Potential emerging roles of the novel adipokines adipolin/CTRP12 and meteorin-like/METRNL in obesity-osteoarthritis interplay.

BACKGROUND: Several insights into obesity-osteoarthritis (OA) relationship have been recently highlighted. Adipolin and metrnl are new adipokines also secreted by chondrocytes. However, their role in OA, and obesity-OA interplay hasn't been elucidated. Therefore, this study was designed to investigate the circulating as well as synovial fluid (SF) levels of adipolin and metrnl in osteoarthritic-patients compared to non-osteoarthritic subjects, and to study their association with OA-severity, dyslipidemia and insulin resistance (IR). METHODS: Patients with osteoarthritis and obesity (n = 30), and subjects with obesity not suffering OA (n = 25) were enrolled in the current study. Circulating and SF-levels of adipolin, metrnl, and insulin, as well as SF-levels of matrix-metalloproteinase-13 (MMP-13) were measured by ELISA. Knee-radiographs using X-ray were done to determine OA-severity, and investigate its association with adipokines' levels. RESULTS: Serum and SF-adipolin levels showed tendency to be lower in OA-patients compared to non-OA-subjects; serum: 0.64 [0.45-0.85] and 0.73 [0.62-0.78] ng/ml, p = 0.174, and SF: 0.53 [0.34-0.69] and 0.63 [0.44-0.74] ng/ml, p = 0.353, respectively. Additionally, serum adipolin showed negative-association with SF-MMP-13. However, when stratifying OA-patients into various severity grades, serum adipolin levels did not show a significant difference between them. Regarding serum metrnl, it was significantly lower in OA-patients compared to non-OA-subjects; 19.68 [10.40-53.40] and 48.83 [20.80-86.60] pg/ml, respectively, p = 0.018. Surprisingly, SF-metrnl levels were higher in OA-patients compared to non-OA-subjects; 912 [367-1524] and 315 [125-484] pg/ml, respectively, p = 0.007. SF-metrnl showed positive-association with insulin resistance, and negative-association with SF-MMP-13. Moreover, higher serum metrnl levels were found to be slightly associated with lower likelihood of OA in subjects with obesity; OR = 0.978, CI (0.960- 0.996), p = 0.02, and its levels were also found to be relatively lower in grade-4 compared to the less severe OAgrades. CONCLUSIONS: Metrnl, and to a lesser extent adipolin seem to be interrelated with OA. Different in-context regulatory mechanisms for metrnl production from various tissues are strongly suggested. Importantly, the findings of the current study shed lights on metrnl as a potential novel mediator and therapeutic target to consider in obesity-OA interplay.

Correlation of Serum Adipolin with Epicardial Fat Thickness and Severity of Coronary Artery Diseases in Acute Myocardial Infarction and Stable Angina Pectoris Patients.

OBJECTIVE: Adipolin/C1q/TNF-related protein-12 is a family of CTRPs highly expressed in adipose tissue with glucose-lowering and anti-inflammatory effects. Various risk factors have been suggested in the incidence of cardiovascular diseases, such as a decrease in anti-inflammatory or an increase in inflammatory factors. The purpose of the present study was to investigate the correlation of adipolin with anthropometric, angiographic, echocardiographic, and biochemical parameters. SUBJECT AND METHODS: A total of 90 patients who were candidates for angiography were included in the study and divided into 3 groups: 30 patients with acute myocardial infarction (AMI), 30 patients with stable angina pectoris (SAP), and 30 subjects as a control group with a history of chest pain but normal angiography. Anthropometric, angiographic, echocardiographic, and biochemical parameters were measured in all subjects. RESULTS: Serum adipolin levels were significantly decreased in patients with AMI compared with the SAP and control groups (p < 0.001 for both). In addition, there was a negative association between serum levels of adipolin and epicardial fat thickness (EFT) and Gensini score in CAD patients. The results of multivariate linear regression analysis revealed that EFT values were independently associated with serum adipolin levels. CONCLUSION: The current study showed an independent association of adipolin with EFT for the first time in patients with AMI. Decreased adipolin levels in patients with AMI may be involved in the process of atherosclerosis, which requires further study.

Decreased serum levels of CTRP12/adipolin in patients with coronary artery disease in relation to inflammatory cytokines and insulin resistance.

Coronary artery disease (CAD) is the leading cause of death worldwide. Atherosclerosis as the main underlying mechanism of CAD is associated with inflammation and adipose tissue dysfunction. C1q/TNF-related protein12 (CTRP12) is a newly discovered adipokine which is a paralog of adiponectin. CTRP12 has anti-inflammatory and insulin sensitizing effects. Circulating levels of this adipokine have been reported to be lower in patients with type 2 diabetes and women with polycystic ovarian syndrome. The present study was undertaken for the first time to evaluate serum levels of CTRP12 in CAD patients and its association with anthropometric and biochemical parameters. Serum levels of CTRP12 were measured using ELISA kit in 188 CAD patients (angiography confirmed) and 70 controls. The serum levels of adiponectin, TNF-α and IL-6 were measured using ELISA kits. Serum levels of CTRP12 were found to be lower in CAD patients (585.48 ±â€¯201.67 pg/mL) than in the controls (814.86 ±â€¯247.85 pg/mL; p < 0.001). CTRP12 also showed an independent association with the risk of CAD (OR [CI] = 0.998 [0.996-0.999]; p = 0.019). Moreover, it showed an inverse correlation with HOMA-IR (r = -0.298; p = 0.012) and TNF-α (r = -0.269; p = 0.023) and a positive correlation with adiponectin (r = 0.344; p = 0.003) in the controls. In CAD patients, CTRP12 was inversely correlated with BMI (r = -0.181, p = 0.013), HOMA-IR (r = -0.199; p = 0.006), TNF-α (r = -0.259; p < 0.001) and IL-6 (r = -320; p < 0.001) and a positive correlation with high density lipoprotein-cholesterol(r = 0.342; p < 0.001) and adiponectin (r = 0.398; p < 0.001). The present study showed for the first time that serum levels of CTRP12 are independently associated with CAD and that CTRP12 is associated with several CAD risk factors. The results suggest a possible link between CTRP12 and pathogenic mechanisms of atherosclerosis, such as inflammation and high density lipoprotein-cholesterol metabolism; however, more study is required in this regard.

Comparative omics and feeding manipulations in chicken indicate a shift of the endocrine role of visceral fat towards reproduction.

BACKGROUND: The mammalian adipose tissue plays a central role in energy-balance control, whereas the avian visceral fat hardly expresses leptin, the key adipokine in mammals. Therefore, to assess the endocrine role of adipose tissue in birds, we compared the transcriptome and proteome between two metabolically different types of chickens, broilers and layers, bred towards efficient meat and egg production, respectively. RESULTS: Broilers and layer hens, grown up to sexual maturation under free-feeding conditions, differed 4.0-fold in weight and 1.6-fold in ovarian-follicle counts, yet the relative accumulation of visceral fat was comparable. RNA-seq and mass-spectrometry (MS) analyses of visceral fat revealed differentially expressed genes between broilers and layers, 1106 at the mRNA level (FDR ≤ 0.05), and 203 at the protein level (P ≤ 0.05). In broilers, Ingenuity Pathway Analysis revealed activation of the PTEN-pathway, and in layers increased response to external signals. The expression pattern of genes encoding fat-secreted proteins in broilers and layers was characterized in the RNA-seq and MS data, as well as by qPCR on visceral fat under free feeding and 24 h-feed deprivation. This characterization was expanded using available RNA-seq data of tissues from red junglefowl, and of visceral fat from broilers of different types. These comparisons revealed expression of new adipokines and secreted proteins (LCAT, LECT2, SERPINE2, SFTP1, ZP1, ZP3, APOV1, VTG1 and VTG2) at the mRNA and/or protein levels, with dynamic gene expression patterns in the selected chicken lines (except for ZP1; FDR/P ≤ 0.05) and feed deprivation (NAMPT, SFTPA1 and ZP3) (P ≤ 0.05). In contrast, some of the most prominent adipokines in mammals, leptin, TNF, IFNG, and IL6 were expressed at a low level (FPKM/RPKM< 1) and did not show differential mRNA expression neither between broiler and layer lines nor between fed vs. feed-deprived chickens. CONCLUSIONS: Our study revealed that RNA and protein expression in visceral fat changes with selective breeding, suggesting endocrine roles of visceral fat in the selected phenotypes. In comparison to gene expression in visceral fat of mammals, our findings points to a more direct cross talk of the chicken visceral fat with the reproductive system and lower involvement in the regulation of appetite, inflammation and insulin resistance.

Serum Levels of Adipolin and Adiponectin and Their Correlation with Perinatal Outcomes in Gestational Diabetes Mellitus.

Objectives: This study aimed to investigate the serum level of adipolin and adiponectin in healthy pregnant women and pregnant women with gestational diabetes mellitus (GDM) during the second trimester, the prepartum period, and in the newborns of these patients. Methods: A total of 55 women diagnosed with GDM and 110 healthy pregnant women were included in this study. Pearson's and Spearman's correlation coefficients were calculated to determine the association of adipolin and adiponectin with anthropometric markers of obesity (body mass index (BMI), mid-upper arm circumference (MUAC), tricipital skinfold thickness (TST)), inflammation markers (neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP)), and maternal glucose homeostasis parameters (fasting glucose, insulin, C peptide, glycosylated hemoglobin A1c (HbA1c), Insulin Resistance-Homeostatic Model Assessment (IR HOMA)). Results: There were no statistical differences between the adipolin value in patients with GDM compared to healthy patients (p = 0.65 at diagnosis and p = 0.50 prepartum) and in newborns from mothers with GDM compared to healthy mothers (p = 0.24). Adipolin levels are significantly higher in patients with GDM who gave birth via cesarean section (p = 0.01). In patients with GDM, the adipolin level correlates positively with HgA1c in the prepartum period. We found a positive correlation between the maternal adipolin values at diagnosis and prepartum and neonatal adipolin (respectively: r = 0.556, p = 0.001; r = 0.332, p = 0.013). Adiponectin levels were significantly lower in patients with GDM at diagnosis and prepartum (p = 0.0009 and p = 0.02), but their levels increased prepartum (5267 ± 2114 ng/mL vs. 6312 ± 3150 ng/mL p = 0.0006). Newborns of mothers with GDM had lower adiponectin levels than newborns of healthy mothers (p < 0.0001). The maternal adiponectin value correlates negatively with maternal BMI, MUAC, and IR HOMA in both groups at diagnosis and prepartum. There were no differences between the groups in terms of cesarean rate (p > 0.99). The relative risk of occurrence of adverse events in patients with GDM compared to healthy ones was 2.15 (95% CI 1.416 to 3.182), and the odds ratio for macrosomia was 4.66 (95% CI 1.591 to 12.69). Conclusions: There was no difference in adipolin levels between mothers with GDM and healthy mothers during the second trimester and the prepartum period. Adipolin is known to enhance insulin sensitivity and reduce inflammation, but unlike adiponectin, it does not appear to contribute to the development of GDM.

Anti-obesity effects of aerobic exercise along with Rosa canina seed extract supplementation in rats: The role of irisin and adipolin.

Aerobic exercise and some bioactive compounds in medicinal plants have anti-obesity effects and can suppress body weight. The aim of this study was to determine the anti-obesity effects of 6 weeks of aerobic exercise (AE) and supplementation of the hydroalcoholic extract of Rosa canina fruit seed (RC) in obese male rats. In this experimental study, 24 high-fat diet (HFD) obese male Wistar rats were used. The animals were randomly divided into 4 groups (6 rat in group), including 1. HFD (the control group), 2. HFD + AE, 3. HFD + RC and 4. HFD + AE + RC. An obesity protocol was implemented for 12 weeks with the consumption of HFD along with the consumption of water containing 1 % fructose. Afterwards, the animals were given access only to HFD food until the end of the study in all the groups. After the obesity protocol, 6 weeks of exercise (50-70 % VO2 max) and access to the extract (1 % of the consumed food) were given. Bodyweight, subcutaneous adipose tissue mass, and some serum lipid profiles were measured in the experimental groups. The serum levels of irisin and adipolin were evaluated by the ELISA method. Expression of FNDC5 and CTRP12 in adipose tissue were determined by real-time PCR. The findings of this study showed that body weight (P = 0.001), subcutaneous adipose tissue mass (P = 0.001), and lipid profile were significantly reduced in HFD + AE and HFD + AE + RC groups compared with the HFD group. Irisin was significantly increased in the HFD + AE and HFD + AE + RC groups compared with the HFD group (P = 0.019 and P = 0.001; respectively) and in the HFD + AE + RC group compared with the HFD + RC group (P = 0.004). Moreover, adipolin, expression of FNDC5 and CTRP12 were significantly increased in the HFD + AE + RC group compared with the HFD group (P = 0.004, P = 0.023, and P = 0.001; respectively). Altogether, HFD + AE with HFD + RC diet supplementation could reduce weight and the risks of obesity, at least, through the up-regulation of irisin and adipolin.

Adipolin and IL-6 Serum Levels in Chronic Obstructive Pulmonary Disease.

Objective(s): One of the adipokines that have insulin-sensitizing properties is adipolin, whose reduced levels have been reported in obesity, oxidative stress, and inflammation. The present study investigated serum interleukin-6 (IL-6) and adipolin levels in chronic obstructive pulmonary disease (COPD) patients. Method: A control case study included 60 COPD patients and 30 healthy subjects in the research and measured adipolin and IL-6 serum levels. In addition, serum adipolin levels in COPD patients were assessed according to the GOLD grade. The relationship between serum adipolin levels and study variables were also analyzed. Results: The results showed reduced adipolin levels in COPD patients compared with healthy individuals (p < 0.001). Furthermore, increased levels of IL-6 were evident in the COPD group compared to the control group (p < 0.001). Adipolin serum levels were positively correlated with PFTs and negatively correlated with IL-6 levels. Conclusion: Decreased adipolin levels enhanced disease severity in COPD patients. It seems that the existence of a significant relationship between adipolin and IL-6 may indicate the role of adipolin in the pathophysiology of COPD.

The effect of omentectomy on the blood levels of adipokines in obese patients with endometrial cancer.

OBJECTIVE: To investigate the blood levels of adipokines in obese patients with endometrial cancer who have and have not undergone omentectomy. METHODS: Between September 2017 and September 2019, the study recruited 54 patients with endometrial cancer. Measurements were taken of blood levels of human leptin, perilipin-1, adiponectin, adipolin, resistin, visfatin, and estrone preoperatively and postoperatively before adjuvant therapy or at the end of one month. The serum samples were separated by centrifugation for 10 mins at 3,000 revolutions/min, then stored at -80 °C until assay. RESULTS: In this prospective study, a total of 54 endometrial cancer patients were analyzed in two separate groups according to the omentectomy status. Comprehensive staging surgery with omentectomy and without omentectomy was performed in 26 patients and 28 patients, respectively. The age, body mass index, body fat index, waist circumference, and skin thickness values of the patients with and without omentectomy were found to be similar. No statistically significant difference was determined between the patients with and without omentectomy in respect of the blood level of the adipokines measured preoperatively. A strong statistically significant correlation was determined between the pre and postoperative levels of Human Leptin (p = 0.002), perilipin-1(p = 0.001), adipolin (p < 0.001), adiponectin (p < 0.001), resistin (p = 0.001), visfatin (p < 0.001), and estrone (p = 0.004) (r = -0.43, -0.47, 0.75, 0.84, -0.47, - 0.58, -0.41, respectively) CONCLUSIONS: Omentectomy affected the postoperative blood levels of adipokines in obese patients with endometrial cancer. As omentectomy may have some positive effects on metabolism in these patients, it may be considered during endometrial cancer surgery due to the possible positive metabolic effects.

Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response.

AIMS: Secreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling. METHODS AND RESULTS: Adipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-ß (TGF-ß) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-ß receptor II (TGF-ßRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-ßRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-ß1 concentration in media from cultured VSMCs and macrophages. CONCLUSION: These data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

CTRP12 inhibits triglyceride synthesis and export in hepatocytes by suppressing HNF-4α and DGAT2 expression.

C1q/TNF-related protein 12 (CTRP12) is an antidiabetic adipokine whose circulating levels are reduced in obesity and diabetes. Although partial and complete loss-of-function mouse models suggest a role for CTRP12 in modulating lipid metabolism and adiposity, its effect on cellular lipid metabolism remains poorly defined. Here, we demonstrate a direct action of CTRP12 in regulating lipid synthesis and secretion. In hepatoma cells and primary mouse hepatocytes, CTRP12 treatment inhibits triglyceride synthesis by suppressing glycerophosphate acyltransferase (GPAT) and diacylglycerol acyltransferase (DGAT) expression. CTRP12 treatment also downregulates the expression of hepatocyte nuclear factor-4α (HNF-4α) and its target gene microsomal triglyceride transfer protein (MTTP), leading to reduced very-low-density lipoprotein (VLDL)-triglyceride export from hepatocytes. Consistent with the in vitro findings, overexpressing CTRP12 lowers fasting and postprandial serum triglyceride levels in mice. These results underscore the important function of CTRP12 in lipid metabolism in hepatocytes.

Role of type 2 diabetes and hemodialysis in serum adipolin concentrations: A preliminary study.

INTRODUCTION: Adipocytokines play a major role in obesity-associated disorders like insulin resistance (IR). IR is prevalent in diabetes and advanced kidney failure. Adipolin is an adipocytokine with major beneficial effects on insulin sensitivity. This study aimed to investigate adipolin concentration and its relationship with IR and other cardiovascular risk factors in patients with diabetes and/or hemodialysis. METHODS: In this preliminary study, 24 obese patients with type 2 diabetes (DM) and 30 with hemodialysis (14 with diabetes and hemodialysis (HD/DM) and 16 with hemodialysis (HD/non-DM)) were studied. Anthropometric indexes, serum concentrations of adipolin, fasting blood glucose (FBG), insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and lipid profile were assessed. FINDINGS: The results showed higher serum adipolin in DM (29 ± 35 ng/mL) than in HD/DM (13 ± 2 ng/mL, P = 0.01) and HD/Non-DM (12 ± 1.6 ng/mL, P = 0.01) groups. Insulin level was lower in DM than HD/DM (P < 0.001) and HD/Non-DM (P < 0.001) groups, and HOMA-IR was also significantly lower in DM compared to HD/DM group (P < 0.001); while, FBG was significantly higher in DM (P < 0.001) and HD/DM (P = 0.006) compared to HD/Non-DM patients. Adipolin was inversely associated with insulin level (r = -0.446, P = 0.001) and HOMA-IR (r = -0.296, P = 0.035). LDL level was higher in DM compared to HD/DM (P = 0.008) and HD/Non-DM (P = 0.005) groups. Adipolin was directly correlated with cholesterol (r = 0.348, P = 0.01) and LDL (r = 0.428, P = 0.001) concentrations. DISCUSSION: Higher adipolin level in DM group might indicate a compensatory elevation in adipolin production or secretion to modulate IR. It might also be due to medications and inflammation. Further studies are required to investigate the precise role of this adipokine in IR.

Proportional correlates of adipolin and cathepsin S in metabolic syndrome patients with and without prediabetes.

BACKGROUND: Adipolin and cathepsin S are intricately involved in pathophysiology of metabolic syndrome (MetS) and prediabetes (PreDM). AIMS & METHODS: This cross-sectional study aimed to compare and correlate between these metabolic biomarkers as well as between them and adiposity, atherogenicity and hematological indices in MetS patients. Our cross-sectional study involved recruiting 29 normoglycemic MetS, 30 newly diagnosed drug naïve PreDM-MetS patients versus 29 lean, healthy and normoglycemic controls. RESULTS: Adipolin and cathepsin S plasma levels were significantly higher in both MetS (normoglycemic and PreDM) groups vs. healthy controls. Evidently proportional adipolin-cathepsin S association was markedly signified in 59 MetS participants (normoglycemic and PreDM). Distinctively unlike adipolin, inverse cathepsin S-diastolic blood pressure (DBP) but direct cathepsin S-monocyte count and its monocyte -to- lymphocyte ratio cross-correlated were marked. Notably unlike cathepsin S, adipolin was positively associated with each of FPG, A1C and TG, visceral adiposity index, lipid accumulation product and atherogenic index of plsama in the MetS pool of participants (N = 59). CONCLUSIONS: Given the intergroup discrepancies in adiposity, atherogenicity indices and their correlations (as well as hematological indices) with biomarkers; this cross-sectional study cannot rule out either biomarker as an associative predictor or as a surrogate indicator and putative prognostic tool for the prediction/prevention and treatment of metabolism dysregularities.

Correlation of Plasma and Salivary Osteocalcin Levels with Nascent Metabolic Syndrome Components with and Without Pre/Diabetes Biochemical Parameters / Correlación de los niveles de osteocalcina en plasma y saliva con los componentes del síndrome metabólico naciente con y sin parámetros bioquímicos de prediabetes

Objectives: This study aimed to compare and correlate plasma and salivary levels of cardiometabolic risk biomarkers’ of pharmacotherapy (appraised using colorimetric assays), adiposity, and atherogenicity indices. Methods: 61 Nascent MetS subjects vs. 30 lean normoglycemic and healthy controls were recruited in Family Medicine outpatient clinics/Jordan University Hospital (a referral medical center). Fasting blood and saliva specimens were collected. Clinical and anthropometric variables were determined along with atherogenecity and adiposity indices. Results: Among nascent MetS (metabolic syndrome) recruits, almost half were normoglycemic, 43% were prediabetic and 8% were diabetic. Pronouncedly Glycemic (FPG and Alc) and lipid parameters (TG, HDL-C and non-HDL-C), adiposity indices (BMI, WHR, WtHR, Conicity-index, BAI, LAP, VAI) and atherogenicity indices (AIP, TC/HDL-C, LDL-C/HDL-C, non-HDL-C/HDL-C and TG/HDL-C) were higher in the nascent MetS group (P<0.05 vs. controls). Markedly among the plasma cardiometabolic risk biomarkers (P<0.05 vs. controls) in the nascent MetS group, adipolin, cathepsin S, ghrelin, irisin, LBP, leptin, and osteocalcin were higher but plasma FGF1 levels were oddly lower. Significantly (P<0.05 vs. controls) nascent MetS –linked salivary levels of adipolin and LBP were higher as opposed to the lower cathepsin S. Only osteocalcin, amongst 9 metabolic risk biomarkers studied, had remarkably significant correlation between plasma and saliva levels, in both total sample and MetS patients (P<0.05). Markedly in the nascent MetS only group, both plasma and salivary osteocalcin correlated with FPG and A1c (P<0.05); salivary osteocalcin correlated with BMI and LAP (P<0.05). Likewise, in the total sample plasma osteocalcin correlated significantly with BMI, BAI, WHt R, SBP, DBP, TG, LAP, VAI, TG/HDL-C and AIP (P<0.05), while salivary osteocalcin had substantial correlations only with FPG and A1c (P<0.05). Conclusion: Association of nascent MetS-related plasma and salivary osteocalcin levels and clinical characteristics and indices propagate salivary osteocalcin as a non-invasive marker for clinical control of MetS-/preDM.(AU)

Role of anti-inflammatory adipokines in obesity-related diseases.

Obesity results in many health complications. Accumulating evidence indicates that the obese state is characterized by chronic low-grade inflammation, thereby leading to the initiation and progression of obesity-related disorders such as type 2 diabetes, hypertension, cardiovascular disease, and atherosclerosis. Fat tissue releases numerous bioactive molecules, called adipokines, which affect whole-body homeostasis. Most adipokines are proinflammatory, whereas a small number of anti-inflammatory adipokines including adiponectin exert beneficial actions on obese complications. The dysregulated production of adipokines seen in obesity is linked to the pathogenesis of various disease processes. In this review we focus on the role of the anti-inflammatory adipokines that are of current interest in the setting of obesity-linked metabolic and cardiovascular diseases.

Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects.

There has been intense interest in the adipokines of the C1q complement/TNF-related protein (CTRP) superfamily. Adipolin (CTRP12) has been described as a novel adipokine, abundantly expressed in adipose tissue with insulin-sensitising and anti-inflammatory effects. We wanted to investigate the effects of acute and chronic hyperinsulinaemia on circulating adipolin concentrations (ELISA) via a prolonged insulin-glucose infusion in humans. We also examined the effects of insulin and the insulin sensitiser, rosiglitazone, on adipolin concentrations (western blotting) in human adipose tissue explants. We found that hyperinsulinaemic induction in healthy lean human subjects significantly increased circulating levels of adipolin (P<0.05 and P<0.01). Furthermore, in subcutaneous adipose tissue explants, insulin significantly increased adipolin protein expression and secretion (P<0.05 and P<0.01). This effect was attenuated by the phosphatidylinositol 3-kinase inhibitor, LY294002 (P<0.05). Moreover, the insulin-sensitising peroxisome proliferator-activated receptor γ (PPARγ) agonist, rosiglitazone, significantly increased adipolin protein expression and secretion in subcutaneous adipose tissue explants (P<0.05 and P<0.01). This effect was inhibited by the PPARγ antagonist, GW9662 (P<0.05). Our data provide novel insights into adipolin physiology in human subjects.

Adipokines and insulin action: A sensitive issue.

Obesity is a major public health concern and a strong risk factor for insulin resistance, type 2 diabetes mellitus (T2DM), and cardiovascular disease. The last two decades have seen a reconsideration of the role of white adipose tissue (WAT) in whole body metabolism and insulin action. Adipose tissue-derived cytokines and hormones, or adipokines, are likely mediators of metabolic function and dysfunction. While several adipokines have been associated with obese and insulin-resistant phenotypes, a select group has been linked with insulin sensitivity, namely leptin, adiponectin, and more recently, adipolin. What is known about these insulin-sensitizing molecules and their effects in healthy and insulin resistant states is the subject of this review. There remains a significant amount of research to do to fully elucidate the mechanisms of action of these adipokines for development of therapeutics in metabolic disease.

Metformin increases the novel adipokine adipolin/CTRP12: role of the AMPK pathway.

Adipolin is a novel adipokine with anti-inflammatory and glucose-lowering properties. Lower levels of adipolin are found in obese and diabetic mice. Polycystic ovary syndrome (PCOS) is a pro-inflammatory state associated with obesity and diabetes. To date, there are no human studies on adipolin. Therefore, we measured serum (ELISA) and adipose tissue adipolin mRNA expression (RT-PCR) and protein concentrations (western blotting) in PCOS and control subjects. We also investigated the ex vivo effect of glucose and metformin on adipolin protein production in human subcutaneous adipose tissue explants. We report novel data that serum and subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were significantly lower in women with PCOS compared with control subjects. Furthermore, Spearman's rank analysis showed that serum adipolin concentrations were significantly negatively correlated with BMI, waist-to-hip ratio, and glucose (P<0.05). However, when subjected to multiple regression analysis, none of these variables were predictive of serum adipolin concentrations (P>0.05). Also, subcutaneous adipose tissue adipolin mRNA expression and protein concentrations were only significantly negatively correlated with glucose (P<0.05). No significant correlations were found with omental adipose tissue adipolin mRNA expression and protein concentrations (P>0.05). Moreover, glucose profoundly reduced and metformin significantly increased adipolin protein production in human adipose tissue explants respectively. Importantly, metformin's effects appear to be via the AMP-activated protein kinase signaling pathway.

Adipolin/CTRP12 protects against LPS-induced ARDS by up-regulating alveolar epithelial sodium channel in mice / 中国病理生理杂志

[ ABSTRACT] AIM:To investigate the effect of adipolin/CTRP12 in LPS-induced acute respiratory distress syn-drome (ARDS) and its potential regulation on alveolar epithelial sodium channel (ENaC) in mice.METHODS:C57BL/6J mice (n=40) were randomly divided into control group, LPS group, adipolin group and wortmannin (PI3K inhibitor) group with 10 mice in each group using random number table.The pathological changes of the lung tissues were evaluated by HE staining.The alveolar fluid clearance ( AFC) was measured by Evans blue-marked albumin, and the concentrations of total protein in bronchoalveolar lavage fluid ( BALF) were assessed by bicinchoninic acid ( BCA) method.In BALF, the levels of IL-1βand TNF-αwere determined by ELISA, and the activity of myeloperoxidase ( MPO) was detected by an MPO assay kit.The total cell counts and polymorphonuclear neutrophil ( PMN) counts in the BALF were analyzed by Gi-emsa staining.The mRNA levels of α-ENaC were assessed by qPCR, while the protein levels of α-ENaC and p-Akt were determined by Western blot.RESULTS: Compared with control group, the classic ARDS pathological changes were ob-served in the mice in LPS group, manifesting by severe pathological lung injury (P 0.05), accompanied by down-regulated levels of α-ENaC and p-Akt in the lung tissues (P<0.05).The deteriorating effects triggered by LPS were significantly reversed by administration of adipolin.However, PI3K inhibitor wortmannin can-celed the beneficial effects of adipolin on LPS-induced ARDS, as evidenced by aggravated lung injury, increased levels of W/D weight ratio, protein levels, cell counts, MPO activity, and IL-1βand TNF-αlevels in the BALF (P<0.05), and decreased levels of AFC,α-ENaC and p-Akt in the lung tissues.CONCLUSION:Adipolin protects against LPS-induced ARDS in the mice by up-regulatingα-ENaC and enhancing AFC via PI3K/Akt signal pathway.