Obese Adipose Tissue Research Articles

Similarities in B Cell Defects between Aging and Obesity.

The aging population is increasing worldwide, and there is also an increase in the aging population living with overweight and obesity, due to changes in lifestyle and in dietary patterns that elderly individuals experience later in life. Both aging and obesity are conditions of accelerated metabolic dysfunction and dysregulated immune responses. In this review, we summarize published findings showing that obesity induces changes in humoral immunity similar to those induced by aging and that the age-associated B cell defects are mainly due to metabolic changes. We discuss the role of the obese adipose tissue in inducing dysfunctional humoral responses and autoimmune Ab secretion.

Adipose Tissues Have Been Overlooked as Players in Prostate Cancer Progression

Obesity is a common risk factor in multiple tumor types, including prostate cancer. Obesity has been associated with driving metastasis, therapeutic resistance, and increased mortality. The effect of adipose tissue on the tumor microenvironment is still poorly understood. This review aims to highlight the work conducted in the field of obesity and prostate cancer and bring attention to areas where more research is needed. In this review, we have described key differences between healthy adipose tissues and obese adipose tissues, as they relate to the tumor microenvironment, focusing on mechanisms related to metabolic changes, abnormal adipokine secretion, altered immune cell presence, and heightened oxidative stress as drivers of prostate cancer formation and progression. Interestingly, common treatment options for prostate cancer ignore the adipose tissue located near the site of the tumor. Because of this, we have outlined how excess adipose tissue potentially affects therapeutics’ efficacy, such as androgen deprivation, chemotherapy, and radiation treatment, and identified possible drug targets to increase prostate cancer responsiveness to clinical treatments. Understanding how obesity affects the tumor microenvironment will pave the way for understanding why some prostate cancers become metastatic or treatment-resistant, and why patients experience recurrence.

Macrophage heterogeneity in cardiometabolic disease

Abstract Metabolic diseases such as obesity and atherosclerosis are characterised by chronic inflammation that leads to the accumulation of immune cells in affected organs. Macrophages in the obese adipose tissue and the atherosclerotic plaque show transcriptional, phenotypic and functional heterogeneity. The accumulation of CD11c+ macrophages in atherosclerosis and obesity suggests the presence of conserved macrophage phenotypes in metabolic tissues. We aimed to characterise shared and distinct features of monocytes and macrophages in the aorta and adipose tissue in the context of metabolic disease using single-cell techniques. Single-cell RNA sequencing of the blood, aorta and visceral adipose tissue during a time course of metabolic disease progression (steady state, 12w western diet, 18w western diet) and data integration with murine aortic and adipose tissue community datasets revealed conserved and tissue specific features of metabolic disease. Resident macrophages in the aorta and adipose tissue displayed tissue specific transcriptional programs, highlighting that cell maintenance and function of tissue resident macrophages differ between metabolic tissues. Further, macrophages in the aorta and adipose tissue undergo disease associated compositional changes. For example, we uncovered distinct CD11c+ macrophage subsets that are conserved in the aorta and adipose tissue across multiple metabolic disease models and share core transcriptional signatures between both metabolic tissues. However, CD11c+ macrophage subsets showed tissue specific dynamics during metabolic disease progression. Overall, our analysis underscores that tissue niche affects macrophage composition as well as activation and transcriptional regulation patterns. Understanding similarities and differences between the two tissues will be important to inform identification of new therapeutic targets for cardiometabolic diseases.

Pericardial adipose tissue (PAT) as a cell model to assess patient responsiveness to docosahexaenoic acid (DHA) and eicopentaenoic acid (EPA)

Abstract Background The abundance of epicardial (EAT) and pericardial adipose tissue (PAT) is associated with several cardiac risk factors and a higher carotid intima-media thickness, with a potential contributory role to the development of atherosclerosis and coronary artery disease (CAD). Under conditions promoting obesity, both epicardial and pericardial adipose tissue undergo a metabolic shift, acquiring an inflammatory and pro-atherogenic phenotype. Addressing dysmetabolism and inflammation associated with EAT and PAT are a promising and innovative therapeutic approach for preventing coronary atherosclerosis. Recent data have highlighted a noteworthy association between the abundance of adipose tissue n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as their ratio to the omega-6 FA arachidonic acid (AA), with a lower risk of myocardial infarction. Purpose To develop an efficient method for isolation of adipocytes from human PAT and evaluation of adipocyte response to DHA and EPA. Methods PAT samples were collected from 9 CAD patients, undergoing coronary artery bypass graft surgery and immediately processed before to assess more than 50 experimental conditions. Isolated adipocytes were morphologically and molecularly characterized. Cell responsiveness was evaluated by cell exposure to inflammatory stimuli, with or without variable amounts of DHA, EPA, or AA assessing a spectrum of gene expressions and pro-inflammatory functional activities. Results Pure cultures of pericardial adipocytes exhibited prolonged viability (beyond 72 hours). and retained responsiveness to pro-inflammatory and lipolytic stimuli, while also showing the capacity to activate the insulin signalling pathway. Cell exposure to DHA or EPA resulted in a downregulation of messenger (m)RNA expression for monocyte chemoattractant protein (MCP)-1, interleukin (IL)-6 and metalloproteinase (MMP)-9 (p<0.05) and in upregulation of uncoupling protein-(UCP)-1, UCP-2 and peroxisome proliferator-activated receptor (PPAR)γ (p< 0.05) (Figure 1). In line with mRNA expression, a significant reduction in both cytokines and MMP-9 protein release was observed (p<0.05) (Figure 2). These effects paralleled a significant incorporation of DHA and EPA into total cell lipids (p<0.05). Functionally, the cell supernatant from DHA- or EPA-conditioned cells displayed diminished ability to attract monocytes in chemotaxis assays. AA exhibited no such activities. Conclusion(s) In a novel cellular model of isolated and cultured adipocytes from PAT, DHA and EPA attenuated the inflammatory and dysmetabolic characteristics of this cardiac adipose tissue.

Insights into the Sex-Related Effects of Dietary Polyphenols and Metabolic Disruptors on Inflammatory and (Neuro) Endocrine Pathways in Obesity: The HEAL Project.

this study was performed under the umbrella of the Health Extended Alliance for Innovative Therapies, Advanced Lab Research, and Integrated Approaches of Precision Medicine (HEAL ITALIA) partnership and funded under the National Recovery and Resilience Plan, Mission 4 Component 2 Investment 1.3, and by the European Union. the overall objective of the HEAL project is to identify innovative and effective therapeutic approaches to reduce disease burden. The present research falls within Spoke 7: Prevention Strategies: Integrated and gender medicine approaches for prevention strategies based on environmental, lifestyle, and clinical biometric data. Obesity represents a primary risk factor worldwide for the onset of numerous life-threatening diseases, including metabolic, cardiovascular, and neurological diseases. Environmental and gender-related factors influence obesity development. However, the molecular mechanisms underlying the effects of those agents on different organs of the human body are not fully understood yet. here, we present a study protocol aimed at shedding light on (i) the complex interplays among adipose tissue, brain and gut in obesity, and (ii) the effects of specific dietary components and environmental metabolism-disrupting compounds on those interactions. To this purpose, we combined ex vivo, in vitro, and in vivo approaches to gain additional knowledge about the molecular mechanisms underlying connections between organs. the data provided by this study will contribute to defining new targets for therapeutic and/or preventive interventions, thereby allowing more personalized approaches to nutrition.

Metabolic syndrome.

The metabolic syndrome (MetS) is a multiplex modifiable risk factor for cardiovascular disease, type 2 diabetes mellitus and other health outcomes, and is a major challenge to clinical practice and public health. The rising global prevalence of MetS, driven by urbanization, sedentary lifestyles and dietary changes, underlines the urgency of addressing this syndrome. We explore the complex underlying mechanisms, including genetic predisposition, insulin resistance, accumulation of dysfunctional adipose tissue and ectopic lipids in abdominal obesity, systemic inflammation and dyslipidaemia, and how they contribute to the clinical manifestations of MetS. Diagnostic approaches vary but commonly focus on abdominal obesity (assessed using waist circumference), hyperglycaemia, dyslipidaemia and hypertension, highlighting the need for population-specific and phenotype-specific diagnostic strategies. Management of MetS prioritizes lifestyle modifications, such as healthy dietary patterns, physical activity and management of excess visceral and ectopic adiposity, as foundational interventions. We also discuss emerging therapies, including new pharmacological treatments and surgical options, providing a forward-looking perspective on MetS research and care. This Primer aims to inform clinicians, researchers and policymakers about MetS complexities, advocating for a cohesive, patient-centred management and prevention strategy. Emphasizing the multifactorial nature of MetS, this Primer calls for integrated public health efforts, personalized care and innovative research to address this escalating health issue.

Decoding visceral adipose tissue molecular signatures in obesity and insulin resistance: a multi-omics approach.

Obesity-associated insulin resistance (IR) is responsible for considerable morbidity and mortality globally. Despite vast genomic data, many areas, from pathogenesis to management, still have significant knowledge gaps. We aimed to characterize visceral adipose tissue (VAT) in obesity and IR through a multi-omics approach. We procured data on VAT samples from the Gene Expression Omnibus (GEO) for the following two groups: 1) populations with obesity (n = 34) versus those without (n = 26); and 2) populations with obesity and IR (n = 15) versus those with obesity but without IR (n = 15). Gene set enrichment, protein-protein interaction network construction, hub gene identification, and drug-gene interactions were performed, followed by regulatory network prediction involving transcription factors (TFs) and microRNAs (miRNAs). Interleukin signaling pathways, cellular differentiation, and regulation of immune response revealed a significant cross talk between VAT and the immune system. Other findings include cancer pathways, neurotrophin signaling, and aging. A total of 10 hub genes, i.e., STAT1, KLF4, DUSP1, EGR1, FOS, JUN, IL2, IL6, MMP9, and FGF9, 24 TFs, and approved hub gene-targeting drugs were obtained. A total of 10 targeting miRNAs (e.g., hsa-miR-155-5p, hsa-miR-34a-5p) were associated with obesity and IR-related pathways. Our multi-omics integration method revealed hub genes, TFs, and miRNAs that can be potential targets for investigation in VAT-relatedinflammatory processes and IR, therapeutic management, and risk stratifications.

Low-intensity pulsed ultrasound improves metabolic dysregulation in obese mice by suppressing inflammation and extracellular matrix remodeling

Chronic inflammation in white adipose tissue is crucial in obesity and related metabolic disorders. Low-intensity pulsed ultrasound (LIPUS) is renowned for its anti-inflammatory effects as a non-invasive treatment, yet its precise role in obesity has been uncertain. Our study investigates the therapeutic effect of LIPUS and its underlying mechanism on obesity in mice, thereby offering a novel approach for non-invasive treatment of obesity and associated metabolic disorders for human. Male C57BL/6J mice aged 10 weeks were fed a high-fat diet (HFD) for 8 weeks to establish obesity model, then underwent 8 weeks of LIPUS (frequency: 1.0 MHz, duty cycle: 20 %, Isata: 58–61 mW/cm2, 20 min per day) stimulation of the epididymal white adipose tissue. Fat and lean mass were measured using nuclear magnetic resonance (NMR), while energy homeostasis was evaluated using metabolic cages. Insulin resistance was assessed using glucose tolerance tests (GTT) and insulin tolerance tests (ITT). Regulatory mechanisms were explored using RNA sequencing. Results showed that LIPUS significantly reduced obesity markers in obese mice, including body and adipose tissue weight, and improved insulin resistance, without affecting food intake. RNA sequencing showed 250 up-regulated and 351 down-regulated genes between HFD-LIPUS group and HFD-Sham group, suggesting anti-inflammatory action. Quantitative PCR confirmed reduced pro-inflammatory gene expression and macrophage infiltration in eWAT. Gene set enrichment analysis showed decreased NF-κB signaling and extracellular matrix-receptor interactions in LIPUS-treated mice. Thus, LIPUS effectively mitigates metabolic dysregulation in HFD-induced obesity through inflammation suppression and extracellular matrix remodeling, which provides a potential physical therapy for metabolic syndrome in clinic.

8729 Role of PARP1 in Macrophage-dependent Regulation of Adipose Tissue Inflammation, Adipogenesis, and Diet-induced Obesity

Abstract Disclosure: J. Zhu: None. R. Gupte: None. T.S. Nandu: None. W.L. Kraus: None. D. Huang: None. Adipose tissue macrophages play a significant role in maintaining adipose tissue homeostasis, as well as promoting chronic low-grade inflammation during the development of obesity and metabolic dysfunction. However, the crosstalk between macrophages and adipocytes, especially how macrophages affect adipogenesis in obese adipose tissue, are still poorly understood. We have investigated the function of PARP1 in the control of adipogenesis by using an adipocyte precursor-specific Parp1 knockout mouse model. Here, to investigate the role of macrophage PARP1 in regulating adipogenesis, we deleted Parp1 in the myeloid lineage by crossing Parp1loxp/loxp mice with LysMCre mice (Parp1 cKOLysMCre). Macrophages-specific knockout of Parp1 dramatically reduced LPS-induced pro-inflammatory gene expression in bone marrow-derived macrophages (BMDMs). To explore whether macrophage-specific Parp1 knockout affects adipocyte differentiation, we treated the primary preadipocytes from stromal vascular fraction (SVF) of white adipose tissue with the conditioned medium from LPS-stimulated control or Parp1 cKOLysMCre BMDMs throughout a 6-day period of differentiation. We observed that exposure of preadipocytes to the conditioned medium of Parp1 cKOLysMCre macrophages promoted adipogenesis by Oil Red O staining, as well as by monitoring the expression of key proadipogenic marker genes (e.g., Adipoq and Fabp4) by RT-qPCR. To further investigate the role of macrophage-specific deletion of Parp1 in metabolic outcomes, we fed the Parp1 cKOLysMCre mice with a high fat diet for 12 weeks. The knockout mice exhibited a significant increase in body weight compared to the control mice. Interestingly, we observed a reduction of the total number of macrophages resident in the adipose tissue from macrophage-specific Parp1 knockout mice. To explore the underlying mechanism, we performed single cell RNA-seq for adipose tissue macrophages using sorted SVF cells collected from HFD-fed mice. The results demonstrated dramatic reductions in macrophage M1 marker genes and pro-inflammatory transcription factors in Parp1 cKOLysMCre mice. Taken together, our study suggests that Parp1 knockout in macrophages selectively affects the recruitment and pro-inflammatory activation of macrophages, as well as adipocyte differentiation in adipose tissue. Importantly, despite the decreased adipose tissue inflammation, macrophage-specific Parp1 knockout enhanced adipogenesis, which leads to obesity in mice.This work was supported by a grant from the NIH/NIDDK (R01 DK069710) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment, to W.L.K., and a grant from NSFC (82270929) to D.H. Presentation: 6/1/2024

Adipose tissue-derived extracellular vesicles aggravate temporomandibular joint osteoarthritis associated with obesity.

Temporomandibular joint osteoarthritis (TMJ OA) is a major disease that affects maxillofacial health and is characterised by cartilage degeneration and subchondral bone remodelling. Obesity is associated with the exacerbation of pathological manifestations of TMJ OA. However, the underlying mechanism between adipose tissue and the TMJ axis remains limited. To evaluate the effects of obesity and the adipose tissue on the development of TMJ OA. The obesity-related metabolic changes in TMJ OA patients were detected by physical signs and plasma metabolites. The effects of adipose tissue-derived EVs (Ad-EVs) on TMJ OA was investigated through histological and cytological experiments as well as gene editing technology. Alterations of Ad-EVs in obese state were identified by microRNA-seq analysis and the mechanism by which EVs affect TMJ OA was explored in vitro and in vivo. Obesity and the related metabolic changes were important influencing factors for TMJ OA. Ad-EVs from obese mice induced marked chondrocyte apoptosis, cartilage matrix degradation and subchondral bone remodelling, which exacerbated the development of TMJ OA. Depletion of Ad-EVs secretion by knocking out the geranylgeranyl diphosphate synthase (Ggpps) gene in adipose tissue significantly inhibited the obesity-induced aggravation of TMJ OA. MiR-3074-5p played an important role in this process . Our work unveils an unknown link between obese adipose tissue and TMJ OA. Targeting the Ad-EVs and the miR-3074-5p may represent a promising therapeutic strategy for obesity-related TMJ OA. High-fat-diet-induced obesity aggravate the progression of TMJ OA in mice. Obese adipose tissue participates in cartilage damage through the altered miRNA in extracellular vesicles. Inhibition of miR-3074-5p/SMAD4 pathway in chondrocyte alleviated the effect of HFD-EVs on TMJ OA.

Increased expression of IL-1β in adipose tissue in obesity influences the development of colon cancer by promoting inflammation

Increased expression of IL-1β in adipose tissue in obesity influences the development of colon cancer by promoting inflammation

Cardiometabolic Crossroads: Obesity, Sleep-Disordered Breathing, and Epicardial Adipose Tissue in Heart Failure with Preserved Ejection Fraction – A Mini-Review

Cardiometabolic Crossroads: Obesity, Sleep-Disordered Breathing, and Epicardial Adipose Tissue in Heart Failure with Preserved Ejection Fraction – A Mini-Review

Long-term exercise training has positive effects on adipose tissue in overweight or obesity.

Long-term exercise training has positive effects on adipose tissue in overweight or obesity.

Untargeted Metabolomics and Gut Microbiota Modulation Study of Fermented Brown Rice for Obesity.

Obesity or excess adipose tissue mass increases the risk of heart disease, hypertension, and diabetes. Obesity might be prevented by consuming plant-based probiotic fermented foods. This study aimed to determine whether adding Pediococcus acidilactici MNL5 to fermented brown rice (FBR) enhances its metabolites, lipase activity, and antioxidant efficiency. UHPLC-Q-TOF-MS/MS analysis revealed significant changes in untargeted metabolite profiles, while, compared with those of raw brown rice (RBR), FBR contained more antioxidant and lipase inhibitors. We evaluated the FBR in HFD (high-fat-diet)-induced obese mice by employing biochemical, histological, gut microbiome, and serum metabolomics approaches. FBR MD (250 mg/kg) decreased body weight (BW) and fat content compared with RBR. With subsequent FBR MD, mice fed a HFD may have reduced serum lipid levels. A HFD with a mid-dose FBR improved the gut microbiota diversity, composition, and structure; reduced the abundance of obesity-related genera such as Helicobacter, Clostridium, and Desulfovibrio; and promoted the abundance of beneficial genera such as Bifidobacterium, Akkermansia, and Lactobacillus, which are inversely correlated with BW, total cholesterol, TG, LDL-C, and HDL-C. In addition, FBR MD has been associated with increased levels of palmitic acid, EPA, oleic acid, α-linolenic acid, indole, dodecanoic acid, and amino acids. FBR, in its entirety, has exhibited promise as a functional material for ameliorating obesity.

Obesity-derived macrophages upregulate TNF-α to induce apoptosis in glial cell via the NF-κB/PHLPP1 axis

Macrophages in obese adipose tissue have been shown to damage nerve fibers, however, the mechanism underlying how macrophages cause glial cell damage remains unknown. This study aimed to characterize the mechanism by which macrophages induce apoptosis in glial cell during obesity formation in mice by single-nucleus RNA sequencing (snRNA-seq). Cells obtained from paraepididymal adipose tissue in obese mice underwent snRNA-seq. Eighteen different clusters were identified, and 12 cell types were annotated, including glial cells, macrophages, and fibroblasts. There was a negative correlation between the number of glial cells and macrophages in mouse adipose tissue during the formation of obesity. The pro-apoptotic factor PHLPP1 was identified in GO Terms. The interaction between adipose tissue glial cells and macrophages was revealed via in-depth analysis, and the cell–cell communication mechanism between the TNF-α and NF-KB/PHLPP1 axes was perfected. Apoptosis of glial cell by upregulation of TNF-α via obesity-derived macrophages and activation of the NF-κB/PHLPP1 axis. We further revealed how macrophages induce apoptosis in glial cells during obesity formation, as well as different changes in the two cell populations. This study provides valuable resources and foundations for understanding the mechanistic effects of macrophages and glial cells during obesity formation, as well as diseases and potential interventions.

Mechanistic insights into metabolic function of dynamin-related protein 1

Dynamin-related protein 1 (DRP1) plays crucial roles in mitochondrial and peroxisome fission. However, the mechanisms underlying the functional regulation of DRP1 in adipose tissue during obesity remain unclear. To elucidate the metabolic and pathological significance of diminished DRP1 in obese adipose tissue, we utilized adipose tissue–specific DRP1 KO mice challenged with a high-fat diet. We observed significant metabolic dysregulations in the KO mice. Mechanistically, DRP1 exerts multifaceted functions in mitochondrial dynamics and endoplasmic reticulum (ER)-lipid droplet crosstalk in normal mice. Loss of function of DRP1 resulted in abnormally giant mitochondrial shapes, distorted mitochondrial membrane structure, and disrupted cristae architecture. Meanwhile, DRP1 deficiency induced the retention of nascent lipid droplets in ER, leading to perturbed overall lipid dynamics in the KO mice. Collectively, dysregulation of the dynamics of mitochondria, ER, and lipid droplets contributes to whole-body metabolic disorders, as evidenced by perturbations in energy metabolites. Our findings demonstrate that DRP1 plays diverse and critical roles in regulating energy metabolism within adipose tissue during the progression of obesity.

MicroRNA Profile of Mouse Adipocyte-Derived Extracellular Vesicles.

The post-transcriptional control of gene expression is a complex and evolving field in adipocyte biology, with the premise that the delivery of microRNA (miRNA) species to the obese adipose tissue may facilitate weight loss. Cells shed extracellular vesicles (EVs) that may deliver miRNAs as intercellular messengers. However, we know little about the miRNA profile of EVs secreted by adipocytes during postnatal development. Here, we defined the miRNA cargo of EVs secreted by mouse adipocytes in two distinct phases of development: on postnatal day 6, when adipocytes are lipolytic and thermogenic, and on postnatal day 56, when adipocytes have active lipogenesis. EVs were collected from cell culture supernatants, and their miRNA profile was defined by small RNA sequencing. The most abundant miRNA of mouse adipocyte-derived EVs was mmu-miR-148a-3p. Adipocyte EVs on postnatal day 6 were hallmarked with mmu-miR-98-5p, and some miRNAs were specific to this developmental stage, such as mmu-miR-466i-5p and 12 novel miRNAs. Adipocytes on postnatal day 56 secreted mmu-miR-365-3p, and 16 miRNAs were specific to this developmental stage. The miRNA cargo of adipocyte EVs targeted gene networks of cell proliferation, insulin signaling, interferon response, thermogenesis, and lipogenesis. We provided here a database of miRNAs secreted by developing mouse adipocytes, which may be a tool for further studies on the regulation of gene networks that control mouse adipocyte development.

A Preliminary Study on Factors That Drive Patient Variability in Human Subcutaneous Adipose Tissues.

Adipose tissue is a dynamic regulatory organ that has profound effects on the overall health of patients. Unfortunately, inconsistencies in human adipose tissues are extensive and multifactorial, including large variability in cellular sizes, lipid content, inflammation, extracellular matrix components, mechanics, and cytokines secreted. Given the high human variability, and since much of what is known about adipose tissue is from animal models, we sought to establish correlations and patterns between biological, mechanical, and epidemiological properties of human adipose tissues. To do this, twenty-six independent variables were cataloged for twenty patients, which included patient demographics and factors that drive health, obesity, and fibrosis. A factorial analysis for mixed data (FAMD) was used to analyze patterns in the dataset (with BMI > 25), and a correlation matrix was used to identify interactions between quantitative variables. Vascular endothelial growth factor A (VEGFA) and actin alpha 2, smooth muscle (ACTA2) gene expression were the highest loadings in the first two dimensions of the FAMD. The number of adipocytes was also a key driver of patient-related differences, where a decrease in the density of adipocytes was associated with aging. Aging was also correlated with a decrease in overall lipid percentage of subcutaneous tissue, with lipid deposition being favored extracellularly, an increase in transforming growth factor-β1 (TGFβ1), and an increase in M1 macrophage polarization. An important finding was that self-identified race contributed to variance between patients in this study, where Black patients had significantly lower gene expression levels of TGFβ1 and ACTA2. This finding supports the urgent need to account for patient ancestry in biomedical research to develop better therapeutic strategies for all patients. Another important finding was that TGFβ induced factor homeobox 1 (TGIF1), an understudied signaling molecule, which is highly correlated with leptin signaling, was correlated with metabolic inflammation. Furthermore, this study draws attention to what we define as "extracellular lipid droplets", which were consistently found in collagen-rich regions of the obese adipose tissues evaluated here. Reduced levels of TGIF1 were correlated with higher numbers of extracellular lipid droplets and an inability to suppress fibrotic changes in adipose tissue. Finally, this study indicated that M1 and M2 macrophage markers were correlated with each other and leptin in patients with a BMI > 25. This finding supports growing evidence that macrophage polarization in obesity involves a complex, interconnecting network system rather than a full switch in activation patterns from M2 to M1 with increasing body mass. Overall, this study reinforces key findings in animal studies and identifies important areas for future research, where human and animal studies are divergent. Understanding key drivers of human patient variability is required to unravel the complex metabolic health of unique patients.

Targeting IRE1α improves insulin sensitivity and thermogenesis and suppresses metabolically active adipose tissue macrophages in obesity.

Overnutrition engenders the expansion of adipose tissue and the accumulation of immune cells, in particular, macrophages, in the adipose tissue, leading to chronic low-grade inflammation and insulin resistance. In obesity, several proinflammatory subpopulations of adipose tissue macrophages (ATMs) identified hitherto include the conventional "M1-like" CD11C-expressing ATM and the newly discovered metabolically activated CD9-expressing ATM; however, the relationship among ATM subpopulations is unclear. The ER stress sensor inositol-requiring enzyme 1α (IRE1α) is activated in the adipocytes and immune cells under obesity. It is unknown whether targeting IRE1α is capable of reversing insulin resistance and obesity and modulating the metabolically activated ATMs. We report that pharmacological inhibition of IRE1α RNase significantly ameliorates insulin resistance and glucose intolerance in diet-induced obesity mice. IRE1α inhibition also increases thermogenesis and energy expenditure, and hence protects against high fat diet-induced obesity. Our study shows that the "M1-like" CD11c+ ATMs are largely overlapping with but yet non-identical to CD9+ ATMs in obese white adipose tissue. Notably, IRE1α inhibition diminishes the accumulation of obesity-induced metabolically activated ATMs and "M1-like" ATMs, resulting in the curtailment of adipose inflammation and ensuing reactivation of thermogenesis, without augmentation of the alternatively activated M2 macrophage population. Our findings suggest the potential of targeting IRE1α for the therapeutic treatment of insulin resistance and obesity.

1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity

1601-P: Regulation of Circadian Rhythmicity of Human Adipose Tissue in Obesity