Dysregulation Of Adipocytokines Research Articles

Probiotic-fermented tomato alleviates high-fat diet-induced obesity in mice: Insights from microbiome and metabolomics

Probiotic-fermented plant-based foods are associated with weight loss. Here, we hypothesized probiotic-fermented tomato (FT) as a functional food with potential to alleviate obesity, thus the obesity-alleviating effects and mechanisms of FT on high-fat diet-induced obese mice were explored via biochemical, gut microbiome, and serum metabolomics analysis. The results showed that FT performed better than unfermented tomato in reducing body weight gain and fat accumulation, improving dyslipidemia and glucose homeostasis, and relieving inflammation and adipocytokine dysregulation. Particularly, live probiotic-fermented tomato (LFT) was associated with improved diversity, composition, and structure of gut microbiota, suppressed obesity-related genera growth (e.g., Clostridium, Olsenella, and Mucispirillum), and promoted beneficial genera growth (e.g., Roseburia, Coprococcus, and Oscillospira), which were associated negatively with body weight, TC, TG, and TNF-α levels. Additionally, LFT was associated with positive changes in glycerophospholipids, sphingolipids, unsaturated fatty acids, and amino acids levels. Collectively, as a functional food, LFT possessed potential for obesity alleviation.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present reviewwas to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

PMON307 Adipokines and Bone Health in Hispanic Children

Abstract Introduction Leptin and adiponectin are adipocytokines with important metabolic functions. Leptin to adiponectin ratio is a marker of adipose tissue dysfunction and is associated with insulin resistance and cardiometabolic risk. We previously reported a negative effect of adiposity on bone health. We examined the relationship of adipokines to bone mass in a large cohort of Hispanic youth. We hypothesized that adipocytokine dysregulation in childhood may contribute to adverse bone health in children with obesity. Methods We studied 501 (237 males and 264 females) children and adolescents from the Viva la Familia Study. They were all pubertal; mean age (SD) 14.1 (2.5) years; 27% were normal weight (NW), 20% overweight (OW) and 53% obese (OB). They underwent measurement of body composition, total body less head bone mineral content (BMC) and density (BMD) by DXA scan; fasting leptin and adiponectin. The leptin to adiponectin ratio was calculated. Results Leptin concentration and leptin to adiponectin ratio were higher in OW and OB compared to NW (p<.001) whereas adiponectin was lower in OW and OB compared to NW (p<.001). After adjusting for sex, age, Tanner stage and lean mass, BMC was inversely related to leptin (r = -0.15, p =.001) and leptin to adiponectin ratio (r = -0.20, p <.001) but positively related to adiponectin (r = 0.12, p =.007). Similar relationships were found for BMD. In a regression model with BMC as the dependent variable, together and independently of sex, age, Tanner stage, lean mass and fat mass, leptin to adiponectin ratio negatively contributed (β = -0.060, p=.002) to the variance of BMC (R2 = 0.877, p <.001). Similar findings were seen with BMD as the dependent variable. Conclusion Elevated leptin to adiponectin ratio, a manifestation of adipokine dysregulation, may contribute negatively to bone health (BMC and BMD) in children with overweight/obesity. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Leonurine Attenuates Obesity-Related Vascular Dysfunction and Inflammation.

Oxidative stress in adipose tissue is a crucial pathogenic mechanism of obesity-associated cardiovascular diseases. Chronic low-grade inflammation caused by obesity increases ROS production and dysregulation of adipocytokines. Leonurine (LEO) is an active alkaloid extracted from Herba Leonuri and plays a protective role in the cardiovascular system. The present study tested whether LEO alleviates inflammation and oxidative stress, and improves vascular function in an obese mouse model. Here, we found that obesity leads to inflammation and oxidative stress in epididymal white adipose tissue (EWAT), as well as vascular dysfunction. LEO significantly improved inflammation and oxidative stress both in vivo and in vitro. Obesity-induced vascular dysfunction was also improved by LEO as evidenced by the ameliorated vascular tone and decreased mesenteric artery fibrosis. Using mass spectrometry, we identified YTHDF1 as the direct target of LEO. Taken together, we demonstrated that LEO improves oxidative stress and vascular remodeling induced by obesity and targets YTHDF1, raising the possibility of LEO treating other obesity-related metabolic syndromes.

Endoplasmic reticulum stress and autophagy are involved in adipocyte-induced fibrosis in hepatic stellate cells.

Liver fibrosis, with the characterization of progressive accumulation of extracellular matrix (ECM), is the common pathologic feature in the process of chronic liver disease. Hepatic stellate cells (HSCs) which are activated and differentiate into proliferative and contractile myofibroblasts are recognized as the main drivers of fibrosis. Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression, but the direct fibrogenic effect of mature adipocytes on HSCs has been rarely reported. Therefore, the purpose of this study was to explore the fibrogenic effect of adipocyte 3T3-L1 cells on hepatic stellate LX-2 cells. The results showed that incubating LX-2 cells with the supernatant of 3T3-L1 adipocytes triggered the expression of ECM related proteins, such as α-smooth muscle actin (α-SMA), type I collagen (CO-I), and activated TGF β/Smad2/3 signaling pathway in LX-2 cells. In addition, 3T3-L1 cells inhibited insulin sensitivity, activated endoplasmic reticulum stress and autophagy to promote the development of fibrosis. These results supported the notion that mature adipocytes can directly activate hepatic stellate cells, and the establishment of an in vitro model of adipocytes on HSCs provides an insight into screening of drugs for liver diseases, such as nonalcoholic fatty liver disease.

Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in HIV-infected adolescents receiving protease inhibitors

BackgroundLipodystrophy is common in HIV-infected patients receiving protease inhibitors (PIs), stavudine, and zidovudine. Adipocytokines may be altered in lipodystrophy. We evaluated risk factors, adipocytokine levels, insulin resistance, and lipid profiles in HIV-infected adolescents with different lipodystrophy types. MethodsA cross-sectional study was conducted in 80 perinatally HIV-infected adolescents receiving PI-based highly active antiretroviral therapy for ≥ 6 months. Patients underwent oral glucose tolerance tests and measurements of high-molecular-weight (HMW) adiponectin, leptin, resistin, insulin, and lipids. They were classified into 3 groups based on the clinical findings: no lipodystrophy, isolated lipoatrophy, and any lipohypertrophy (isolated lipohypertrophy or combined type). ResultsOf the 80 patients (median age, 16.7 years), 18 (22.5%) had isolated lipoatrophy, while 8 (10%) had any lipohypertrophy (four with isolated lipohypertrophy, and four with the combined type). In a multivariate analysis, longer exposure to stavudine (OR: 1.03; 95% CI, 1.01–1.06; p = 0.005) and indinavir (OR: 1.03; 95% CI, 1.01–1.06; p = 0.012) were associated with lipoatrophy, while longer exposure to didanosine (OR: 1.04; 95% CI, 1.01–1.08; p = 0.017) and indinavir (OR: 1.10; 95% CI, 1.00–1.21; p = 0.045) were associated with any lipohypertrophy. Leptin levels were highest in the any-lipohypertrophy group and lowest in the isolated-lipoatrophy group (p = 0.013). HMW adiponectin levels were significantly lowest in the any-lipohypertrophy group and highest in the no-lipodystrophy group (p = 0.001). There were no significant differences in the levels of resistin among the three groups (p = 0.234). The prevalence of insulin resistance (p = 0.002) and prediabetes/diabetes (p < 0.001) were significantly highest in the any-lipohypertrophy group. Patients with lipoatrophy and those without lipodystrophy had comparable degrees of insulin resistance (p = 0.292). In multiple linear regression analysis, adjusted for age, sex, and waist-height ratio, HMW adiponectin levels were associated with Matsuda index (β = 0.5; p = 0.003) and quantitative insulin sensitivity check index (QUICKI) (β = 40.1; p = 0.010) and almost significantly associated with homeostatic model assessment of insulin resistance (HOMA-IR) (p = 0.054). Leptin and resistin levels were not associated with HOMA-IR, Matsuda index, or QUICKI (all p > 0.05). ConclusionsAbnormal glucose metabolism and dysregulation of adipocytokines were common in the HIV-infected adolescents with lipohypertrophy and the combined type. Preventive screening for cardiovascular diseases caused by metabolic alterations should be routinely performed.

Alpha-lipoic acid effect on leptin and adiponectin concentrations: a systematic review and meta-analysis of randomized controlled trials.

New evidence suggests that dysregulation of adipocytokines caused by excess adiposity plays an important role in the pathogenesis of various obesity comorbidities. Our aim in this meta-analysis was to determine the effect of alpha-lipoic acid (ALA) supplementation on serum levels of leptin and adiponectin. We searched Scopus, PubMed, Google Scholar, and ISI Web of Science from inception up to July 2019. Mean difference for leptin and adiponectin were calculated by subtracting the change from baseline in each study group. Summary estimates for the overall effect of ALA on serum leptin and adiponectin concentrations were calculated using random effects model. Results were presented as weighted mean difference (WMD) and their 95% confidence intervals (CI). Between-study heterogeneity was examined using the I2 statistics. Eight studies were included in systematic review and seven studies in meta-analysis. The overall effect suggested a significant decrement in serum leptin concentrations (WMD = - 3.63; 95% CI, - 5.63, - 1.64μg/ml; I2= 80.7%) and a significant increase in serum levels of adiponectin (WMD = 1.98μg/ml; 95% CI, 0.92, 3.04; I2= 95.7%). Subgroup analyses based on age showed a significant reduction in leptin levels only in younger adults, and subgroup analysis based on duration indicated in studies with a duration of more than 8weeks adiponectin levels increased significantly and leptin levels decreased significantly. Our results revealed ALA decreased leptin and increased adiponectin especially in studies lasted more than 8weeks. We still need more studies with different ALA dose, intervention duration, and separately on male and female.

Adiponectin, Obesity, and Cancer: Clash of the Bigwigs in Health and Disease.

Adiponectin is one of the most important adipocytokines secreted by adipocytes and is called a “guardian angel adipocytokine” owing to its unique biological functions. Adiponectin inversely correlates with body fat mass and visceral adiposity. Identified independently by four different research groups, adiponectin has multiple names; Acrp30, apM1, GBP28, and AdipoQ. Adiponectin mediates its biological functions via three known receptors, AdipoR1, AdipoR2, and T-cadherin, which are distributed throughout the body. Biological functions of adiponectin are multifold ranging from anti-diabetic, anti-atherogenic, anti-inflammatory to anti-cancer. Lower adiponectin levels have been associated with metabolic syndrome, type 2 diabetes, insulin resistance, cardiovascular diseases, and hypertension. A plethora of experimental evidence supports the role of obesity and increased adiposity in multiple cancers including breast, liver, pancreatic, prostrate, ovarian, and colorectal cancers. Obesity mediates its effect on cancer progression via dysregulation of adipocytokines including increased production of oncogenic adipokine leptin along with decreased production of adiponectin. Multiple studies have shown the protective role of adiponectin in obesity-associated diseases and cancer. Adiponectin modulates multiple signaling pathways to exert its physiological and protective functions. Many studies over the years have shown the beneficial effect of adiponectin in cancer regression and put forth various innovative ways to increase adiponectin levels.

Impact of a group-based treatment program on adipocytokines, oxidative status, inflammatory cytokines and arterial stiffness in obese children and adolescents.

Background Dysregulation of adipocytokines, inflammatory cytokines and oxidative stress are associated with the pathogenesis of obesity-related complications. This study aimed to evaluate the effect of a group-based lifestyle modification program on adipocytokines, inflammatory cytokines, oxidative status and arterial stiffness in obese youth. Methods A 1-year weight-reduction program was conducted. The program consisted of initial hospitalization and five outpatient group-based sessions held at 1, 2, 3, 6 and 9 months. Pre- and post-intervention measurements included anthropometric data, blood tests, body composition and brachial-ankle pulse wave velocity (ba-PWV). Results A total of 126 obese youths were recruited, and 115 of those completed the study. Twenty-four participants had increased percentage weight for height at the end of the study (group A), 30 had minimal reduction (group B) and 61 had substantial reduction (group C). Lean mass significantly increased in all three groups (all p<0.001). A significant decrease in leptin (group A, p=0.021; group B, p=0.005; group C, p<0.001), interleukin-6 (IL-6) (group A, p=0.019; group B, p=0.004; group C, p<0.001) and ba-PWV (group A, p=0.031; group B, p=0.015; group C, p<0.001) was also observed. No significant change in the oxidative status was found among the groups. Reduction in ba-PWV was correlated with decreases in plasma malondialdehyde (pMDA) (r=0.233, p=0.036) and homeostasis model assessment of insulin resistance (HOMA-IR) (r=0.253, p=0.025). Conclusions A group-based healthy lifestyle program for obese youths had beneficial effects on adipocytokines, inflammatory cytokines and arterial stiffness. Participants without change in weight status also benefited. These improvements may reduce the risk of obese youths developing atherosclerosis.

Long-term soft drink and aspartame intake induces hepatic damage via dysregulation of adipocytokines and alteration of the lipid profile and antioxidant status

Dietary intake of fructose corn syrup in sweetened beverages is associated with the development of metabolic syndrome and obesity. We hypothesized that inflammatory cytokines play a role in lipid storage and induction of liver injury. Therefore, this study intended to explore the expression of adipocytokines and its link to hepatic damage. Rats were assigned to drink water, cola soft drink (free access) and aspartame (240 mg/kg body weight/day orally) for 2 months. The lipid profiles, liver antioxidants and pathology, and mRNA expression of adipogenic cytokines were evaluated. Subchronic intake of soft drink or aspartame substantially induced hyperglycemia and hypertriacylglycerolemia, as represented by increased serum glucose, triacylglycerol, low-density lipoprotein and very low-density lipoprotein cholesterol, with obvious visceral fatty deposition. These metabolic syndromes were associated with the up-regulation of leptin and down-regulation of adiponectin and peroxisome proliferator activated receptor-γ (PPAR-γ) expression. Moreover, alterations in serum transaminases accompanied by hepatic oxidative stress involving induction of malondialdehyde and reduction of superoxide dismutase, catalase, and glutathione peroxidase and glutathione levels are indicative of oxidative hepatic damage. Several cytoarchitecture alterations were detected in the liver, including degeneration, infiltration, necrosis, and fibrosis, predominantly with aspartame. These data suggest that long-term intake of soft drink or aspartame-induced hepatic damage may be mediated by the induction of hyperglycemia, lipid accumulation, and oxidative stress with the involvement of adipocytokines.

Methotrexate improves perivascular adipose tissue/endothelial dysfunction via activation of AMPK/eNOS pathway.

Adipose and endothelial dysfunction is associated with cardiovascular disease. Perivascular adipose tissue (PVAT) directly surrounds vessels and influences vessel function via a paracrine effect, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) modulates the metabolic pathway, thus, the present study hypothesized that activation of AMPK in PVAT may regulate endothelial function in pathological settings. The present study investigated the effect of methotrexate (MTX) on adipocytokine expression in PVAT with an emphasis on the regulation of endothelial function. The effects of MTX and the mechanisms involved were investigated using a relaxation assay and western blot analysis. Reverse transcription‑quantitative polymerase chain reaction and western blotting were used to detect the mRNA and protein expression levels. ELISA assay was used to quantify the level of TNF‑α and IL‑6. Palmitic acid (PA) stimulation induced inflammation and dysregulation of adipocytokine expression in PVAT. MTX treatment inhibited nuclear factor‑κB p65 phosphorylation and downregulated expression of pro‑inflammatory cytokines, including tumor necrosis factor‑α and interleukin-6, whereas adiponectin expression increased. MTX increased AMPK phosphorylation under basal and inflammatory conditions in PVAT, whereas knockdown of AMPK via small interfering RNA diminished its modulatory effect, indicating that MTX inhibits inflammation in an AMPK‑dependent manner. The present study prepared conditioned medium from PA‑stimulated PVAT to induce endothelial dysfunction and observed that pre‑treatment of PVAT with MTX effectively restored the loss of acetylcholine‑induced vasodilation and increased endothelial nitric oxide synthase phosphorylation in the rat aorta. The results of the present study demonstrated that MTX ameliorated inflammation-associated adipocytokine dysregulation and thus prevented endothelial dysfunction. These data provide further pharmacological evidence regarding the beneficial effects of MTX in cardiovascular diseases.

Adiponectin, Leptin and Inflammatory Markers in HIV-associated Metabolic Syndrome in Children and Adolescents.

Metabolic syndrome (MetS) is more common in HIV-infected adults and children than in the general population. Adipocytokines and inflammatory markers may contribute to the pathophysiology of this condition and could be useful indices for monitoring MetS. The objective of this study was to provide information on the prevalence of MetS and investigate the role of adipocytokines and other biomarkers in this syndrome in HIV-infected pediatric patients. A cross-sectional study was conducted between October 2013 and March 2014 in the outpatient clinics of 2 tertiary pediatric referral hospitals. Fifty-four HIV-infected children and adolescents were included. MetS was defined according to the International Diabetes Federation and modified National Cholesterol Education Program Adult Treatment Panel III criteria. Measurements included anthropometry, waist circumference, blood pressure, fasting lipids, glucose and insulin, adiponectin, leptin, interleukin-6, vitamin D and C-reactive protein and clinical lipodystrophy assessment. Among the total, 3.7% of patients met the International Diabetes Federation criteria for MetS and 7.4% met the National Cholesterol Education Program Adult Treatment Panel III criteria. C-reactive protein and leptin levels were significantly higher and adiponectin level significantly lower in patients with MetS, regardless of the criteria used. Insulin resistance was observed in 40.7% of patients; abnormal quantitative insulin sensitivity check index values were found in 88.9%. Eighteen patients (33.3%) had vitamin D deficiency. The prevalence of MetS was similar to that observed in larger cohorts of HIV-infected patients in our setting. Adipocytokine dysregulation seems to be related to MetS in HIV-infected children. A high percentage of patients showed insulin resistance, which should be strictly monitored.

Increased Levels of Inflammatory Marker hsCRP, MDA and Lipid Profile in Non-obese Hypertension Subjects

Introduction: High sensitive C-reactive protein (hsCRP) is a very sensitive marker of inflammation, which is synthesized in the liver and has been a widely used biomarker for risk stratifying in Cardio vascular disease (CVD). It is positively correlated with abdominal fat and closely correlated with increased risk of cardiovascular events and obesity had the predominant association with cytokine levels. Obesity induces systemic oxidative stress and causes dysregulation of adipo cytokines and development of metabolic syndrome. In our study, we investigated hsCRP levels in non-obese hypertensive subjects on treatment and its relationship with oxidative stress and lipid profile. Methods: Patients with secondary hypertension, past history of stroke, coronary artery disease, myocardial infarction, and diabetes mellitus were excluded. Serum lipid profile and thiobarbituric acid reactive substances, hsCRP were estimated in these patients by standard procedures and the values were compared with healthy controls. Totally 160 subjects were included in the study.115 were considered as Hypertension with blood pressure >140/90 mmHg and 45 as healthy controls after obtaining consent. Results: There is significant difference in hsCRP levels between study groups, and hsCRP levels correlate with blood pressure. The level of MDA and hsCRP levels were significantly increased in hypertensive subjects compared to control group. Conclusion: Our study shows that even in non-obese hypertensive subjects there was significant increase of hsCRP, LDL Cholesterol. Hence elevated hsCRP levels in addition to lipid profile screening may be a valuable tool for prediction of CVD risk in hypertensive subjects.

Mitochondrial epigenetic changes and progression from metabolically healthy obesity to metabolically unhealthy obesity: a cross-sectional study

BackgroundObesity is heterogeneous, and more than 40% of metabolically healthy obese (MHO) individuals transition to a metabolically unhealthy obese (MUO) state within 8–10 years. However, the molecular determinants of these two states, and this transition, remain largely unknown. Mitochondria have a key role in metabolic homeostasis, and mitochondrial derangement might induce adipose dysfunction and adipocytokine dysregulation, leading to endocrine and metabolic disorders. In particular, epigenetic changes in mitochondria have been identified in obese individuals with diabetes. We aimed to test the hypotheses that the MHO and MUO states have different mitochondrial epigenetic signatures and that the transition from MHO to MUO is associated with mitochondrial epigenetic changes. MethodsIn this cross-sectional study, we recruited obese participants (BMI >30 kg/m2, aged 26–72 years) in Roanoke, VA, USA. Clinical data (eg, blood pressure) and blood samples were collected. Mitochondrial DNA methylation was assessed by methylation-specific PCR. Metabolic health status (MHO vs MUO) was assessed by several metabolic syndrome criteria: parameters distinguishing MUO from MHO include HDL less than 1·04 mmol/L for men and less than 1·30 mmol/L for women and no treatment; LDL above 2·60 mmol/L; blood pressure above 130/85 mm Hg and no treatment; triglycerides above 1·70 mmol/L; total cholesterol above 5·20 mmol/L; homeostatic model assessment for insulin resistance above 1·95 or 5·13, or 75th percentile; and fasting glucose at least 5·60 mmol/L or 6·10 mmol/L and no treatment. We used ANOVA to determine p values, with values less than 0·05 considered significant. Ethics approval was granted by Institutional Review Boards at Carilion Clinic and at Virginia Tech College, and all participants provided written informed consent. FindingsBetween April 15, 2014, and Jan 29, 2015, we recruited 73 participants (21 men and 52 women, mean BMI 36·5 kg/m2 [SD 7·4], mean age 49·4 years [11·9]). Use of panels of different metabolic syndrome criteria led to a wide range of diagnoses. Specifically, 34–55 (47–75%) individuals had MHO and 18–39 (25–53%) had MUO. Stratification of health status by scoring features of metabolic syndrome showed a consistent increase in DNA methylation in the mitochondrial genes MT-CO1 and MT-ND6, as well as in the mitochondrion-related nuclear gene PPARGC1A, in participants who had a high metabolic syndrome score. For instance, DNA methylation was upregulated by 2·22 times (p=0·0056) in MT-ND6 and by 2·18 times (p=0·0066) in PPARGC1A when the metabolic syndrome score increased from 0 to 4. InterpretationThe disparity of diagnosis underscores the need to improve understanding of the molecular determinants of MHO and MUO. To our knowledge, this is the first study showing mitochondrial epigenetic differences between individuals with MHO versus MUO. Mitochondrial epigenetic signature could potentially be used to stratify the risk of metabolic syndrome for obese individuals. FundingUS Department of Agriculture National Institute of Food and Agriculture Hatch Project1007334 and US National Institutes of Health.

Wasabi leaf extracts attenuate adipocyte hypertrophy through PPARγ and AMPK.

Hypertrophy of adipocytes in obese adipose tissues causes metabolic abnormality by adipocytokine dysregulation, which promotes type 2 diabetes mellitus, hypertension, and dyslipidemia. We investigated the effects of wasabi (Wasabia japonica Matsum) leaf extracts on metabolic abnormalities in SHRSP.Z-Leprfa/IzmDmcr rats (SHRSP/ZF), which are a model of metabolic syndrome. Male SHRSP/ZF rats aged 7weeks were divided into two groups: control and wasabi leaf extract (WLE) groups, which received water or oral treatment with 4g/kg/day WLE for 6weeks. WLE improved the body weight gain and high blood pressure in SHRSP/ZF rats, and the plasma triglyceride levels were significantly lower in the WLE group. Adipocyte hypertrophy was markedly prevented in adipose tissue. The expression of PPARγ and subsequent downstream genes was suppressed in the WLE group adipose tissues. Our data suggest that WLE inhibits adipose hypertrophy by suppressing PPARγ expression in adipose tissue and stimulating the AMPK activity by increased adiponectin.

Adipocytokines in Cardiovascular and Metabolic Diseases.

Obesity, particularly excess visceral fat accumulation, is highly associated with the development of metabolic syndrome and atherosclerotic cardiovascular disease. Adipose tissue produces a variety of secreted proteins, referred to as adipocytokines, which directly affect nearby or remote organs. Dysregulation of adipocytokines caused by obese conditions contributes to the pathogenesis of various metabolic and cardiovascular disorders. This review focuses on the significance of several adipocytokines that potentially exert beneficial actions on obesity-related diseases, including atherosclerosis and ischemic heart disease.

Effects of NAMPT polymorphisms and haplotypes on circulating visfatin/NAMPT levels in hypertensive disorders of pregnancy.

Dysregulation of adipocytokines may be associated with endothelial dysfunction in women with preeclampsia (PE), who are at increased risk of future cardiovascular disease. Visfatin, an adipocytokine with a potential cardiovascular role, is also known as nicotinamide phosphorybosil transferase (NAMPT). NAMPT gene polymorphisms affect circulating visfatin/NAMPT levels in obesity. Most findings provide evidence for increased visfatin/NAMPT circulating levels in PE. However, no previous study has tested the hypothesis that NAMPT polymorphisms affect visfatin/NAMPT levels in hypertensive disorders of pregnancy. We studied the effects of the NAMPT polymorphisms T>C (rs1319501) and A>G (rs3801266), and the haplotypes formed by them on visfatin/NAMPT levels and whether these genetic markers are associated with gestational hypertension (GH) and PE. We studied 212 healthy pregnant (HP), 181 patients with GH and 208 with PE. Genotypes were determined by Taqman allele discrimination assays. Plasma visfatin/NAMPT levels were measured by ELISA. No significant differences in visfatin/NAMPT levels were found among the groups. However, higher visfatin/NAMPT levels (P<0.05) were found in GH patients carrying the AG or the GG genotypes for the rs3801266 polymorphism or the 'T, G' haplotype. The TC and CC genotypes and the C allele for the rs1319501 polymorphism were more frequent in the HP than in the PE group (P<0.05). Moreover, the 'C, A' haplotype was also more frequent in the HP than in the PE group (P<0.01). Our findings suggest that although the rs3801266 polymorphism and the 'T, G' haplotype affect visfatin/NAMPT levels in GH, the rs1319501 polymorphism and the 'C, A' haplotype affect the susceptibility to PE.

Secreted frizzled‐related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis

Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression. Recently, a natural Wnt5a inhibitor, secreted frizzled-related protein 5 (Sfrp5), was identified as a novel adipocytokine that has reduced expression in obese adipose tissue in both rodents and human. In addition, hepatic gene expression of Wnt5a and its receptor frizzled 2 (Fz2) is elevated during fibrosis progression. Therefore, Sfrp5 could have biological significance in liver fibrosis. We first investigated the effects of Sfrp5 on primary cultured mouse hepatic stellate cells (HSCs) in vitro. Next, to elucidate the roles of Sfrp5 in liver fibrosis, we investigated a carbon-tetrachloride (CCl4 )-induced liver fibrosis model using Sfrp5 knockout (KO) and wild type (WT) mice in vivo. Each mouse was injected intraperitoneally with CCl4 (0.5ml/kg) or olive oil as a single dose (acute liver injury model), or twice a week for 6weeks (liver fibrosis model). In in vitro studies, Wnt5a enhanced both proliferation and migration of HSCs, and these effects could be completely blocked by Sfrp5. Moreover, siRNA knockdown of Fz2 in HSCs could block the effects of Wnt5a on both HSC proliferation and migration. In in vivo studies, there were no differences in the CCl4 -induced liver injury between KO and WT mice. Hepatic Wnt5a gene expression and plasma Wnt5a levels significantly increased after a singleCCl4 injection in both mice. Sfrp5 knockout significantly enhanced CCl4 -induced liver fibrosis. Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosis through inhibition of Wnt5a/Fz2 signalling.

Pigment Epithelium–Derived Factor Improves Metabolic Derangements and Ameliorates Dysregulation of Adipocytokines in Obese Type 2 Diabetic Rats

Oxidative stress and inflammation in the adipose tissues contribute to the metabolic syndrome. Pigment epithelium-derived factor (PEDF) inhibits vascular inflammation through its anti-oxidative properties. However, it remains unclear whether PEDF could suppress adipocyte inflammation. We investigated the effects of long-term administration or suppression of PEDF on adipocyte inflammation and metabolic derangements in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes with insulin resistance. Circulating and adipose tissue PEDF levels were increased as OLETF rats became more obese and insulin resistant. Long-term administration of PEDF improves metabolic parameters, ameliorates dysregulation of adipocytokines, and suppresses NADPH oxidase-induced oxidative stress and macrophage infiltration in the adipose tissues of OLETF rats, whereas these variables are exacerbated by the knockdown of PEDF by administering siRNAs. Our study suggests that PEDF could improve metabolic derangements by suppressing the inflammatory and oxidative reactions in adipose tissues of OLETF rats. PEDF levels may be elevated as a countersystem against obesity-related metabolic derangements.

Abstract 372: Upregulation of the Mineralocorticoid System in Obesity-associated Diabetes Leads to Increased Adipocyte Rho Kinase Activation and Dysregulation of Adipocytokines

Increased activation of the renin-angiotensin-aldosterone (RAAS) system is often associated with obesity and metabolic syndrome. We previously reported that aldosterone (aldo) produced by adipocytes regulate vascular function. Despite the fact that aldo production by adipocytes is increased in obesity, the role of aldo and its receptor, the mineralocorticoid receptor (MR), in the regulation of adipocytes biology and their downstream signaling remain elusive. Since Rho kinase (Rock) signaling has recently been implicated in the development of obesity, we tested the hypothesis that MR upregulation leads to dysregulation of adipokines through Rock-dependent mechanisms in obesity. Here we used obese db/db and lean db/+ mice, treated for 4 weeks with K canrenoate (MR antagonist, 30 mg/kg/day) and fasudil (Rock inhibitor, 30 mg/kg/day). Aldo production and Rock activation were measured by ELISA. mRNA and protein levels of adipokines and Rock signaling were assayed by real time PCR and immunoblotting. Plasma and adipocyte-derived aldo levels were increased in db/db mice (plasma: pg/mL, db/+ 310±33, db/db 567±43, p&lt;0.05; adipocytes: pg/mL/μgRNA, db/+ 329±130, db/db 3125±494, p&lt;0.002), an effect partially prevented by MR blockade (pg/mL/μgRNA: db/db 1278±176, p&lt;0.01) and not by fasudil. Aldosterone synthase mRNA levels were increased (2.3 fold) as well as Nr3c2 (MR) (1.8 fold) and markers of MR activation ( Sgk1 and Ngal - 2.3 and 2.9 fold) in mature adipocytes from db/db mice. In mature adipocytes from db/db, adiponectin mRNA levels were decreased (2.6 fold; p&lt;0.01), whereas leptin and IL-6 mRNA levels were increased (2 and 4.8 fold; p&lt;0.01). All changes were blocked by K canrenoate. Rock activity and downstream effectors, such as activation of MYPT1 and ERM, were increased in perivascular adipose tissue from db/db mice, an effect prevented by MR blockade. In conclusion, our data demonstrate that in db/db mice adipocyte MR-dependent activation of Rock is associated with a pro-inflammatory adipose phenotype that is normalized by MR blockade. Our results implicate a potential role of adipocyte aldo/MR through RhoA/Rock in adipocyte dysfunction in obesity/diabetes, important co-morbidities often associated with metabolic syndrome and hypertension.