Reduced Adiponectin Levels Research Articles

From diabetes to renal aging: the therapeutic potential of adiponectin.

Nowadays, the complications related to diabetes, such as nephropathy, cardiovascular problems, and aging, are highly being considered. Renal cell aging is affected by various mechanisms of inflammation, oxidative stress, and basement membrane thickening, which are significant causes of renal dysfunction in diabetes. Due to recent studies, adiponectin plays a key role in diabetes-related kidney diseases as a fat-derived hormone. In diabetes, reduced adiponectin levels are associated to renal cell aging. Oxidative stress and related signaling pathways are the main routes in which adiponectin may be effective to decline diabetes-associated aging. Therefore, adiponectin signaling in target tissues becomes one of the research areas of interest in metabolism and clinical medicine. Studies on adiponectin signaling will increase our understanding of adiponectin role in diabetes-linked diseases as well as shortening life span conditions which may guide the design of antidiabetic and anti-aging drugs.

Lack of adiponectin in mice accelerates high-fat diet-induced progression of chronic kidney disease

Obesity is an independent risk factor for the development of chronic kidney disease. The pathophysiology of the obesity-induced kidney injury is complex, but evidence suggests the involvement of reduced adiponectin levels and signaling. We investigated the extent by which adiponectin contributes to the establishment and progression of renal disease in wild type (WT) and adiponectin null (adipoKO) mice fed a control or a high-fat diet (HFD) for 16 weeks. HFD induced obesity, kidney hypertrophy, albuminuria, renal lipid accumulation and decreased nephrin expression in both mice genotypes. Notably, HFD in adipoKO mice exacerbated progression of albuminuria in comparison to WT mice. In addition, lack of adiponectin per se increased kidney weight, reduced nephrin levels, up-regulated Fabp4 expression, reduced Cpt1a expression and increased miR-130 levels in kidney. Our results demonstrate that lack of adiponectin combined with a HFD contributes to accelerated kidney dysfunction.

1716-P: L-PGDS Inhibition Reduces Adiponectin Levels and Insulin Sensitivity in 3T3-L1 Adipocytes

The prevalence of obesity has increased steadily over the last few decades and is a major risk factor for type 2 diabetes and cardiovascular disease. Obesity is associated with alterations in adipose tissue functioning leading to metabolic dysfunction. In previous studies, we have reported the role of lipocalin-type prostaglandin D2 synthase (L-PGDS) in glucose intolerance and atherosclerosis. More recently, we demonstrated that L-PGDS KO mice develop NAFLD even on a low fat diet. Our present study explored the role of L-PGDS in adipose tissue. We found decreased expression of L-PGDS in insulin resistant 3T3-L1 adipocytes. Enzymatic inhibition of L-PGDS in 3T3-L1 adipocytes using AT56 impaired insulin signaling by reducing the phosphorylation of AKT protein and the expression and translocation of GLUT4 to plasma membrane. Furthermore, we found that inhibition of L-PGDS reduces the expression of adiponectin and AMPK phosphorylation in 3T3-L1 adipocytes. Rosiglitazone treatment in insulin resistant 3T3-L1 adipocytes significantly increased L-PGDS expression. Treatment with rosiglitazone restored the expression of adiponectin and phosphorylation of AMPK in AT56 treated 3T3-L1 adipocytes. Correspondingly, we found decreased L-PGDS expression in visceral fat of obese humans. Cumulatively, these data confirm that the absence of L-PGDS results in decreased insulin sensitivity via impaired insulin signaling and reduced adiponectin levels in 3T3-L1 adipocytes. Thus, our findings suggest that L-PGDS plays a significant role in maintaining the insulin sensitivity in 3T3-L1 adipocytes and provides a novel opportunity for therapeutic intervention of obesity-associated metabolic syndrome. Disclosure A. Srivastava: None. T. Palaia: None. J. Lee: None. C. Hall: None. M. Stevenson: None. A.G. Fernando: None. L. Ragolia: None. Funding American Heart Association (15GRNT22420001); George Link, Jr. Foundation, Inc.

Effect of Sleeve Gastrectomy on Kisspeptin Expression in the Hypothalamus of Rats with Polycystic Ovary Syndrome

ObjectivesThe purpose of this study was to determine changes in the expression levels of kisspeptin‐1 (Kiss1) in the hypothalamus during the development of polycystic ovary syndrome (PCOS) and after treatment with sleeve gastrectomy (SG).MethodsThis study used chronic dehydroepiandrosterone (DHEA) alone and DHEA plus a high‐fat diet (HFD) to generate a PCOS rat model. Subsequently, SG was performed in the animals with PCOS and the effects on glucose tolerance, insulin sensitivity, sex hormones, estrous cyclicity, adiponectin, and Kiss1 expression in the hypothalamus were investigated.ResultsImpaired glucose tolerance, decreased insulin sensitivity, reduced adiponectin levels, disrupted estrous cyclicity, and elevated sex hormone levels associated with PCOS models were restored to normal following SG. In addition, SG was able to restore the increase in the expression of Kiss1 mRNA and Kiss1‐positive neurons in the arcuate nucleus of rats with PCOS. Interestingly, although SG did not result in a significant loss of body weight in rats administered DHEA under a chow diet, it resulted in comparable metabolic improvements and Kiss1 expression in rats that had been administered DHEA along with an HFD.ConclusionsThe recovery of normal levels of Kiss1 expression in the hypothalamus after SG in this study suggests that Kiss1 might play an important role in the development of PCOS and its improvement by SG.

Sex-specific Effects of α2δ-1 in the Ventromedial Hypothalamus of Female Mice Controlling Glucose and Lipid Balance.

The thrombospondin receptor alpha2delta-1 (α2δ-1) plays essential roles promoting the activity of SF1 neurons in the ventromedial hypothalamus (VMH) and mediating glucose and lipid metabolism in male mice. Its role in the VMH of female mice remains to be defined, especially considering that this hypothalamic region is sexually dimorphic. We found that α2δ-1 depletion in SF1 neurons differentially affects glucose and lipid balance control and sympathetic tone in females compared to males. Mutant females show a modest increase in relative body weight gain when fed a high-fat diet (HFD) and normal energy expenditure, indicating that α2δ-1 is not a critical regulator of energy balance in females, similar to males. However, diminished α2δ-1 function in the VMH leads to enhanced glycemic control in females fed a chow diet, in contrast to the glucose intolerance reported previously in mutant males. Interestingly, the effects of α2δ-1 on glucose balance in females are influenced by diet. Accordingly, females but not males lacking α2δ-1 exhibit diminished glycemic control as well as susceptibility to hepatic steatosis when fed a HFD. Increased hepatic sympathetic tone and CD36 mRNA expression and reduced adiponectin levels underlie these diet-induced metabolic alterations in mutant females. The results indicate that α2δ-1 in VMH SF1 neurons critically regulates metabolic function through sexually dimorphic mechanisms. These findings are clinically relevant since metabolic alterations have been reported as a side effect in human patients prescribed gabapentinoid drugs, known to inhibit α2δ-1 function, for the treatment of seizure disorders, neuropathic pain, and anxiety disorders.

Influence of obese phenotype on metabolic profile, inflammatory mediators and stemness of hADSC in adipose tissue.

Unhealthy dietary practices, sedentary life style and lack of physical exercise in developing countries like India are major contributors of metabolic syndrome like obesity and diabetes. Obesity in Indians is defined at Body Mass Index (BMI, kg/m2) >25 and characterized as metabolically obese. A preliminary study performed to explore ramification of obesity on metabolic profile of adipose tissue and adipose derived stem cells (ADSC) from control and obese Indians. Adipose tissue/lipoaspirates from both control (BMI≤23) subjects, and non-diabetic obese Indians subjects (BMI≥25), were scrutinized for expressions of lipogenic genes, inflammatory mediators, stored adipokine levels, and insulin signaling proteins. Further, hADSC were isolated and immune-phenotyped from both the subject groups. Comparative assessments between chADSC and ohADSC were carried out for growth kinetics, expressions of pluripotent genes, adipogenic transcriptional factors, RUNX2, inflammatory mediators (IM), insulin signaling proteins, adipogenic and osteogenic differentiation. Adipose tissue of obese subjects depicted high leptin and resistin levels with reduced adiponectin levels. Expressions of IM and insulin signaling proteins were elevated compared to those of control subjects. hADSC of obese subjects demonstrated diminished proliferation, altered pluripotent genes, aggravated inflammation, adipogenesis with reduced osteogenesis. hADSC of obese had established insulin resistance compared to those of control subjects. This is the first study that describes hADSC of metabolically obese Indians have insulin resistance at lower BMI compared to Caucasians exemplifying plausible role in diminishing stemness of hADSC. Study alarms Indians to restore healthy dietary habits and assess quality of hADSC in regenerative therapy.

Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model.

Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN-/-) mice developed Alzheimer's like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer's disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN-/- mice to generate APN-deficient 5xFAD (5xFAD;APN-/-). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood-brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN-/- mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.

Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression.

This review describes the multifaceted effects of adiponectin on breast cancer cell signalling, tumour metabolism, and microenvironment. It is largely documented that low adiponectin levels are associated with an increased risk of breast cancer. However, it needs to be still clarified what are the extents of the decrease of local/intra-tumoural adiponectin concentrations, which promote breast tumour malignancy. Most of the anti-proliferative and pro-apoptotic effects induced by adiponectin have been obtained in breast cancer cells not expressing estrogen receptor alpha (ERα). Here, we will highlight recent findings demonstrating the mechanistic effects through which adiponectin is able to fuel genomic and non-genomic estrogen signalling, inhibiting LKB1/AMPK/mTOR/S6K pathway and switching energy balance. Therefore, it emerges that the reduced adiponectin levels in patients with obesity work to sustain tumour growth and progression in ERα-positive breast cancer cells. All this may contribute to remove the misleading paradigm that adiponectin univocally inhibits breast cancer cell growth and progression independently on ERα status. The latter concept, here clearly provided by pre-clinical studies, may have translational relevance adopting adiponectin as a potential therapeutic tool. Indeed, the interfering role of ERα on adiponectin action addresses how a separate assessment of adiponectin treatment needs to be considered in novel therapeutic strategies for ERα-positive and ERα-negative breast cancer.

Hypothalamic POMC deficiency increases circulating adiponectin despite obesity

ObjectiveThe steep rise in the prevalence of obesity and its related metabolic syndrome have become a major worldwide health concerns. Melanocortin peptides from hypothalamic arcuate nucleus (Arc) POMC neurons induce satiety to limit food intake. Consequently, Arc Pomc-deficient mice (ArcPomc−/−) exhibit hyperphagia and obesity. Previous studies demonstrated that the circulating levels of adiponectin, a protein abundantly produced and secreted by fat cells, negatively correlate with obesity in both rodents and humans. However, we found that ArcPomc−/− mice have increased circulating adiponectin levels despite obesity. Therefore, we investigated the physiological function and underlying mechanisms of hypothalamic POMC in regulating systemic adiponectin levels. MethodsCirculating adiponectin was measured in obese ArcPomc−/− mice at ages 4–52 weeks. To determine whether increased adiponectin was a direct result of ArcPomc deficiency or a secondary effect of obesity, we examined plasma adiponectin levels in calorie-restricted mice with or without a history of obesity and in ArcPomc−/− mice before and after genetic restoration of Pomc expression in the hypothalamus. To delineate the mechanisms causing increased adiponectin in ArcPomc−/− mice, we determined sympathetic outflow to adipose tissue by assessing epinephrine, norepinephrine, and tyrosine hydroxylase protein levels and measured the circulating adiponectin in the mice after acute norepinephrine or propranolol treatments. In addition, adiponectin mRNA and protein levels were measured in discrete adipose tissue depots to ascertain which fat depots contributed the most to the high level of adiponectin in the ArcPomc−/− mice. Finally, we generated compound Adiopoq−/−:ArcPomc−/− mice and compared their growth, body composition, and glucose homeostasis to the individual knockout mouse strains and their wild-type controls. ResultsObese ArcPomc−/− female mice had unexpectedly increased plasma adiponectin compared to wild-type siblings at all ages greater than 8 weeks. Despite chronic calorie restriction to achieve normal body weights, higher adiponectin levels persisted in the ArcPomc−/− female mice. Genetic restoration of Pomc expression in the Arc or acute treatment of the ArcPomc−/− female mice with melanotan II reduced adiponectin levels to control littermate values. The ArcPomc−/− mice had defective thermogenesis and decreased epinephrine, norepinephrine, and tyrosine hydroxylase protein levels in their fat pads, indicating reduced sympathetic outflow to adipose tissue. Injections of norepinephrine into the ArcPomc−/− female mice reduced circulating adiponectin levels, whereas injections of propranolol significantly increased adiponectin levels. Despite the beneficial effects of adiponectin on metabolism, the deletion of adiponectin alleles in the ArcPomc−/− mice did not exacerbate their metabolic abnormalities. ConclusionIn summary, to the best of our knowledge, this study provides the first evidence that despite obesity, the ArcPomc−/− mouse model has high circulating adiponectin levels, which demonstrated that increased fat mass is not necessarily correlated with hypoadiponectinemia. Our investigation also found a previously unknown physiological pathway connecting POMC neurons via the sympathetic nervous system to circulating adiponectin, thereby shedding light on the biological regulation of adiponectin.

Serum leptin, resistin, and adiponectin levels in obese and non-obese patients with newly diagnosed type 2 diabetes mellitus: A population-based study.

Disturbances in adipocytokine profiles can contribute to peripheral insulin resistance and impairment of insulin production, which are 2 primary pathophysiological mechanisms involved in type 2 diabetes mellitus (T2DM). Previous studies of disturbed adipocytokine profiles have resulted in ambiguous findings; therefore, we conducted the current study comparing leptin, resistin, and adiponectin concentrations in patients with newly diagnosed T2DM who had normal body mass index (BMI) and those who were obese.We studied a population-based cohort of healthy participants and those with newly diagnosed T2DM. A normal BMI group was randomly selected; age- and sex-matched obese participants were recruited. Circulating leptin, resistin, and adiponectin concentrations were measured and compared between groups using analysis of variance; binary logistic regression analysis was then performed to compare the normal BMI and obese groups.In total, 85 healthy participants and 38 patients with diabetes (19 with normal BMI and 17 who were obese) were enrolled. After adjustment for BMI and waist circumference, the median leptin concentration was higher in the obese group (6.77 (3.89–10.73) ng/mL) than in the normal BMI group (1.69 (0.80–3.89) ng/mL) (P = .007), whereas the median adiponectin concentration was lower in the obese group (1.03 (0.75–2.36) μg/mL vs 3.36 (0.59–7.63) μg/mL, P = .03). In addition, the adiponectin/leptin ratio was higher in the normal BMI group (145.6 (41.3–495.9) ng/mL) than in the obese group (20.55 (8.74–36.94) ng/mL, P = .002).Compared with the normal BMI T2DM group, the obese T2DM group exhibited a disturbed adipocytokine profile in the form of a significantly increased leptin concentration and reduced adiponectin level. Further studies are needed to determine the causal relationship for this difference and evaluate its importance for personalized diabetic treatment.

Correlation between transient elastography controlled attenuation parameter and metabolic syndrome components

Objective To investigate the relationship between Fibroscan® data controlled attenuation parameter(CAP), liver stiffness measurement(LSM), and the risk of metabolic syndrome(MS). Methods A total of 817 subjects in this year′s staffs physical checkup screening for fatty liver were recruited. Questionnaires were filled, anthropometries including neck and waist circumferences were collected, and fasting glucose, lipid profiles, insulin, adiponectin levels were measured, CAP and LSM were recorded using FibroScan®. The subjects were divided into MS and control groups. Clinical characteristic parameters were compared, and independent predictors for MS were analyzed. Results There were 231 subjects(28.3%) in the MS group and 586(71.7%) in the control group. As compared to the controls, MS group had significantly higher CAP, LSM, neck circumference, and fasting insulin levels [(277±48 vs 237±44)dB/m, (4.9±2.2 vs 4.1±1.0)kPa, (37.1±3.3 vs 34.1±3.0)cm, (9.3±4.7 vs 5.7±2.9)μIU/ml, all P<0.01], whereas adiponectin levels were lower [(10.6±8.8 vs 18.7±14.9)ng/ml, P<0.01]. With the accumulation of MS components, CAP and LSM increased. When CAP and LSM were divided into quartiles, the number of MS components increased with increasing quartiles, along with proportions and odds ratios for the occurrence of MS, and CAP showed a stronger correlation with MS than LSM. Binary Logistic regression analysis revealed that CAP, age, neck circumference, adiponectin, and fasting insulin levels were independent predictors for MS. Even with no MS component, subjects with CAP≥248 dB/m had elevated body mass index, neck and waist circumference, waist to hip ratio, increased fasting insulin, triglyceride, uric acid and reduced adiponectin levels. Conclusion CAP showed a close relationship with MS. Increased CAP was associated with increased body weight, dyslipidemia, elevated uric acid, and fasting insulin, whereas reduced adiponectin even before the occurrence of MS. Key words: Metabolic syndrome; Transient elastography; Controlled attenuation parameter; Liver stiffness measurement

316-OR: Suppressing Adipose Tissue Inflammation Promotes Insulin Resistance in Mice

Obesity is frequently concomitant with chronic adipose inflammation, although its role in the pathophysiology of obesity remains inconclusive. We previously described that constitutively suppressing adipose inflammation indeed impairs adipose development and leads to profound systemic metabolic disturbances. RIDα/β is an adenoviral protein complex that inhibits several inflammatory pathways, including TNFα and IL1β. To avoid developmental issues, we generated a tet-responsive promoter-driven RIDα/β (“TRE-RID”) mouse and crossed it to an adiponectinP-rtTA mouse to achieve doxycycline(dox)-inducible, adipocyte-specific expression of this transgene (referred to as fatRID mice). We induced RIDα/β expression with dox-chow diet at 8-weeks of age. Upon induction, RIDα/β is specifically expressed in adipocytes, but not in the liver. LPS-stimulated inflammatory markers, such as TNFα, IL1β and Saa3 are significantly decreased in transgenic mice. Under dox-chow fed conditions, fatRID mice display higher levels of glucose and insulin upon refeeding. FatRID mice exhibit glucose intolerance and insulin resistance. Under obesogenic condition with high-fat-diet (HFD, supplement with dox) feeding, fatRID mice gain less weight, but also display insulin resistance. Moreover, to precondition the mice with inflammation and obesity, mice were pre-fed with HFD without dox for 30 days, and then switched to dox-containing HFD. Under these conditions, fatRID mice exhibit similar body weights, but still display glucose intolerance, insulin resistance, massive fatty liver and reduced adiponectin levels. These metabolic impairments were seen despite the fact that inflammatory pathways (including TNFα and IL1β) are effectively reduced. Combined, suppressing adipose inflammation under either normal or obese conditions promotes insulin resistance, despite beneficial (or minimally no negative) effects on body weight. Disclosure Q. Zhu: None. P.E. Scherer: None. Funding National Institutes of Health

Gender disparity in HCC: Is it the fat and not the sex?

Men are more likely to develop hepatocellular carcinoma (HCC) than women, but it is not clear why. In this issue of JEM, Manieri et al. (https://doi.org/10.1084/jem.20181288) identify reduced adiponectin levels as responsible for the increased incidence of HCC in males.

Association between serum/plasma levels of adiponectin and obstructive sleep apnea hypopnea syndrome: a meta-analysis

BackgroundThe relationship between obstructive sleep apnea hypopnea syndrome (OSAHS) and a variety of disease from obesity, type 2 diabetes mellitus and cardiovascular disease has been investigated previously. Reduced adiponectin levels are also associated with increased risk of these disease. However, whether serum/plasma adiponectin levels in OSAHS patients are lower than their counterparts remain controversial. Therefore, this study evaluated the association between serum/plasma adiponectin levels and OSAHS.MethodsWe performed a comprehensive literature search to locate eligible articles published on electronic databases including PubMed, EMBASE, Cochrane Library, WANFANG (Chinese database), VIP (Chinese Database) and Chinese National Knowledge Infrastructure (CNKI). The methodological quality of included studies was evaluated using the Newcastle-Ottawa scale (NOS). Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated as effect size. Heterogeneity test was performed by Cochrane Q test and I2 test. Subgroup analysis and meta-regression analysis were employed to detect the sources of the heterogeneity. RevMan 5.3 and Stata 12.0 software were used in this meta-analysis for data synthesis.ResultsA total of 20 eligible studies with 28 databases involving 1356 participants were included in this meta-analysis. Results revealed that serum/plasma adiponectin levels in OSAHS patients were significantly lower than that in controls [SMD = − 0.71, 95% CI = − 0.92 to − 0.49, p < 0.001]. Subgroup analysis indicated that the heterogeneity would decreased when subgroup analysis was stratified by race. In addition, meta-regression analysis also suggested that the adiponectin levels were only significantly correlated with race. The removal of any independent study did not affect the pooled SMD in the sensitivity analysis.ConclusionThe serum/plasma adiponectin levels were significantly lower in OSAHS patients than that in control subjects, suggesting a possible role of adiponectin in OSAHS pathogenesis, deserves further studies as a potential marker of OSAHS.

The Appetite-Regulating Hormones Leptin, Adiponectin and Ghrelin and the Development of Prostate Cancer: A Systematic Review

Background: Obesity may be associated with prostate cancer (PC), although the underlying mechanisms are not completely characterized. Levels of the appetite-regulating hormones leptin, adiponectin, and ghrelin, deregulate during obesity and a number of epidemiologic and molecular studies have indicated that they may play a role in PC incidence and progression. We conducted a systematic search and review of the published epidemiologic evidence. Aim: To collect and compare evidence analyzing the serum levels of appetite-regulating hormones in patients with PC, with a view to outline their place in the development of this disease. Methods: Adhering to PRISMA guidelines, we conducted a systematic search of peer-reviewed evidence using the databases MEDLINE/PubMed, Embase, Web of Science, and the Cochrane Library. Predefined eligibility criteria was used to screen the articles, including the study design of “case-control” or “nested case-control”, and measurement of patients' serum hormone levels. Two independent readers screened 609 articles by title and abstract, and 68 by full text. We obtained 34 studies in the final selection that was analyzed by systematic review. Results: Twenty-four studies analyzed leptin levels, 17 analyzed adiponectin levels and 2 analyzed ghrelin levels, either in PC patients versus cancer-free controls or in patients with an aggressive form of the disease compared with patients with a less-aggressive form (classified by Gleason grading or TNM staging). In general, results from case-control studies concluded that leptin levels of PC patients were significantly increased compared with cancer-free controls and low-stage or low-grade controls. Conversely, results from nested case-control studies reported no association between leptin levels and PC outcome, indicating that leptin levels increase only at the time of diagnosis. Frequently, reduced adiponectin levels were predictive of the incidence of PC and the occurrence of the aggressive form in both case-control and nested case-control studies, suggesting that adiponectin levels correlated with PC outcome prior to and during time of diagnosis. Therefore, reduced adiponectin may be an early predictor and potentially contributing factor in PC. The 2 studies that analyzed ghrelin levels reported contradictory results, revealing a lack of data on serum ghrelin in PC. In the studies that we reviewed, there was considerable heterogeneity. For example, some authors provided risk estimates for PC after adjusting for patients´ anthropometric measurements, and authors used inconsistent classifications of high- and low-risk PC. Conclusion: Abnormal levels of leptin and adiponectin may occur during PC development, and adiponectin levels may be deregulated prior to the onset of the disease. Dysregulation of the appetite-regulating hormones may partly underlie the association between obesity and PC, and they may represent a modifiable risk factor or treatment target in the future.

P2526Rosuvastatin dose-dependently improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients

P2526Rosuvastatin dose-dependently improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients

DEHP deregulates adipokine levels and impairs fatty acid storage in human SGBS-adipocytes

DEHP is a plasticizer which has been used in plastic products of everyday use for decades. Studies in mice and murine cell culture models identified DEHP as an endocrine disruptor that may also act as an obesogen. As this is of high concern in respect of the worldwide obesity epidemic, our aim is the translation of these findings into a human model system. On the basis of DOHaD, we investigated the influence of an environmentally relevant dose of DEHP [50 µg/ml] on adipogenesis in the human cell culture model SGBS. Pre-adipocytes were exposed to DEHP and differentiated into mature adipocytes. At different stages of differentiation, markers of adipogenesis like GLUT4, FABP4, LPL and PPARs, and of signaling pathways like AMPK/ACC2, JAK/STAT and MAPK were analyzed. Functional markers like adipokine secretion and triglyceride content as well as ROS production were measured in mature adipocytes. We found significantly lower expression levels of adipogenic markers, a reduction in lipid accumulation, higher leptin- and reduced adiponectin levels in the supernatant of treated adipocytes. Moreover, ROS production was significantly elevated after DEHP-exposure. In conclusion, DEHP led to lower grade of adipogenic differentiation in human SGBS-adipocytes under the chosen conditions.

Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression.

Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.

Inflammatory Markers in Older Women with a History of Gestational Diabetes and the Effects of Weight Loss

The purpose of this study was to compare systemic inflammation in older women with a history of gestational diabetes (GDM) who developed impaired glucose tolerance (IGT) or type 2 diabetes (T2DM) to that in those with normal glucose tolerance (NGT) and to determine, in these women, the effect of weight loss (WL) induced by diet and exercise training on systemic inflammation and adipokine levels. This was a longitudinal clinical investigation of overweight/obese (BMI: 32 ± 1 kg/m2) women (59 ± 1 years) with a GDM history (n = 19) who had normal glucose tolerance (NGT, n = 7) or IGT/T2DM (n = 12). Women completed 6 months of weight loss induced by diet and exercise and underwent VO2max, body composition, blood draw, glucose tolerance testing, and 2-hour hyperinsulinemic-euglycemic clamps (40 mU·m−2·min−1). Glucose utilization (M) was 42% higher in the NGT group (P < 0.05). CRP was two-fold higher in the IGT/T2DM group than that in the NGT group (P < 0.01). Adiponectin levels were 59% higher in the NGT group than those in the IGT/T2DM group (P < 0.01). IL-6sR was higher in the NGT group (P < 0.01). The women lost body weight, body fat, visceral fat, and subcutaneous abdominal fat (P < 0.001). Fasting glucose (P < 0.05), fasting insulin, glucose, and insulin AUC decreased (all P < 0.005) after the intervention. M increased by 21% (P < 0.05). CRP (−16%) and TNFR1 (−6%) tended to decrease, whereas TNFα, IL-6, SAA, and adiponectin did not change in the group. In conclusion, older women with a history of GDM who have developed IGT or T2DM have higher CRP and reduced adiponectin levels despite similar BMI and total and abdominal obesity to those with NGT. Six months WL induced by diet and exercise improves body composition and increases insulin sensitivity without a significant modification of inflammatory markers and adiponectin levels.

GW28-e0706 Rosuvastatin dose-dependently improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients

GW28-e0706 Rosuvastatin dose-dependently improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients