Obese Adipose Tissue Research Articles

Epidemiology of Breast Cancer in Mexican Women with Obesity as a Risk Factor.

Purpose. Adipose tissue in overweight and obesity shows metabolic imbalance in the function of adipocytes and macrophages, this leads to altered regulation of hunger, lipid storage, and chronic inflammation possibly related to the development of breast cancer. Methods. The study was retrospective of 653 breast cancer patients treated at a tertiary care hospital. Histopathology, hormone receptors, grade, clinical stage, clinical biometry analysis, CEA and CA 15-3 antigens were analyzed. The analyses were performed at diagnosis and at the end of oncological treatments. Results. Mexican women studied and treated for breast cancer have an BMI of 29 from diagnosis and at the end of their cancer treatments. The average age was 52 ± 12 years, 54% in women older than 55 years. Cancer recurrence occurs in any molecular type; however, the common factor was overweight and obesity with 73% vs. 21% in normal weight patients. The most frequent tumor tissue in the population was positive hormone receptors of the luminal type (65%), HER2 (15%), and NT (15%). The analyses of macrophages/lymphocytes (M/L), CEA, and CA 15-3 antigens evaluated in women >55 and <55 years, with and without recurrence are elevated at the end of oncological treatments. Conclusions. The analysis of Mexican women with breast cancer showed a predominance of overweight and obesity at diagnosis and at the end of treatment. A relationship between obesity and cancer recurrence with a low response to treatment due to elevation in Ag CEA and CA 15-3 is suggested. The L/M ratio could be an indicator of inflammation related to adipose tissue since diagnosis.

High-refined carbohydrate diet alters different metabolic functions in female rats

A diet containing refined carbohydrate (HCD) caused obesity and white adipose tissue (WAT) abnormalities, but it is unclear if HCD is linked with other metabolic dysfunctions in female models. Thus, we assessed whether HCD results in WAT, pancreas, liver, skeletal muscle (SM) and thyroid (TH) abnormalities in female rats. Female rats were fed with HCD for 15 days and metabolic morphophysiology, inflammation, oxidative stress (OS), and fibrosis markers were assessed. HCD rats presented large adipocytes, hyperleptinemia, and WAT OS. HCD caused irregular glucose metabolism, low insulin levels, and large pancreatic isle. Granulomas, reduced glycogen, and OS were observed in HCD livers. HCD caused hypertrophy and increased in glycogen in SM. HCD caused irregular TH morphophysiology, reduced colloid area and high T3 levels. In all selected tissues, inflammation and fibrosis were observed in HCD rats. Collectively, these data suggest that the HCD impairs metabolic function linked with irregularities in WAT, pancreas, liver, SM and TH in female rats.

Regulation of Adipose Progenitor Cell Expansion in a Novel Micro-Physiological Model of Human Adipose Tissue Mimicking Fibrotic and Pro-Inflammatory Microenvironments.

The expansion of adipose progenitor cells (APCs) plays an important role in the regeneration of the adipose tissue in physiological and pathological situations. The major role of CD26-expressing APCs in the generation of adipocytes has recently been highlighted, revealing that the CD26 APC subtype displays features of multipotent stem cells, giving rise to CD54- and CD142-expressing preadipocytes. However, a relevant human in vitro model to explore the regulation of the APC subpopulation expansion in lean and obese adipose tissue microenvironments is still lacking. In this work, we describe a novel adipose tissue model, named ExAdEx, that can be obtained from cosmetic surgery wastes. ExAdEx products are adipose tissue units maintaining the characteristics and organization of adipose tissue as it presents in vivo. The model was viable and metabolically active for up to two months and could adopt a pathological-like phenotype. The results revealed that inflammatory and fibrotic microenvironments differentially regulated the expansion of the CD26 APC subpopulation and its CD54 and CD142 APC progenies. The approach used significantly improves the method of generating adipose tissue models, and ExAdEx constitutes a relevant model that could be used to identify pathways promoting the expansion of APCs in physiological and pathological microenvironments.

Circadian signatures of adipose tissue in diet-induced obesity.

High-fat diet (HFD) feeding rewires circadian rhythms of peripheral organs including the liver and adipose tissue. While the liver has been extensively studied, it remains largely unknown whether and how HFD organizes circadian biology in adipose tissue. Here, we took a systems approach to profile the diurnal transcriptome of adipose tissue in diet-induced obese mice either fed a low-fat diet (LFD) that reduces weight or still fed HFD. We detected about 200 and 2,500 diurnal genes in HFD and LFD, respectively. Pathway analysis revealed that rhythmic pathways in HFD are represented by circadian rhythm, ribosome biogenesis, and nucleosome organization, whereas those in LFD are represented by myeloid cell function. Remarkably, the majority of the circadian clock genes, except Clock, exhibited robust diurnal rhythm in the adipose tissue of HFD-fed mice. Analysis of mRNAs and proteins in another cohort of HFD-fed mice confirmed that Clock lost rhythmicity at the transcript, but not protein level. Diet reversal to LFD specifically restored diurnal difference of the Clock transcripts in adipose tissue. We matched transcriptomics data with global profiling of neutral lipids and found that lipid metabolism catalyzed by triglycerol hydrolase Ces1d is a key circadian feature that is activated by diet reversal. Together, our work defines the circadian signatures in the adipose tissue of diet-induced obese mice, and their flexibility upon dietary intervention, thereby shedding light on potential clock-modulated tissue-specific pathways during obesity.

The emerging roles and mechanisms of exosomal non-coding RNAs in the mutual regulation between adipose tissue and other related tissues in obesity and metabolic diseases

Exosomes (EXs) are the major types of extracellular vesicles (EVs) of 30-100 nm diameter that can be secreted by most cells to the extracellular environment. EXs transport endogenous cargoes (proteins, lipids, RNAs, etc.) to target cells and thereby triggers the release of these bioactive components, which then play important roles in regulating numerous biological processes under both physiological and pathological conditions. Throughout the studies in recent years, growing evidences have shown that EXs-derived non-coding RNAs (EXs-ncRNAs) are emerging as key players in cell-to-cell communication between adipose tissue and other related tissues in obesity and metabolic diseases. In this review, we will summarize the recent findings about EXs-ncRNAs, especially focus on the following aspects: 1) the biogenesis of EXs and emerging roles of EXs-ncRNAs, 2) the role of EXs-ncRNAs (EXs-miRNAs, EXs-lncRNAs, EXs-circRNAs, etc.) that were secreted by adipose-related tissues in promoting the differentiation of preadipocytes into mature and fully functional adipocytes, and 3) the crosstalk between the adipose tissue derived EXs-ncRNAs and the development of insulin resistance, obesity and various cancers. This review aims to reveal the emerging roles and mechanisms of EXs-ncRNAs in the mutual regulation of adipose tissue and its related tissues in obesity and metabolic diseases, so as to provide references for elucidating the etiology of obesity and related metabolic diseases and screening novel therapeutic targets.

Differences in circulating obesity-related microRNAs in Austrian and Japanese men: A two-country cohort analysis

BackgroundThe prevalence of obesity is higher in Western countries than in East Asian countries. It remains unknown whether microRNAs (miRNAs) are involved in the pathogenesis of the ethnic difference in obesity. The purpose of this study was to determine whether expression levels of circulating obesity-associated miRNAs are different in Europeans and Asians. MethodsThe subjects were middle-aged healthy male Austrians (n = 20, mean age of 49.9 years) and Japanese (n = 20, mean age of 48.7 years). Total miRNAs in serum from each subject were analyzed using the 3D-Gene miRNA Oligo chip. miRNAs that showed significant differences between the Austrian and Japanese groups were uploaded into Ingenuity Pathway Analysis (IPA). ResultsAmong 16 miRNAs that were revealed to be associated with obesity in previous studies and showed expression levels that were high enough for a reasonable comparison, serum levels of 3 miRNAs displayed significant differences between the Austrian and Japanese groups: miR-125b-1-3p was significantly lower with a fold change of −2.94 and miR-20a-5p and miR-486–5p were significantly higher with fold changes of 1.73 and 2.38, respectively, in Austrians than in Japanese. In IPA including all 392 miRNAs that showed significant differences between Austrians and Japanese, three canonical pathways including leptin signaling in obesity, adipogenesis pathway and white adipose tissue browning pathway were identified as enriched pathways. ConclusionsmiRNAs are thought to be involved in the ethnic difference in the prevalence of obesity, which may in part be caused by different expression levels of miR-125b-1-3p, miR-20a-5p and miR-486–5p.

Macrophages in obesity are characterised by increased IL-1β response to calcium-sensing receptor signals

ObjectiveObesity is complicated by inflammatory activation of the innate immune system. Stimulation of the calcium-sensing receptor (CaSR) by extra-cellular calcium ions ([Ca2+]ex) can trigger NLRP3 inflammasome activation and inflammation. We hypothesised, that this mechanism might contribute to the activation of adipose tissue (AT) in obesity, and investigated [Ca2+]ex-induced, CaSR mediated IL-1β release by macrophages in obesity.Methods[Ca2+]ex-induced IL-1β release was investigated in monocyte-derived macrophages (MDM) generated from peripheral blood of patients with obesity and from normal-weight controls. Visceral and subcutaneous AT biosamples were stimulated with [Ca2+]ex, and IL-1β release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined.ResultsBoth MDM and AT readily responded with concentration-dependent IL-1β release already at low, near physiological concentrations to addition of [Ca2+]ex, which was more than 80 fold higher than the LPS-induced effect. IL-1β levels induced by [Ca2+]ex were significantly higher not only in MDM from patients with obesity compared to controls, but also in visceral versus subcutaneous AT. This fat-depot difference was also reflected by mRNA expression levels of inflammasome and cytokine genes.ConclusionsObesity renders macrophages more susceptible to [Ca2+]ex-induced IL-1β release and pyroptosis. Increased susceptibility was independent of the response to LPS and circulating CRP arguing against mere pro-inflammatory pre-activation of monocytes. Instead, we propose that CaSR mediated signalling is relevant for the deleterious innate immune activation in obesity.

Abstract P3128: Obesogenic Diet Promotes Endothelial-to-Mesenchymal Transition In Adipose Tissue

Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive Endothelial-to-Mesenchymal Transition (EndoMT), where endothelial cells transition into mesenchymal-like interstitial cells that leave the vascular wall and promote tissue inflammation and fibrosis. In this study, we aimed to determine whether obesogenic diet can promote EndoMT in adipose tissue. EndoMT was assessed in 1) transgenic endothelial cell lineage-tracing mice subjected to High-Fat/High-Sucrose (HF/HS) diet, 2) available single cell RNA sequencing datasets from human obese adipose tissue, and 3) cell culture models using primary human adipose-derived endothelial cells. In lineage-tracing mice, obesogenic diet induced EndoMT in a time-dependent manner at 13, 26, and 52 weeks on HF/HS diet in both subcutaneous and visceral adipose tissue. Interestingly, rate of EndoMT was greater in visceral compared to subcutaneous adipose tissue. After 52-weeks on HF/HS diet, EndoMT cells in visceral adipose tissue upregulate inflammatory response and TGF-Beta signaling transcriptional pathways compared to endothelial cells in the same adipose tissue depot. Initiation of EndoMT was also found in single cell RNA sequencing datasets of stromal cells from human obese adipose tissue, indicated by endothelial cells in these datasets containing sub-clusters with reduced Pecam1 and increased Acta2 expression. Finally, the capacity for EndoMT in primary human adipose-derived endothelial cells was validated by bulk RNA sequencing after treatment with proinflammatory cytokines (TNF-Alpha, IFN-Gamma, TGF-Beta1), confirming decreased expression of endothelial cell genes and increased expression of genes associated with EndoMT, inflammatory response, and TGF-Beta signaling. Together, these clinical and experimental findings indicate that chronic obesity can promote EndoMT in adipose endothelial cells.

Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice

During obesity, tissue macrophages increase in number and become proinflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lepob/ob mice with mice lacking the Lpl gene in myeloid cells (Lplm−/m−) to generate Lplm−/m−;Lepob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lplm−/m−;Lepob/ob mice compared with Lepob/ob mice due to substantial accumulation of both adipose tissue macrophages and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lplm−/m−;Lepob/ob mice, we observed an increase in collagen VI and high mobility group box 1, while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore, the adipose tissue macrophages from Lplm−/m−;Lepob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lplm−/m−;Lepob/ob mice were more hypertriglyceridemic than Lepob/ob mice. Lplm−/m−;Lepob/ob mice also showed slower weight gain than Lepob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating triglyceride levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.

MicroRNA-29 Ameliorates Fibro-Inflammation and Insulin Resistance in HIF1α-Deficient Obese Adipose Tissue by Inhibiting Endotrophin Generation.

Dysregulation of extracellular matrix proteins in obese adipose tissue (AT) induces systemic insulin resistance. The metabolic roles of type VI collagen and its cleavage peptide endotrophin in obese AT are well established. However, the mechanisms regulating endotrophin generation remain elusive. Herein, we identified that several endotrophin-containing peptides (pre-endotrophins) were generated from the COL6A3 chain in a stepwise manner for the efficient production of mature endotrophin, partly through the action of hypoxia-induced matrix metalloproteinases (MMPs), including MMP2, MMP9, and MMP16. Hypoxia is an upstream regulator of COL6A3 expression and the proteolytic processing that regulates endotrophin generation. Hypoxia-inducible factor 1α (HIF1α) and the hypoxia-associated suppression of microRNA-29 (miR-29) cooperatively control the levels of COL6A3 and MMPs, which are responsible for endotrophin generation in hypoxic ATs. Adipocyte-specific Hif1α knock-out (APN-HIF1αKO) mice fed a chronic high-fat diet exhibited the significant amelioration of both local fibro-inflammation in AT and systemic insulin resistance compared with their control littermates, partly through the inhibition of endotrophin generation. Strikingly, adenovirus-mediated miR-29 overexpression in the ATs of APN-HIF1αKO mice in obesity significantly decreased endotrophin levels, suggesting that miR-29, combined with HIF1α inhibition in AT, could be a promising therapeutic strategy for treating obesity and related metabolic diseases.

Small fragments of hyaluronan are increased in individuals with obesity and contribute to low-grade inflammation through TLR-mediated activation of innate immune cells

Background and aimExtracellular matrix (ECM) components released during excessive fat mass expansion are considered potential endogenous danger/alarm signals contributing to innate immune system activation. The aim of the current study was to specifically measure plasma levels of low molecular weight (LMW) hyaluronan (HA) and to evaluate its role as pro-inflammatory damage-associated molecular pattern (DAMP) on leukocyte response in the context of human obesity.Subjects and methodsParticipants were selected according to their body mass index (BMI, kg/m2) as non-obese (BMI < 29.9, n = 18) and obese (BMI > 29.9, n = 33). Plasma samples were size-dependent fractionated using ion-exchange chromatography to specifically obtain LMW HA fractions that were subsequently quantified by ELISA. Cell incubation experiments with synthetic HA molecules were performed on freshly Ficoll-isolated neutrophils (PMN) and peripheral blood monocytes (PBMC). Leukocyte and adipose tissue gene expression was assessed by real-time PCR and NF-κB activation by western blot. Plasma cytokine levels were measured by fluorescent bead-based (Luminex) immunoassay.ResultsWe observed a statistically significant increase in the circulating levels of HA fragments of LMW in individuals with obesity which were consistent with significant up-regulated expression of the LMW HA synthesizing enzyme hyaluronan synthase-1 (HAS-1) in obese adipose tissue. Gene expression assessment of HA receptors revealed up-regulated levels for TLR2 in both obese PMN and PBMC. Synthetic HA molecules of different sizes were tested on leukocytes from healthy donors. LMW HA fragments (15–40 kDa) and not those from intermediate molecular sizes (75–350 kDa) induced a significant up-regulation of the expression of major pro-inflammatory cytokines such as IL-1β, MCP-1 and IL-8 in PBMC. Importantly, LMW HA was able to induce the phosphorylation of IKK α/β complex supporting its pro-inflammatory role through NF-κB activation.ConclusionCirculating LMW HA molecules are elevated in obesity and may play an important role in triggering low-grade inflammation and the development of metabolic complications.

Maternal Adipocyte Connexin43 Gap Junctions Affect Breastmilk Lactose Levels and Neonate Growth in Mice.

Simple SummaryBreastfeeding offers many health benefits for both mothers and infants. However, overnutrition and a steady increase in obesity in the U.S. has made it harder for many mothers to produce and express breastmilk. Moreover, the quality of breastmilk from obese mothers is frequently compromised in that it contains fewer nutrients and more inflammatory components. In this study, we used mice to model this phenomenon. We found that short-term high-fat feeding at the start of breeding reduces litter size and pups’ body weight. It also impairs adipocyte remodeling during lactation. Connexin43 is the primary building block for gap junctions in the adipose tissue. It is postulated to play an essential role in adipose tissue remodeling to accommodate mammary gland development and breastmilk production. Using genetically engineered mice without Connexin43 in their adipocytes, we demonstrated that the deletion of adipocyte Connexin43 affects the disappearance of adipocytes during lactation and affects milk composition, which is postulated to impair the pups’ growth. Altogether, this study suggests that increasing or enhancing adipocyte Connexin43 gap junctions may help obese mothers produce better breastmilk to support their neonates.Breastfeeding offers a broad spectrum of health benefits for infants. However, overnutrition and a steady increase in maternal obesity in the U.S. have made it harder for many mothers to produce and express breastmilk, and the quality of milk from obese mothers is also frequently compromised. Adipocytes, the primary cell type in the non-lactating breast, display a drastic morphological and functional change during lactation in mice. Lipid-filled adipocytes undergo lipolysis, and lipid droplets disappear to provide fatty acids and energy for breastmilk production. Once the animal stops lactation, these lipid-depleted adipocytes return as lipid-laden cells. This dynamic remodeling of the tissue is likely the result of active intercellular communications. Connexin43 (Cx43) is the most abundant connexin in the mammary adipose tissue that makes up the gap junctions for direct intercellular communications. Its expression is increased during lactation and reduced in obese mammary adipose tissue, which is resistant to lactation-induced remodeling. However, whether Cx43 is required for adipocyte remodeling and breastmilk production to support neonates’ growth has not been established. In this study, we used doxycycline-inducible adipocyte-specific Cx43-deleted mice and demonstrated that adipocyte Cx43 played a vital role in determining the carbohydrate levels in breastmilk, which may subsequently affect neonates’ growth.

Modulation of adipose inflammation by cellular retinoic acid-binding protein 1

ObjectivesObesity, a metabolic syndrome, is known to be related to inflammation, especially adipose tissue inflammation. Cellular interactions within the expanded white adipose tissue (WAT) in obesity contribute to inflammation and studies have suggested that inflammation is triggered by inflamed adipocytes that recruit M1 macrophages into WAT. What causes accumulation of unhealthy adipocytes is an important topic of investigation. This study aims to understand the action of Cellular Retinoic Acid Binding Protein 1 (CRABP1) in WAT inflammation.MethodsEight weeks-old wild type (WT) and Crabp1 knockout (CKO) mice were fed with a normal diet (ND) or high-fat diet (HFD) for 8 weeks. Body weight and food intake were monitored. WATs and serum were collected for cellular and molecular analyses to determine affected signaling pathways. In cell culture studies, primary adipocyte differentiation and bone marrow-derived macrophages (BMDM) were used to examine adipocytes’ effects, mediated by CRABP1, in macrophage polarization. The 3T3L1-adipocyte was used to validate relevant signaling pathways.ResultsCKO mice developed an obese phenotype, more severely under high-fat diet (HFD) feeding. Further, CKO’s WAT exhibited a more severe inflammatory state as compared to wild type (WT) WAT, with a significantly expanded M1-like macrophage population. However, this was not caused by intrinsic defects of CKO macrophages. Rather, CKO adipocytes produced a significantly reduced level of adiponectin and had significantly lowered mitochondrial DNA content. CKO adipocyte-conditioned medium, compared to WT control, inhibited M2-like (CD206+) macrophage polarization. Mechanistically, defects in CKO adipocytes involved the ERK1/2 signaling pathway that could be modulated by CRABP1.ConclusionsThis study shows that CRABP1 plays a protective role against HFD-induced WAT inflammation through, in part, its regulation of adiponectin production and mitochondrial homeostasis in adipocytes, thereby modulating macrophage polarization in WAT to control its inflammatory potential.

Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer.

A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC. Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n= 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods. WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p< .05). WAT inflammation was associated with greater body mass index (p< .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p< .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue. WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Cross-Talk Between Gut Microbiota and Adipose Tissues in Obesity and Related Metabolic Diseases.

The rapid increase of obesity and associated diseases has become a major global health problem. Adipose tissues are critical for whole-body homeostasis. The gut microbiota has been recognized as a significant environmental factor in the maintenance of energy homeostasis and host immunity. A growing body of evidence suggests that the gut microbiota regulates host metabolism through a close cross-talk with adipose tissues. It modulates energy expenditure and alleviates obesity by promoting energy expenditure, but it also produces specific metabolites and structural components that may act as the central factors in the pathogenesis of inflammation, insulin resistance, and obesity. Understanding the relationship between gut microbiota and adipose tissues may provide potential intervention strategies to treat obesity and associated diseases. In this review, we focus on recent advances in the gut microbiota and its actions on adipose tissues and highlight the joint actions of the gut microbiota and adipose tissue with each other in the regulation of energy metabolism.

An Iron Refractory Phenotype in Obese Adipose Tissue Macrophages Leads to Adipocyte Iron Overload.

Adipocyte iron overload is a maladaptation associated with obesity and insulin resistance. The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance.

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity.

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction.

Obesity-related prepartal insulin resistance in dairy cows is associated with increased lipin 1 and decreased FATP 1 expression in skeletal muscle

A number of alterations have been identified in lipid metabolism within adipose tissue and liver in obesity. Less is known about the capacity of skeletal muscle for the metabolism of fatty acids in obesity-related insulin resistance, though it is evident that dry cow muscles may contain increased triglyceride content. The current study was therefore undertaken to evaluate the skeletal muscle expression of proteins of the fatty acid metabolism in dry cows with different body condition scores (BCS). Sixteen Holstein-Friesian close-up cows were divided into 2 equal groups based on their BCS as optimal (3.25 ≤ BCS ≤ 3.5) and high (4.0 ≤ BCS ≤ 4.25). Blood samples collection and skeletal muscle biopsies were carried out at day 10 before calving. Blood serum was assayed for concentration of resistin using a bovine specific ELISA. Protein expression of insulin receptor beta subunit (IRβ), glucose transporter 4 (GLUT4), fatty acid translocase (FAT/CD36), fatty acid transporter 1 (FATP1), carnitine palmitoyltransferase 1 (CPT1), AMP-acitvated protein kinase (AMPK) and lipin 1 were analyzed in semitendinosus muscle by immunoblot. Resistin differed non-significantly between high-BCS and optimal-BCS cows. Insulin-resistant lipid metabolism in obese cows was paralleled with increased skeletal muscle expression of lipin 1 and GLUT4, and decreased expression of IRβ and FATP1. These data suggest that in obesity-related insulin resistance, metabolic capacity in dry cow skeletal muscles appears to be organized towards the synthesis of signaling intermediates rather than fatty acids oxidation and that altered fatty acid uptake does not contribute to this disposition.

Adipose tissue LECT2 expression is associated with obesity and insulin resistance in Korean women.

Leukocyte cell-derived chemotaxin 2 (LECT2) is an obesity-upregulated hepatokine inducing skeletal muscle insulin resistance. The study's aim was to explore whether LECT2 is expressed in human adipose tissue and whether the expression is dysregulated during obesity and associated with obesity-related metabolic disorders. This study measured metabolic parameters, serum LECT2, and expression of LECT2 and CD209, a gene encoding a putative receptor for LECT2, in abdominal subcutaneous and visceral adipose tissues in women with obesity (with or without type 2 diabetes) and women with normal weight. The expression/secretion of LECT2 and its putative effects were assessed in human adipocytes. Adipose tissue LECT2 mRNA and serum LECT2 were higher in women with obesity and were significantly correlated with parameters related to insulin resistance. LECT2 was mainly expressed by adipocytes. Both LECT2 and CD209 expression was higher in adipocytes from women with obesity. Incubating adipocytes with substances mimicking the microenvironment of obesity adipose tissue increased LECT2 expression/secretion. LECT2 treatment of adipocytes suppressed insulin-stimulated Akt phosphorylation; it reduced adiponectin (ADIPOQ) and increased leptin (LEP) expression in a CD209-dependent manner. This study demonstrates that LECT2 expression in adipose tissue is high in patients with obesity and associated with insulin resistance and suggests that adipocyte-derived LECT2 may contribute to adipose tissue dysfunction.

Insulin-inducible THRSP maintains mitochondrial function and regulates sphingolipid metabolism in human adipocytes

BackgroundThyroid hormone responsive protein (THRSP) is a lipogenic nuclear protein that is highly expressed in murine adipose tissue, but its role in humans remains unknown.MethodsWe characterized the insulin regulation of THRSP in vivo in human adipose tissue biopsies and in vitro in Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. To this end, we measured whole-body insulin sensitivity using the euglycemic insulin clamp technique in 36 subjects [age 40 ± 9 years, body mass index (BMI) 27.3 ± 5.0 kg/m2]. Adipose tissue biopsies were obtained at baseline and after 180 and 360 min of euglycemic hyperinsulinemia for measurement of THRSP mRNA concentrations. To identify functions affected by THRSP, we performed a transcriptomic analysis of THRSP-silenced SGBS adipocytes. Mitochondrial function was assessed by measuring mitochondrial respiration as well as oxidation and uptake of radiolabeled oleate and glucose. Lipid composition in THRSP silencing was studied by lipidomic analysis.ResultsWe found insulin to increase THRSP mRNA expression 5- and 8-fold after 180 and 360 min of in vivo euglycemic hyperinsulinemia. This induction was impaired in insulin-resistant subjects, and THRSP expression was closely correlated with whole-body insulin sensitivity. In vitro, insulin increased both THRSP mRNA and protein concentrations in SGBS adipocytes in a phosphoinositide 3-kinase (PI3K)-dependent manner. A transcriptomic analysis of THRSP-silenced adipocytes showed alterations in mitochondrial functions and pathways of lipid metabolism, which were corroborated by significantly impaired mitochondrial respiration and fatty acid oxidation. A lipidomic analysis revealed decreased hexosylceramide concentrations, supported by the transcript concentrations of enzymes regulating sphingolipid metabolism.ConclusionsTHRSP is regulated by insulin both in vivo in human adipose tissue and in vitro in adipocytes, and its expression is downregulated by insulin resistance. As THRSP silencing decreases mitochondrial respiration and fatty acid oxidation, its downregulation in human adipose tissue could contribute to mitochondrial dysfunction. Furthermore, disturbed sphingolipid metabolism could add to metabolic dysfunction in obese adipose tissue.