16 Loss of function markedly represses brown adipogenesis whereas in WAT results in reduced expression of pan-adipogenic markers and BAT-selective markers. Also reduces expression of Prdm16 in WAT but not in BAT.
Sun et al. 29 lncRNA-p5549 LncRNA expression is negatively correlated with BMI, waist circumference, waist-to-hip ratio and fasting insulin.
Sun et al. 29 MIST Knockdown in adipose tissue macrophages increases M1-associated genes, whereas gain of function reduces genes associated with inflammation and lipid metabolism. Epigenetically regulates pro-inflammatory genes through an interaction with PARP1. Diabetes ANRIL Methylation of ANRIL promoter is reduced in subcutaneous adipose; ANRIL expression is induced by high glucose and diabetes and is positively correlated with pro-inflammatory factors. ANRIL is also transcriptionally regulated by NF-κB-meditated TNFα.

SRA1
Overexpression increases insulin-stimulated uptake of glucose and represses proinflammatory chemokine CCL2; however, SRA−/− mice are protected from dietinduced obesity, are more sensitive to insulin and are less inflammatory with reduced expression of TNFα, CCL2 and IL-6.
Xu et al. 49  and lncRNA-p19461, was negatively correlated with BMI, waist circumference, waist-to-hip ratio and fasting insulin. 29 Furthermore, the circulatory expression of lncRNA-p19461 was significantly increased in eight individuals with obesity following a 12-week diet-induced weight loss programme. 29 These findings support the notion that the effect of obesity on lncRNA expression may extend to peripheral tissues with implications for age-related conditions influenced by obesity-associated chronic inflammation.

| LncRNAs AND OBESITY-ASSOCIATED CHRONIC INFLAMMATORY DISEASE
Obesity-associated chronic inflammation largely features the energystoring endocrine organ AT. AT is not only recognized for its endocrine role in regulating energy homeostasis but also in the regulation of immunity and inflammation. 30 AT is largely composed of fat cells known as adipocytes, which store energy as fat. Increased adiposity directly impacts AT remodelling as adipocytes overaccumulate to accommodate an increased demand for lipid storage. This can have severe effects on lipogenesis, lipolysis and AT adipokine responses leading to metabolic stress, adipocyte cell death and hypoxia. These events culminate in the activation of JNK and NF-κB signalling pathways, which regulate the production and release of pro-inflammatory signalling molecules known as cytokines, contributing to an inflammatory AT microenvironment and their accumulation in multiple tissues including skeletal muscle. [30][31][32] LncRNAs are now being recognized as contributing intermediates in obesity and inflammation, although the exact molecular processes involving lncRNAs in obesity-associated inflammatory conditions is still unclear. Here, with the focus on obesity-associated chronic inflammatory diseases, this section will highlight the fundamental lncRNAs involved in AT remodelling and those that may contribute to obesity-associated inflammation.

| Insulin resistance and type 2 diabetes (mellitus)
Obesity-linked insulin resistance leads to increased lipolysis, elevated plasma fatty acid levels and reduced tissue glucose transport, which, coupled with simultaneous dysfunction of pancreatic β-cells, may result in the development of type 2 diabetes (T2D). 33 AT becomes less responsive to insulin during obesity as adipocytes become enlarged (hypertrophic) and more inflammatory. However, the mechanism linking insulin resistance to inflammation remain unclear. There is evidence that low-grade inflammation may play a role in the development of insulin resistance and pathogenesis of T2D and its co-morbidities, 34,35 but a reverse causation has also been suggested whereby insulin resistance and dysregulation of metabolic control can lead to low-grade inflammation and contribute to pancreatic β-cell dysfunction, and hence glycaemic control, in T2D. 36,37 However, the use of anti-inflammatory compounds (salicylic acid, salsalate and specific antagonists against pro-inflammatory molecules such as IL-1 and TNFα) as potential antidiabetic treatments in human clinical trials has produced small or modest fasting glucose and HbA1c-lowering effects, which were a consequence of improved β-cell function (possibly as a result of a decrease in islet inflammation), but had no effect on peripheral insulin resistance. [38][39][40][41][42][43][44] As such, lncRNAs are now gathering interest as potential alternative therapeutic targets.
associated insulin resistance has involved increasing expression of adiponectin and its receptors. 47 Further work is required to fully understand the mechanisms by which these ASMER-lncRNAs impact upon adiponectin, and it remains yet to be seen whether these may have a therapeutic potential in obesity and insulin resistance.
The steroid receptor RNA activator 1 (SRA1) was the first steroid receptor coactivator lncRNA discovered over 20 years ago. 48 The The antisense noncoding RNA in the INK4 locus, ANRIL, is expressed from the 9p21 locus, which is frequently mutated containing several diabetes-associated and age-related disease polymorphisms. 51 CpG methylation marks in the ANRIL promoter in umbilical cord tissue at birth was a predictor of increased adiposity in childhood. 52 The ANRIL promoter in subcutaneous AT of adults with obesity also has reduced methylation, compared with those who are lean. 52 Additionally, ANRIL is reportedly induced by high glucose and diabetes in retinal endothelial cell lines. 55 Although there is limited knowledge in the context of adiposity, ANRIL's role in inflammation is well developed, and its expression is positively correlated with pro-inflammatory factors. In human endothelial cells, ANRIL is regulated by NF-κBmeditated TNFα, which induces ANRIL expression. Inflammatory markers were dysregulated on silencing of ANRIL, which was shown to be necessary in YY1 transcriptional regulation at the IL-6 and IL-8 promoters. 56 Given that ANRIL expression correlates with obesity and diabetes, as well as its sensitivity to glucose and TNFα, together with its influence on downstream inflammatory factors, ANRIL may also have a contributing role in obesity-associated inflammation, which remains to be fully investigated.

Degirmenci et al. identified 343 lncRNAs in adipocytes that
responded to insulin stimulation of which 80 were superenhancer lncRNAs involved in energy metabolism. 57 Enhancer RNAs are thought to be important for recruitment of RNA polymerases to the promoter of neighbouring genes and to influence the threedimensional architecture of DNA and chromatin-chromatin interactions ( Figure 2). 58 It is believed these enhancer RNAs may facilitate and stabilize chromatin loops acting as tethers that allow them to influence genes in cis on the same chromosome as well as on other chromosomes in trans (Figure 2A,B). The adipose-specific insulin responsive lncRNA (lncASIR) was identified as one such superenhancer lncRNA containing several binding sites for PPARγ, an adipogenesis master regulator. CRISPRi-mediated silencing of lncASIR resulted in the downregulation of several metabolic pathways downstream of insulin signalling including PPAR and adipocytokine signalling as well as lipolysis. Overexpression of this lncRNA was unable to rescue these effects, suggesting that lncASIR transcription from its endogenous locus drives its functionality. 57 Unfortunately, the study does not mention the genes under adipocytokine signalling, although unsurprisingly supplementary data find that leptin is particularly responsive to insulin, which is important for lipolysis and is also reportedly regulated by the PPARγ signalling pathway. 59 Adiposity-associated inflammation in AT is well correlated with More recently, RNA-seq analysis of skeletal muscle cells has identified 147 differentially expressed lncRNAs that potentially contribute to palmitic acid-induced insulin resistance. 65 Given the importance of skeletal muscle tissue in glucose utilization and insulin sensitivity, lncRNAs that have been implicated in mediating changes to skeletal muscle mass (Section 3.2) may also play important roles in regulating muscle metabolic function and in turn insulin sensitivity.

| Sarcopenia and skeletal muscle atrophy
Sarcopenia is the decline of skeletal muscle mass and strength with age, which is often associated with increased muscle atrophy and accompanied by an increased systemic inflammatory burden 66 and accumulation of AT. 67 Furthermore, it is known that sarcopenia is more prevalent in persons with increased adiposity. 68 This is believed to be due to the antimyogenic and muscle atrophic activity of several obesity-associated cytokines and adipokines. Indeed, it has been shown that obese, but not normal-weight, subcutaneous AT secretome impairs the myogenesis of old myoblasts. 69 Also, AT in older individuals with increased adiposity secretes differential amounts of adipokines that can impact the metabolic health and insulin sensitivity of older skeletal muscle tissue. 70  Evidence for MALAT1's role in the regulation of skeletal muscle is conflicting. On the one hand, MALAT1 expression has been demonstrated to increase during human primary myotube differentiation, remaining elevated up to Day 6. 80 Additionally, MALAT1 knockdown in C 2 C 12 cells has been associated with a small reduction in myogenin and reduced proliferation, suggesting that MALAT1 may positively regulate myogenesis. [80][81][82] In support of this, myostatin, a negative regulator of muscle mass, was shown to suppress MALAT1 expression. 80  Future studies investigating the role of such lncRNAs with increased adiposity and inflammation will also be important in identifying their potential roles in the regulation of sarcopenia.
Of the lncRNAs that have been associated with muscle ageing, Gm17281 (also referred to as Chronos) was found to be significantly increased with age in the skeletal muscle of mice, promoting atrophy mediated by repression of Bmp7, a positive regulator of hypertrophic gene expression. 84 Critically, a mean 42% increase in myofiber cross sectional area was observed in vivo following 14 days of siRNA treatment, an effect similar to that seen following myostatin inhibition. 84 In contrast, the expression of muscle anabolic regulator 1 (MAR1) in skeletal muscle declines with age in mice. 85  In addition to age, MAR1 was regulated by other external stimuli; its expression decreased with muscle unloading and was restored with reloading. 85 Other lncRNAs have also been demonstrated to respond to alterations in load. In a comprehensive study, Hitachi et al. utilized eight different animal models to investigate the impact of both hypertrophy and atrophy on skeletal muscle lncRNA expression. 86 Of note, this study highlighted the varied regulation of lncRNA expression depending on the type of model used, in addition to identifying Gtl2, IG-DMR and DUM1 as potentially important lncRNAs mediating hypertrophy. 86 In a similar study, the novel atrophy-related lncRNA-1 (Atrolnc-1) was upregulated in the skeletal muscle of murine models of muscle wasting. 87 Furthermore, Atrolnc-1 was demonstrated to bind A20 binding inhibitor of NF-κB-1 (ABIN-1) in the cytoplasm of C 2 C 12 myotubes, impairing its function as an inhibitor of NF-κB. As a result, Atrolnc-1 appears to facilitate an NF-κB-mediated upregulation of MuRF-1 expression, resulting in increased proteolysis. In support of these in vitro findings, Atrolnc-1 knockout mice exhibit skeletal muscle hypertrophy, whereas overexpression results in atrophy, again associated with upregulated MuRF-1 expression. 87

| Osteoarthritis
Obesity-mediated chronic low-grade inflammation is associated with dysregulated innate immune system activity. The innate immune system is the first line of defence utilizing leukocytes, which recognize pathogen or damage-associated molecular patterns and activate a cascade of pro-inflammatory pathways through pattern-recognition receptors. 93,94 Leukocytes secrete pro-inflammatory cytokines, which further promotes the pro-inflammatory secretory environment leading to increases in TNFα, IL-1β, IL-6, IL-8, leptin and growth hormone. 95

| Rheumatoid arthritis
RA is a chronic inflammatory autoimmune disease where abdominal adiposity is prevalent amongst 20%-50% of patients. 108 Immune dysfunction in RA leads to destruction of bone and cartilage, immune cell infiltration and inflammation. 109 Several lncRNAs have been recognized to influence inflammatory pathways such as NF-κB signalling, p38 MAPK and toll-like receptor pathways in RA. 109 Although the precise mechanisms are poorly defined, especially in the context of obesity, the epigenetic regulation of the synovial RA fibroblast phenotype is considered to be central in mediating the inflammatory and autoimmunity RA joint pathology. 110 Unsurprisingly, MALAT1 has also been identified to regulate synovial fibroblast proliferation and inflammation in RA. In RA synovial tissue, MALAT1 expression is found to be downregulated.
Additionally, in contrast to the previously detailed findings in OA, silencing of MALAT1 in RA fibroblast-like synoviocytes (FLSs) results in an increase in IL-6, IL-10 and TNFα secretion and elevated proliferation. 111 Li et al. found that MALAT1 binds to the promoter of CTNNB1 regulating DNA methylation to inhibit β-catenin and thus the Wnt-signalling pathway.
The pro-adipogenic lncRNAs HOTAIR has also been implicated in RA. HOTAIR is expressed from the HOXC gene cluster on chromosome 12 and selectively binds components of the PRC2 complex including the histone methyltransferase EZH2. 12 Whereas the 5 0 region of HOTAIR associates with PRC2 proteins, the 3 0 domain also has been found to interact with the histone demethylase complex LSD1/CoREST/REST. 13 HOTAIR expression is elevated in adiposederived exosomes in individuals with obesity and is also reported in RA serum exosomes. 112,113 In RA, profiling of exosomal lncRNAs identified several differentially expressed lncRNAs including HOTAIR, MEG9, SNHG4, TUG1, NEAT1, MALAT1 and SNHG1. HOTAIR expression was found to be increased fourfold in obese RA exosomes, compared with healthy controls. Exosomal HOTAIR contributed to the migration and activation of macrophages as well as the production of matrix metalloproteinases. 113 Exosomes from adipose-derived mesenchymal stem cells are also of therapeutic interest in OA. 114 Exosomes isolated from serum and synovial fluid of patients with OA contain HOTAIR, GAS5 and PCGEM1 lncRNA transcripts, although HOTAIR and GAS5 were not significantly different compared to prearthritic controls. 115 However, as those patients who were prearthritic controls had also presented with incidental knee pain, it is difficult to dissect the functional significance of HOTAIR in the context of OA. The exact implications of HOTAIR in adipose-derived exosomes in both RA and OA have yet to be fully explored especially with the added complexity of obesity.

| LncRNA CHALLENGES AND CLINICAL PROSPECTS
In the context of obesity-associated inflammation, it will be important to distinguish between lncRNAs that are simply associated with increased adiposity and those that are implicated in mediating a chronic low-grade inflammatory obese state, particularly as lncRNAs have the potential to be the next generation of biomarkers and therapeutic targets owing to their tissue-specific nature of expression. 116 However, the functional study of lncRNAs is not without its challenges. Owing to their poor primary sequence conservation across species, in vivo GOF and LOF studies can be nonpredictive. However, in some cases, it is thought that lncRNA functional conservation is geared towards the maintenance of genomic position (synteny) rather than the transcript itself. 94,117,118 Importantly, it has been reported that around 10% of human lncRNAs associated with the innate immune inflammatory response have syntenic versions in the mouse. 74 Therefore, a future focus on syntenic lncRNAs, such as the aforementioned IL7-AS, 94 would give the greatest opportunity for in vivo validation studies to translate to humans, alongside LOF studies in primary human cells.
Clinical trials involving lncRNAs are largely diagnostic and predominantly in the cancer field, where lncRNAs are being examined as biomarkers of disease state or prognostic markers. To date, PCA3 is the only lncRNA to have gained biomarker approval from the Food and Drug Administration for detecting human prostate cancer. 119,120 The length of lncRNA sequences and their complex secondary and tertiary structures have added complexity to pharmacological approaches where much is yet to be determined. 121 However, in recent years, drug classes have broadened to include RNAi-based therapeutics, many of which show great promise having reached preclinical stages for some cancer lncRNA-targeted therapeutics. 120 Many of these RNAi approaches have been demonstrated in animal models against protein-coding targets and include locked nucleic acid GapmeRs (LNA) and antisense oligonucleotides (ASO) technologies, although siRNA approaches have proven to be most successful owing to their gene targeting efficacy in cancer preclinical trials. 122 Therefore, many of the lncRNAs mentioned in this review could provide a new class of targets for RNAi-based therapeutics.
Additionally, lifestyle changes including dietary interventions and exercise have long been advocated as measures to tackle the effects of adiposity on age-related inflammatory conditions. Indeed, lncRNAs linked to weight loss, which show promising mechanistic relevance, have been identified such as lncRNA-p19461. 29 Coupling both lifestyle changes and targeting of lncRNAs in various obesity-associated inflammatory conditions may be of therapeutic benefit. Furthermore, determining their mode of action and understanding the lncRNA commonalities that regulate obesity-related inflammatory processes across different conditions could identify lncRNA-mediated targets that are suitable for therapeutic intervention.

| CONCLUSION
Our understanding of the role of lncRNAs in mediating obesityassociated inflammatory disease is very much in its infancy. However, a growing number of lncRNAs have been identified as differentially expressed in the obese state, and several have been implicated as regulators of AT and skeletal muscle mass and obesity-associated inflammatory pathways. Therefore, determining the mode of action of these disease-associated lncRNAs will be insightful and potentially clinically relevant, as will more extensive tissue expression profiling in humans to fully determine their functional roles.
ACKNOWLEDGEMENT S. W. J. and S. N. W. are supported by Versus Arthritis (21812).