Elevated Adipose Tissue Research Articles

Metabolic dysfunction in mice with adipocyte specific ablation of the adenosine A2A receptor.

It has been well established that adenosine plays a key role in the control of inflammation through G protein coupled receptors and recently shown that it can regulate thermogenesis. Here we investigated the specific requirements of the adenosine A2A receptor (A2AR) in mature adipocytes for thermogenic functionality and metabolic homeostasis. We generated fat tissue specific adenosine A2A receptor knock-out mice to assess the influence of signaling through this receptor on brown and beige fat functionality, obesity, insulin sensitivity, inflammation and liver function. Fat specific A2AR knock-out and wild type littermate mice were compared for potential differences in cold tolerance and energy metabolism. In addition, we measured glucose metabolism, AT inflammation and liver phenotypes in mice of the two genotypes after exposure to a diet rich in fat. Our results provide novel evidence indicating that loss of the adenosine A2A receptor specifically in adipocytes is associated with cold intolerance and decreased oxygen consumption. Furthermore, mice with fat specific ablation of the A2AR exposed to a diet rich in fat showed increased propensity to obesity, decreased insulin sensitivity, elevated adipose tissue inflammation and hepato-steatosis and -steatitis. Overall, our data provide novel evidence that A2AR in mature adipocytes safeguards metabolic homeostasis, suggesting the possibility of targeting this receptor selectively in fat for the treatment of metabolic disease.

Transcriptional regulation of adipocyte lipolysis by IRF2BP2.

Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by post-translational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify the transcriptional factor interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a repressor of adipocyte lipolysis. Deletion of IRF2BP2 in primary human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA-seq and ChIP-seq analyses reveal that IRF2BP2 directly represses several lipolysis-related genes, including LIPE ( HSL , hormone sensitive lipase), which encodes the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of Irf2bp2 in mice increases Lipe expression and free fatty acid levels, resulting in elevated adipose tissue inflammation and glucose intolerance. Altogether, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens new avenues to target lipolysis for the treatment of metabolic disease.

Body composition as a determinant of the therapeutic index with androgen signaling inhibition.

Androgen signaling is central to prostate cancer and men's health. Prior data indicates that increasing body fat is unfavorable in the localized setting yet associated with favorable outcomes in men with metastatic disease. Understanding the biological links between adiposity and prostate cancer may optimize the therapeutic index with ASI. We hypothesized that host adiposity and androgen synthesis are linked to the efficacy and toxicity of ASI for men with metastatic castration-resistant prostate cancer (mCRPC). A post-hoc analysis was done of NCT02703623 where men with mCRPC (n = 186) were treated for 8 weeks with abiraterone acetate, prednisone, and apalutamide (AAPA), and a satisfactory response was defined as a PSA decline >50%. Body composition was measured on baseline CT scans. Germline DNA WES was performed with a focus on variants in steroidogenic genes. Adipokine levels were measured in pre-treatment plasma. Germline polymorphisms in 3 genes involved in androgen synthesis (AKR1C3 rs12529, CYP17A1 rs6162, SRD5A2 rs523349) were associated with differences in body composition at baseline on ADT alone (prior to receipt of AAPA). Elevated subcutaneous adipose tissue index (SATi, p = 0.02), visceral adipose tissue index (VATi, p = 0.03), and BMI (p = 0.04) were associated with satisfactory response to AAPA. Leptin had positive correlation with VATi (r = 0.47) and SATi (r = 0.48). Inherited polymorphisms in androgen synthesis correlated with differences in body composition after exposure to ADT and warrant further investigation as candidate markers for body composition toxicity. Elevated subcutaneous and visceral adiposity were associated with improved response to ASI.

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer.

Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association between body mass index (BMI), body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAE) after ICI was also assessed based on BMI status. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared to normal BMI patients after treatment with ICI. Multivariable Cox regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number-high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared to normal BMI individuals. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype. NIH/NCI Cancer Center Support Grant P30CA008748 (MSK). K08CA266740 and MSK Gerstner Physician Scholars Program (J.C.O). RUCCTS Grant #UL1 TR001866 (N.G-B and C.S.J). Cycle for survival and Breast Cancer Research Foundation grants (B.W).

Effect of subcutaneous adipose tissue-associated CSRP2 on the progression of prostate cancer via the WDR5/USP44 pathway.

Elevated subcutaneous adipose tissue in obese men correlates strongly with a higher risk of aggressive prostate cancer and poor treatment outcomes, but the exact mechanism underlying the increased risk remains elusive. To address this question, we analyzed prostate cancer transcriptomic data from The Cancer Genome Atlas as well as single-cell RNA sequencing and tissue microarray data from prostate cancer cells. Subcutaneous adipose tissue-associated cysteine-rich protein 2 (CSRP2) was significantly downregulated in prostate cancer epithelial cells. Knockdown of CSRP2 promoted proliferation of prostate cancer cell lines DU145 and PC3, whereas the opposite effect was observed with CSRP2 overexpression. In vivo xenograft assays confirmed that CSRP2 overexpression inhibits the growth of prostate cancer cells. Importantly, co-immunoprecipitation and mass spectrometry assays confirmed that CSRP2 inhibits the deubiquitination of WD40 repeat protein 5 (WDR5) by ubiquitin-specific protease 44 (USP44). Overexpression of WDR5 reversed the growth inhibition of CSRP2 overexpression on prostate cancer cells. Altogether, our data indicate that CSRP2 suppresses prostate cancer cell proliferation via a CSRP2/WDR5/USP44 dependent pathway to control prostate cancer progression, suggesting a potential mechanism for prostate cancer treatment.

Lipopolysaccharide-induced persistent inflammation ameliorates fat accumulation by promoting adipose browning in vitro and in vivo

This work aimed to explore whether the persistent inflammation induced by lipopolysaccharide (LPS) ameliorates fat accumulation by promoting adipose browning in vitro and in vivo. LPS over 1 ng/mL reduced lipid accumulation while increasing the expressions of specific genes involved in inflammation, mitochondrial biogenesis, and adipose browning in 3T3-L1 adipocytes. Moreover, LPS in intraperitoneal injection decreased white adipose tissue weight and elevated interscapular brown adipose tissue weight in mice. According to RT-PCR and western blot analysis results, the expressions of genes and proteins related to inflammation, mitochondrial biogenesis, lipolysis, and brown or beige markers in different tissues were elevated after LPS intervention. Cumulatively, LPS-induced persistent inflammation may potentially ameliorate fat accumulation by facilitating adipose browning in 3T3-L1 adipocytes and mice. These results offer new perspectives into the effect of persistent inflammation induced by LPS on regulating fat metabolism, thereby reducing fat accumulation by boosting adipose browning procedure.

Epicardial adipose tissue in patients with chronic obstructive pulmonary disease: systematic review with meta‑analysis and trial sequential analysis

BackgroundLimited data suggest that chronic obstructive pulmonary disease (COPD) patients have pathologic elevated epicardial adipose tissue (EAT), which is splanchnic fat tissue with anti-inflammatory properties and regulating free fatty acids functions. Therefore, there is a need for meta-analysis to explore the relationship between EAT and COPD.MethodsOnline databases were systematically searched for studies about EAT in COPD patients published up to October 5th, 2022. The EAT data of the COPD patient group and the control group were included. Trial sequential analysis (TSA) and meta-analysis were applied to assess the difference in EAT between patients with and without COPD. TSA software and Stata 12.0 were used in all statistical analyses.ResultsThe final analysis included 5 studies (n = 596 patients). COPD patients had significantly more EAT than control subjects (SMD: 0.0.802; 95% CI: 0.231, 1.372; P = 0.006; TSA-adjusted 95% CI 1.20, 1.80; P < 0.0001). And higher CRP levels in COPD patients than non-COPD patients, whereas triglycerides and LDL were not significantly different between patients with and without COPD.ConclusionEAT is abnormally elevated in COPD patients, which may be related to systemic inflammatory responses in COPD.PROSPERO numberCRD42021228273.

Characterization of plaque phenotypes exhibiting an elevated pericoronary adipose tissue attenuation: insights from the REASSURE-NIRS registry.

Inflammation has been considered to promote atheroma instability. Coronary computed tomography angiography (CCTA) visualizes pericoronary adipose tissue (PCAT) attenuation, which reflects coronary artery inflammation. While PCAT attenuation has been reported to predict future coronary events, plaque phenotypes exhibiting high PCAT attenuation remains to be fully elucidated. The current study aims to characterize coronary atheroma with a greater vascular inflammation. We retrospectively analyzed culprit lesions in 69 CAD patients receiving PCI from the REASSURE-NIRS registry (NCT04864171). Culprit lesions were evaluated by both CCTA and near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS) imaging prior to PCI. PCAT attenuation at proximal RCA (PCATRCA) and NIRS/IVUS-derived plaque measures were compared in patients with PCATRCA attenuation ≥ and < -78.3 HU (median). Lesions with PCATRCA attenuation ≥ -78.3 HU exhibited a greater frequency of maxLCBI4mm ≥ 400 (66% vs. 26%, p < 0.01), plaque burden ≥ 70% (94% vs. 74%, p = 0.02) and spotty calcification (49% vs. 6%, p < 0.01). Whereas positive remodeling (63% vs. 41%, p = 0.07) did not differ between two groups. On multivariable analysis, maxLCBI4mm ≥ 400 (OR = 4.07; 95%CI 1.12-14.74, p = 0.03), plaque burden ≥ 70% (OR = 7.87; 95%CI 1.01-61.26, p = 0.04), and spotty calcification (OR = 14.33; 95%CI 2.37-86.73, p < 0.01) independently predicted high PCATRCA attenuation. Of note, while the presence of only one plaque feature did not necessarily elevate PCATRCA attenuation (p = 0.22), lesions harboring two or more features were significantly associated with higher PCATRCA attenuation. More vulnerable plaque phenotypes were observed in patients with high PCATRCA attenuation. Our findings suggest PCATRCA attenuation as the presence of profound disease substrate, which potentially benefits from anti-inflammatory agents.

Deep learning of image-derived measures of body composition in pediatric, adolescent, and young adult lymphoma: association with late treatment effects.

The objective of this study was to translate a deep learning (DL) approach for semiautomated analysis of body composition (BC) measures from standard of care CT images to investigate the prognostic value of BC in pediatric, adolescent, and young adult (AYA) patients with lymphoma. This 10-year retrospective, single-site study of 110 pediatric and AYA patients with lymphoma involved manual segmentation of fat and muscle tissue from 260 CT imaging datasets obtained as part of routine imaging at initial staging and first therapeutic follow-up. A DL model was trained to perform semiautomated image segmentation of adipose and muscle tissue. The association between BC measures and the occurrence of 3-year late effects was evaluated using Cox proportional hazards regression analyses. DL-guided measures of BC were in close agreement with those obtained by a human rater, as demonstrated by high Dice scores (≥ 0.95) and correlations (r > 0.99) for each tissue of interest. Cox proportional hazards regression analyses revealed that patients with elevated subcutaneous adipose tissue at baseline and first follow-up, along with patients who possessed lower volumes of skeletal muscle at first follow-up, have increased risk of late effects compared to their peers. DL provides rapid and accurate quantification of image-derived measures of BC that are associated with risk for treatment-related late effects in pediatric and AYA patients with lymphoma. Image-based monitoring of BC measures may enhance future opportunities for personalized medicine for children with lymphoma by identifying patients at the highest risk for late effects of treatment. • Deep learning-guided CT image analysis of body composition measures achieved high agreement level with manual image analysis. • Pediatric patients with more fat and less muscle during the course of cancer treatment were more likely to experience a serious adverse event compared to their clinical counterparts. • Deep learning of body composition may add value to routine CT imaging by offering real-time monitoring of pediatric, adolescent, and young adults at high risk for late effects of cancer treatment.

A20 EARLY-LIFE FUNGAL COLONIZATION MEDIATES HOST METABOLISM AND WHITE ADIPOSE TISSUE INFLAMMATION IN MICE

Abstract Background The gut microbiome has been linked to metabolic diseases including obesity, however the role of fungi (mycobiome) remains understudied. Recently, fungal taxa have been correlated with obesity in humans, though their causal contribution to obesity development, especially in the context of early life, is unknown. Obesity has been associated with metabolic inflammation, including alterations to the white adipose tissue (WAT) immune landscape, which has been shown to be influenced by the microbiome. Given the potent modulation of host immunity by the mycobiome, it is plausible that it also influences WAT inflammation. Purpose This research aimed to explore the role of early-life colonization by specific fungal taxa in obesity development and WAT inflammation. Method Gnotobiotic mice were colonized from birth with 12 mouse-derived bacteria (Oligo-MM12) alone or in combination with Candida albicans or Rhodotorula mucilaginosa. Mice were weaned onto a control or high-fat-high-sugar diet (HFHS) and evaluated at 12 weeks for metabolic and associated inflammatory outcomes. Result(s) C. albicans colonization reduced body weight in mice fed control diet, and induced resistance to weight and adiposity gain in mice fed HFHS. In contrast, R. mucilaginosa colonization was associated with increased adiposity in mice fed control diet, and elevated glycemia and LDL-cholesterol in mice fed HFHS. Fungal colonization had a broad impact on immune cells in white adipose tissue. C. albicans colonization was associated with increased adipose tissue inflammation with elevated Th1, Th17, ɣδT cells, ILC1, NK cells, cDC1 and neutrophils independently of diet. Additionally, vascular associated macrophages (VAM), CX3CR1+ macrophages and DCs, and ILC3 were elevated in mice fed control diet, while mice fed HFHS displayed elevated Th2, CD8+ T cells and eosinophils. In contrast, R. mucilaginosa colonized mice displayed decreased adipose tissue B cells and increased VAMs when fed control diet, and increased CX3CR1+ DCs when fed HFHS. Interestingly, C. albicans colonization was associated with increased relative expression of mPgc1⍺ in white adipose tissue of HFHS fed mice, indicative of enhanced mitochondrial biogenesis. Conclusion(s) Elevated adipose tissue inflammation with C. albicans colonization suggests dysfunction of energy storage and may explain the decreased body weight and resistance to diet-induced obesity, while the immune changes in R. mucilaginosa colonized mice may exacerbate obesity development. This work revealed that two common fungal colonizers have distinct and striking influences on obesity and metabolic inflammation and prompts for the inclusion of fungi in microbiome studies on host metabolism. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding Cumming School of Medicine Disclosure of Interest None Declared

P458 Low adherence to Mediterranean diet is associated with increased adipose tissue in patients with ulcerative colitis (UC) after pouch surgery: a cross sectional study

Abstract Background Obesity [body mass index (BMI) ≥30 kg/m2 ] prevalence in patients with inflammatory bowel diseases (IBD) ranges between 15-40%. Dual-energy x-ray absorptiometry (DEXA) is the gold standard for body composition evaluation. Patients with ulcerative colitis (UC) who undergo total proctocolectomy and pouch surgery may develop small bowel inflammation (pouchitis) resembling Crohn's disease (CD). We aimed to assess body composition of patients with UC-pouch and potential risk factors for high adiposity. Methods Patients with UC-pouch ages 18-50 were recruited. Adipose tissue was assessed by DEXA (increased adipose tissue defined as &amp;gt; 26% male, &amp;gt;31% female), sarcopenia- assessed by hand-grip (defined as &amp;lt;30 kg male, &amp;lt;20 kg female). Clinical data, biochemical and inflammatory markers documented, Mediterranean diet adherence assessed by the Israeli Mediterranean diet (I-MEDAS) questionnaire. Results Recruited patients: 30: male/female 14/16; median age 45 (IQR 31-51.7) years; median BMI 23.2 (IQR 21-26.5); median pouch age 17 (IQR 10-25) years. One patient was obese (BMI ≥ 30 kg/m2) and seven-overweight (BMI 25-29.9 kg/m2). Median fat percentage 34.7 (IQR 30.1-39.7); 23/30 (76.6%) had increased adipose tissue. 14/30 (46%) patients were defined as normal weight obesity- normal BMI with increased adipose tissue. In univariate analysis comparing males to females, age and I-MEDAS score were comparable. Females were less physically active (p=0.028), had lower BMI (p=0.043), and higher rates of elevated adipose tissue (p=0.002). In multivariate analysis adherence to the Mediterranean diet was associated with lower adipose tissue regardless of sex and BMI (p&amp;lt;0.001). Sarcopenia was found in 1 (3.33%) female patient. Conclusion Patients with UC-pouch are at risk for "Normal-weight obesity", an uprising health concern, having increased adipose tissue regardless of BMI and sarcopenia. Adherence to the Mediterranean diet is inversely associated with increased adiposity, and may be used to modify adiposity in patients with UC after pouch surgery, irrespectively of BMI.

Elevated intramuscular adipose tissue content with a high Ishak fibrosis stage (>3) had a negative effect on liver regeneration in cirrhotic patients undergoing portal vein embolization.

This study investigated the relationship between body composition parameters and changes in future liver remnant volume (FLRV) in hepatocellular carcinoma (HCC) patients undergoing portal vein embolization (PVE) in preparation for right hepatectomy. This retrospective study enrolled 21 patients between May 2013 and October 2020. Body composition parameters, including skeletal muscle attenuation (SMA), skeletal muscle mass index (SMI), intramuscular adipose tissue content (IMAC), and visceral-to-subcutaneous adipose tissue area ratio (VSR), were measured by computed tomography (CT) prior to PVE. Liver volumetry was measured before and at least 5 weeks after PVE. The mean interval between two CT volumetries was 9.1 ± 4.9 weeks, the mean value of increase in FLRV (ΔFLRV) was 236.0 ± 118.3cm3 , the ratio of increased FLRV (ΔFLRV%) was 55.7 ± 29.4%, and the rate of increased FLRV was 31.0 ± 18.8 (cm3 /week). Subjects with high IMAC showed significantly lower (p=0.044) ΔFLRV% than those with normal IMAC. Furthermore, ΔFLRV% was linearly reduced (p for trend=0.043) among those with low Ishak fibrosis stage (<3) + normal IMAC (76.1 ± 36.8%), those with low Ishak fibrosis stage (<3) + high IMAC or high Ishak fibrosis stage (>3) + normal IMAC (54.0 ± 24.1%), and those with high Ishak fibrosis stage (>3) + low IMAC (28.7 ± 1.6%) (p for trend=0.043). Our data indicated that high IMAC with a high Ishak fibrosis stage (>3) had a significant negative effect on ΔFLRV%.

Interleukin-6 initiates muscle- and adipose tissue wasting in a novel C57BL/6 model of cancer-associated cachexia.

Cancer-associated cachexia (CAC) is a wasting syndrome drastically reducing efficacy of chemotherapy and life expectancy of patients. CAC affects up to 80% of cancer patients, yet the mechanisms underlying the disease are not well understood and no approved disease-specific medication exists. As a multiorgan disorder, CAC can only be studied on an organismal level. To cover the diverse aetiologies of CAC, researchers rely on the availability of a multifaceted pool of cancer models with varying degrees of cachexia symptoms. So far, no tumour model syngeneic to C57BL/6 mice exists that allows direct comparison between cachexigenic- and non-cachexigenic tumours. MCA207 and CHX207 fibrosarcoma cells were intramuscularly implanted into male or female, 10-11-week-old C57BL/6J mice. Tumour tissues were subjected to magnetic resonance imaging, immunohistochemical-, and transcriptomic analysis. Mice were analysed for tumour growth, body weight and -composition, food- and water intake, locomotor activity, O2 consumption, CO2 production, circulating blood cells, metabolites, and tumourkines. Mice were sacrificed with same tumour weights in all groups. Adipose tissues were examined using high-resolution respirometry, lipolysis measurements in vitro and ex vivo, and radioactive tracer studies in vivo. Gene expression was determined in adipose- and muscle tissues by quantitative PCR and Western blotting analyses. Muscles and cultured myotubes were analysed histologically and by immunofluorescence microscopy for myofibre cross sectional area and myofibre diameter, respectively. Interleukin-6 (Il-6) was deleted from cancer cells using CRISPR/Cas9 mediated gene editing. CHX207, but not MCA207-tumour-bearing mice exhibited major clinical features of CAC, including systemic inflammation, increased plasma IL-6 concentrations (190pg/mL, P≤0.0001), increased energy expenditure (+28%, P≤0.01), adipose tissue loss (-47%, P≤0.0001), skeletal muscle wasting (-18%, P≤0.001), and body weight reduction (-13%, P≤0.01) 13days after cancer cell inoculation. Adipose tissue loss resulted from reduced lipid uptake and -synthesis combined with increased lipolysis but was not associated with elevated beta-adrenergic signalling or adipose tissue browning. Muscle atrophy was evident by reduced myofibre cross sectional area (-21.8%, P≤0.001), increased catabolic- and reduced anabolic signalling. Deletion of IL-6 from CHX207 cancer cells completely protected CHX207IL6KO -tumour-bearing mice from CAC. In this study, we present CHX207 fibrosarcoma cells as a novel tool to investigate the mediators and metabolic consequences of CAC in C57BL/6 mice in comparison to non-cachectic MCA207-tumour-bearing mice. IL-6 represents an essential trigger for CAC development in CHX207-tumour-bearing mice.

Circulating adipokine concentrations and risk of non-alcoholic fatty liver disease: A Mendelian randomization study

Background and Aims : Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases of the liver. Elevated adipose tissue (AT) accumulation is an important risk factor for NAFLD. Adipocytes release cytokines called adipokines that stimulate anti and pro-inflammatory pathways which may influence liver steatosis and fibrosis. Adiponectin, leptin, resistin, and plasminogen activator inhibitor-1 [PAI-1] are well-known adipokines that may be involved in the pathogenesis of NAFLD. Epidemiological evidence suggests that these adipokines may be associated with the development of NAFLD, but it is unclear if these associations are causal. The aim of our study is to explore the potential causal associations of adipokines with NAFLD among individuals of European ancestry.Methods: We performed two-sample Mendelian randomization (MR) analyses using publicly available genome-wide association studies (GWAS) for adiponectin, leptin, soluble leptin receptor, resistin, and PAI-1. We used summary-level data from our recent GWAS on NAFLD (8434 cases and 770,180 controls). To construct the genetic instruments, we included genetic variants with the P-value for association with study exposures <5×10-6 and linkage disequilibrium (R2=0.01).Results: In the inverse-variance weighted models, out of all adipokines tested, only soluble leptin receptor was significantly associated with NAFLD with beta [95% CI] = -0.075 [-0.173 – -0.133]; and P-value = 0.01.Conclusions: The plasma level of the soluble leptin receptor, but not leptin levels or other adipokines might be significantly associated with the development of NAFLD. These results suggest that adipokines may not have a key role in the development of NAFLD. Background and Aims : Non-alcoholic fatty liver disease (NAFLD) is one of the most common diseases of the liver. Elevated adipose tissue (AT) accumulation is an important risk factor for NAFLD. Adipocytes release cytokines called adipokines that stimulate anti and pro-inflammatory pathways which may influence liver steatosis and fibrosis. Adiponectin, leptin, resistin, and plasminogen activator inhibitor-1 [PAI-1] are well-known adipokines that may be involved in the pathogenesis of NAFLD. Epidemiological evidence suggests that these adipokines may be associated with the development of NAFLD, but it is unclear if these associations are causal. The aim of our study is to explore the potential causal associations of adipokines with NAFLD among individuals of European ancestry. Methods: We performed two-sample Mendelian randomization (MR) analyses using publicly available genome-wide association studies (GWAS) for adiponectin, leptin, soluble leptin receptor, resistin, and PAI-1. We used summary-level data from our recent GWAS on NAFLD (8434 cases and 770,180 controls). To construct the genetic instruments, we included genetic variants with the P-value for association with study exposures <5×10-6 and linkage disequilibrium (R2=0.01). Results: In the inverse-variance weighted models, out of all adipokines tested, only soluble leptin receptor was significantly associated with NAFLD with beta [95% CI] = -0.075 [-0.173 – -0.133]; and P-value = 0.01. Conclusions: The plasma level of the soluble leptin receptor, but not leptin levels or other adipokines might be significantly associated with the development of NAFLD. These results suggest that adipokines may not have a key role in the development of NAFLD.

L-Serine Supplementation Blunts Fasting-Induced Weight Regain by Increasing Brown Fat Thermogenesis.

Weight regain after fasting, often exceeding the pre-fasting weight, is a common phenomenon and big problem for the treatment of obesity. Thus, novel interventions maintaining reduced body weight are critically important to prevent metabolic disease. Here we investigate the metabolic effects of dietary L-serine supplementation, known to modulate various organ functions. C57BL/6N-Rj male mice were supplemented with or without 1% L-serine in their drinking water and fed with a chow or high-fat diet. Mice were fed either ad libitum or subjected to repeated overnight fasting. Body weight, body composition, glucose tolerance and energy metabolism were assessed. This was combined with a detailed analysis of the liver and adipose tissues, including the use of primary brown adipocytes to study mitochondrial respiration and protein expression. We find that L-serine supplementation has little impact on systemic metabolism in ad libitum-fed mice. Conversely, L-serine supplementation blunted fasting-induced body weight regain, especially in diet-induced obese mice. This reduction in body weight regain is likely due to the increased energy expenditure, based on elevated brown adipose tissue activity. Thus, L-serine supplementation during and after weight-loss could reduce weight regain and thereby help tackle one of the major problems of current obesity therapies.

Organ fat in Latino youth at risk for type 2 diabetes.

Obesity in youth increases the risk for type 2 diabetes (T2D) and elevated abdominal adipose tissue and organ fat may be particularly deleterious. The purpose of this study was to examine associations among measures of adiposity including total, visceral, and organ fat (hepatic and pancreatic) and whether these measures were independently associated with glycemia in Latino youth at risk for diabetes. Latino adolescents (47 boys and 32 girls, 13.7 ± 1.4 years) with obesity (BMIz 2.3 ± 0.3) were assessed for total fat by DXA and visceral and organ fat by 3 T magnetic resonance imaging. Glycemic indicators included HbA1c, fasting glucose (FG), and 2-h glucose (2-HrG) following an oral glucose tolerance test. Pearson correlations and stepwise linear regression analyses controlling for age and sex were used to examine independent associations between adiposity and glycemia. Total fat was associated with visceral (r=0.66, p=0.001) and hepatic fat (r=0.34, p < 0.01) while visceral fat was associated with hepatic (r=0.42, p < 0.001) and pancreatic fat (r=0.36, p < 0.001). In stepwise linear regression analysis, hepatic and pancreatic fat were significant predictors of FG, explaining 4.7% and 5.2% of the variance, respectively (total R2 =0.14, p=0.02). Hepatic fat was the only significant predictor of 2-HrG explaining 9.9% of the variance in the model (total R2 =0.12, p=0.03). No measure of adiposity was retained as a significant predictor of HbA1c. Hepatic and pancreatic fat were the only adiposity measures independently associated with glycemia but the small amount of variance explained underscores the need for additional T2D biomarkers in high risk youth.

Olfactomedin 2 deficiency protects against diet-induced obesity

Background and aimsOlfactomedin 2 (OLFM2; also known as noelin 2) is a pleiotropic protein that plays a major role in olfaction and Olfm2 null mice exhibit reduced olfactory sensitivity, as well as abnormal motor coordination and anxiety-related behavior. Here, we investigated the possible metabolic role of OLFM2. MethodsOlfm2 null mice were metabolically phenotyped. Virogenetic modulation of central OLFM2 was also performed. ResultsOur data showed that, the global lack of OLFM2 in mice promoted anorexia and increased energy expenditure due to elevated brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT). This phenotype led to resistance to high fat diet (HFD)-induced obesity. Notably, virogenetic overexpression of Olfm2 in the lateral hypothalamic area (LHA) induced weight gain associated with decreased BAT thermogenesis. ConclusionOverall, this evidence first identifies central OLFM2 as a new molecular actor in the regulation of whole-body energy homeostasis.

Systemic inflammation mediates the negative relationship between visceral adiposity and cognitive control

Elevated visceral adipose tissue (VAT) has been associated with cardiometabolic risk factors including chronic systemic low-grade inflammation. Whereas the cognitive implications of inflammation have been extensively studied in preclinical models, the influence of inflammatory cytokines on cognitive function in humans is unclear. This study aimed to investigate the relations among VAT, inflammatory cytokines, and cognitive control. We hypothesized that inflammatory markers would mediate the negative influence of VAT on selective attention. Participants between 25 and 46 years (N = 115, 43 females) underwent a DXA scan to estimate VAT. A modified Eriksen Flanker task was used to assess attentional inhibitory control while event-related potentials were recorded. ELISA was used to quantify plasma C-reactive protein (CRP) and Interleukin-6 (IL-6) concentrations. Mediation modeling while controlling for diet quality and education level revealed that CRP concentrations significantly mediated the relationship between VAT and incongruent trial accuracy (indirect effect 95% CI {−0.24, −0.01}). Further, IL-6 concentrations had a significant mediation effect on the relationship between VAT and incongruent P3 peak latency (indirect effect 95% CI {0.05, 1.39}). These results suggest that mechanisms by which visceral adiposity exerts a negative influence on cognitive function includes systemic inflammation.

Beneficial Metabolic Effects of TREM2 in Obesity Are Uncoupled From Its Expression on Macrophages.

Obesity-induced white adipose tissue (WAT) hypertrophy is associated with elevated adipose tissue macrophage (ATM) content. Overexpression of the triggering receptor expressed on myeloid cells 2 (TREM2) reportedly increases adiposity, worsening health. Paradoxically, using insulin resistance, elevated fat mass, and hypercholesterolemia as hallmarks of unhealthy obesity, a recent report demonstrated that ATM-expressed TREM2 promoted health. Here, we identified that in mice, TREM2 deficiency aggravated diet-induced insulin resistance and hepatic steatosis independently of fat and cholesterol levels. Metabolomics linked TREM2 deficiency with elevated obesity-instigated serum ceramides that correlated with impaired insulin sensitivity. Remarkably, while inhibiting ceramide synthesis exerted no influences on TREM2-dependent ATM remodeling, inflammation, or lipid load, it restored insulin tolerance, reversing adipose hypertrophy and secondary hepatic steatosis of TREM2-deficient animals. Bone marrow transplantation experiments revealed unremarkable influences of immune cell–expressed TREM2 on health, instead demonstrating that WAT-intrinsic mechanisms impinging on sphingolipid metabolism dominate in the systemic protective effects of TREM2 on metabolic health.