Reduction In Adiponectin Research Articles

Variations of serum levels of adiponectin and resistin in chronic viral hepatitis.

Several studies investigated the possible role of adipokines during chronic viral hepatitis, not producing defined results neither clearly establishing their behavior in course of anti-viral treatment. Our study evaluated blood concentrations of adiponectin and resistin in patients with chronic hepatitis C (CHC), B (CHB), and D (CHD) receiving anti-viral treatment, at baseline and after therapy. We examined 122 subjects, divided into two groups: 64 patients with chronic hepatitis C virus (HCV) infection (38 males and 26 females, mean age 47.25 yr) and 58 patients including 39 ones with chronic hepatitis B virus (HBV) infection (26 males and 13 females, mean age 48.46 yr) and 19 ones with chronic HBV-hepatitis D virus (HDV) infection (15 males and 4 females, mean age 45.79 yr). Serum levels of adiponectin and resistin were assayed by enzyme-linked immunosorbent assay. In the group of CHC patients we observed a significant decrease in resistin after therapy (p=0.006), while not a significant increase in adiponectin after treatment (p=0.32). Evaluation of changes in adiponectin and resistin levels after anti-viral treatment, both in responders and non-responders, revealed no significant variations. In the group of HBV+ and HBV-HDV+ patients, we found a decrease in resistin after therapy (p=0.0016) and a not significant reduction in adiponectin after treatment (p=0.13). Furthermore, we noticed a significant reduction of resistin (p=0.006) in the sub-group of responders. Our data suggested the possible marker role of adiponectin and resistin in the inflammatory process in course of chronic viral hepatitis.

Hypoxia in obesity - from bench to bedside

It is generally accepted that hypoxia is related to sleep apnea in obesity. This concept has been changed since the report of hypoxia response in adipose tissue of obese mice by our group in 2007 [1]. The observation has been confirmed by many laboratories in multiple obesity model systems including mouse and human [2-8]. The adipose tissue hypoxia has been a new concept to explain the adipose tissue dysfunction in obesity [9,10]. It provides a unified answer to all of the pathological changes in the adipose tissue under obesity, such as chronic inflammation, ER stress, leptin expression, adiponectin reduction, adipocyte death, elevated lipolysis and adipocyte insulin resistance [9,10]. Studies suggest that capillary dysfunction occurs during expansion of adipose tissue [11,12], and leads to reduction in adipose blood supply [13], which is responsible for the tissue hypoxia. In this aspect, the adipose tissue dysfunction is a result of local vascular failure in obesity [13]. In addition, the hypoxia-induced inflammation response has beneficial effects in the body. For example, inflammatory response stimulates adipose tissue remodeling [11,14] and promotes energy expenditure to fight against obesity [15,16]. These new insights into the adipose tissue biology suggest that the hypoxia response may be a feedback mechanism in the protection of body against obesity. In translation of this view into clinical setting, it is believed that sleep apnea is also a protection mechanism in the body to maintain energy homeostasis in obesity. It uses the hypoxia response to trigger the onset of multiple protection mechanisms in the body.

Hepatic lipase activity is increased in non‐alcoholic fatty liver disease beyond insulin resistance

Hepatic lipase is a lipolytic enzyme mostly synthesized and localized at the surface of liver sinusoidal capillaries, which hydrolyses triglycerides and phospholipids of intermediate density, large low density (LDL) and high density lipoproteins. Hepatic lipase activity is increased in insulin resistant states. Non-alcoholic fatty liver disease (NAFLD) is characterized by insulin resistance. However, at present, no data are available regarding the behaviour of hepatic lipase with regard to the degree of hepatic steatosis. Our aim was to evaluate hepatic lipase activity in NAFLD patients and its relationship to the severity of hepatic steatosis. We studied 48 patients with NAFLD (diagnosed by ultrasonography and confirmed by liver biopsy) and 30 controls. Steatosis was semi-quantitatively assessed and considered as mild or grade 1, moderate or grade 2 and severe or grade 3. hepatic lipase activity, lipid and lipoprotein profile (including intermediate density lipoproteins and dense LDL), adiponectin, insulin, glucose and high sensitivity C-reactive protein were measured. Homeostasis model assessment for insulin resistance (HOMA) index was calculated. Patients with hepatic steatosis presented with higher hepatic lipase activity, HOMA and dense LDL and lower levels of adiponectin, high density lipoproteins, cholesterol and apoA-I. Hepatic lipase activity positively correlated significantly with the severity of hepatic steatosis. Hepatic lipase correlated with a more atherogenic profile and persisted higher in patients even after corrected for age, gender, body mass index, HOMA and adiponectin. The higher hepatic lipase activity in NAFLD patients contributes to a more atherogenic profile linked to increased cardiovascular risk, beyond the insulin resistance and the reduction in adiponectin.

C-Reactive Protein in the Inflammatory Scene: Still a Long and Winding Road

Over the last decades, inflammation and obesity have deserved particular attention to explain the etiopathogenesis of atherosclerosis. (1, 2) White adipose tissue produces tumor necrosis factor-alpha and specific neutralizing antibodies reverse insulin resistance in obese animals. (3) Therefore, the study of adipose tissue has attracted great interest, as it has been recognized as a real endocrine organ. (2) In most subjects, obesity is associated with changes in adipocytes and macrophage function, expressing a “chronic low-grade inflammation” which leads to insulin resistance (IR) and to the development of diabetes mellitus (DM). (4) Adipose tissue is the main source of interleukin-6 (IL-6), a potent marker of inflammation. This cytokine is also associated with IR and increases the risk of DM, independently of body weight. (5) Adipocytes also produce adiponect in, a cytokine with anti-atherosclerotic effects that increases insulin sensitivity by inhibiting the production of hepatic glucose, improves peripheral glucose utilization and increases fatty acid oxidation. Adiponect in synthesis is reduced in IR, obesity, metabolic syndrome (MS) and DM. Recently, the key role of IR has lost importance while more attention is being paid to the theory of lipotoxicity due to leptin resistance and ectopic lipid deposition.(6) Finally, truncal obesity is related to IR, determining a pro inflammatory condition with increased levels of adipocytokines as IL-6 and tumor necrosis factor-alpha and adiponect in reduction. Prothrombotic mechanisms, such as increase in fibrinogen levels and PAI-1 with subsequent inhibition of fibrinolysis, are also activated. All these factors predispose to other major risk factors as DM, hypertension and dyslipidemia. Under this scenario, the development of atherosclerotic disease may be just a matter of time. Obesity predisposes to the development of DM, one of the main risk factors for cardiovascular disease. In a multicenter study, Yusuf et al,(7) have insisted on the importance of truncal obesity as a major cardiovascular risk factor. The MS is a possible intermediary between risk factors and the likelihood of presenting cardiovascu-

Roles for Peroxisome Proliferator-activated Receptor γ (PPARγ) and PPARγ Coactivators 1α and 1β in Regulating Response of White and Brown Adipocytes to Hypoxia

Obese white adipose tissue is hypoxic but is incapable of inducing compensatory angiogenesis. Brown adipose tissue is highly vascularized, facilitating delivery of nutrients to brown adipocytes for heat production. In this study, we investigated the mechanisms by which white and brown adipocytes respond to hypoxia. Brown adipocytes produced lower amounts of hypoxia-inducible factor 1α (HIF-1α) than white adipocytes in response to low O(2) but induced higher levels of hypoxia-associated genes. The response of white adipocytes to hypoxia required HIF-1α, but its presence alone was incapable of inducing target gene expression under normoxic conditions. In addition to the HIF-1α targets, hypoxia also induced many inflammatory genes. Exposure of white adipocytes to a peroxisome proliferator-activated receptor γ (PPARγ) ligand (troglitazone) attenuated induction of these genes but enhanced expression of the HIF-1α targets. Knockdown of PPARγ in mature white adipocytes prevented the usual robust induction of HIF-1α targets in response to hypoxia. Similarly, knockdown of PPARγ coactivator (PGC) 1β in PGC-1α-deficient brown adipocytes eliminated their response to hypoxia. These data demonstrate that the response of white adipocytes requires HIF-1α but also depends on PPARγ in white cells and the PPARγ cofactors PGC-1α and PGC-1β in brown cells.

Ascorbic acid‐induced reduction in adiponectin is not improved by alpha tocopherol and is accompanied by a small reduction in protein levels of Peroxisome Proliferator‐ Activated Receptor Gamma in 3T3‐L1 adipocytes

Adipocytes play a role in metabolism and regulation of homeostasis through the release of cytokines such as adiponectin. Adiponectin is an anti‐inflammatory adipokine and has been shown to improve insulin sensitivity and enhance beta‐oxidation of fatty acids. A reduction in adiponectin has been associated with increased inflammation, metabolic syndrome and chronic diseases. Since oxidative stress has been known to regulate metabolic disease, we previously investigated the role of ascorbic acid and found that it abolished adiponectin expression in adipocytes. We hypothesized that treatment with ascorbic acid may cause a reduction in PPARgamma protein levels and that alpha tocopherol may mitigate the effect of ascorbic acid on adiponectin synthesis. We used 3T3‐L1 cells to monitor adiponectin protein levels. Differentiated 3T3‐L1 (Day 8), cells were treated with ascorbic acid, with and without alpha tocopherol. We found that the reduction of adiponectin in cell lysates was not overcome with the addition of alpha tocopherol. Further, we also observed a small reduction in PPARgamma in adipocytes treated with ascorbic acid. These results suggest that adipocyte metabolism may be influenced by dietary antioxidants. This research was funded by Florida International University.

Obesity, inflammation and the immune system

Obesity shares with most chronic diseases the presence of an inflammatory component, which accounts for the development of metabolic disease and other associated health alterations. This inflammatory state is reflected in increased circulating levels of pro-inflammatory proteins, and it occurs not only in adults but also in adolescents and children. The chronic inflammatory response has its origin in the links existing between the adipose tissue and the immune system. Obesity, like other states of malnutrition, is known to impair the immune function, altering leucocyte counts as well as cell-mediated immune responses. In addition, evidence has arisen that an altered immune function contributes to the pathogenesis of obesity. This review attempts to briefly comment on the various plausible explanations that have been proposed for the phenomenon: (1) the obesity-associated increase in the production of leptin (pro-inflammatory) and the reduction in adiponectin (anti-inflammatory) seem to affect the activation of immune cells; (2) NEFA can induce inflammation through various mechanisms (such as modulation of adipokine production or activation of Toll-like receptors); (3) nutrient excess and adipocyte expansion trigger endoplasmic reticulum stress; and (4) hypoxia occurring in hypertrophied adipose tissue stimulates the expression of inflammatory genes and activates immune cells. Interestingly, data suggest a greater impact of visceral adipose tissue and central obesity, rather than total body fat, on the inflammatory process. In summary, there is a positive feedback loop between local inflammation in adipose tissue and altered immune response in obesity, both contributing to the development of related metabolic complications.

Resistin Exacerbates Insulin Resistance under the Condition of Low Adiponectin in 3T3-L1 Adipocytes

Adipocytokines such as resistin, TNF-α, and adiponectin, which are adipocyte-derived peptides, play important roles in glucose metabolism. Resistin and TNF-α have been implicated as factors associated with the development of insulin resistance in obesity. In contrast, adiponectin has been shown to improve insulin sensitivity in insulin resistance. However, the interaction among these adipocytokines is still unknown. In this study, we investigated the mechanism of the effects of these 3 adipocytokines (resistin, adiponectin, and TNF-α) on glucose transport in 3T3-L1 adipocytes. Glucose uptake was evaluated by 2-[3H] deoxy-glucose (DOG) uptake assay in 3T3-L1 adipocytes. Resistin and adiponectin secretion were analyzed by western blotting. Adenovirus-mediated overexpression of resistin inhibited insulin-stimulated 2-DOG uptake by only 15% compared with control cells. In contrast, pretreatment of cells with 10 ng/mL TNF-α for 3 hrs did not inhibit insulin stimulated 2-DOG uptake compared with control cells, whereas overexpression of resistin led to a ~ 40% decrease in insulin stimulated 2-DOG uptake following pretreatment with TNF-α. TNF-α has been shown to suppress the expression and secretion of adiponectin from adipocytes. Therefore, we speculated that this potentiating effect of resistin might be caused by the reduction in adiponectin secretion. We confirmed that the secretion of adiponectin was decreased by ~ 50% in TNF-α treated cells compared to control cells. Furthermore, overexpression of adiponectin prevented this additive effect of resistin and TNF-α. In conclusion, these results suggest that: (1) TNF-α enhances the action of resistin via the reduction of adiponectin, 2) Resistin may cause severe insulin resistance under low adiponectin levels.

The H6D variant of NAG‐1/GDF15 inhibits prostate xenograft growth in vivo

Non-steroidal anti-inflammatory drug-activated gene (NAG-1), a divergent member of the transforming growth factor-beta superfamily, has been implicated in many cellular processes, including inflammation, early bone formation, apoptosis, and tumorigenesis. Recent clinical studies suggests that a C to G single nucleotide polymorphism at position 6 (histidine to aspartic acid substitution, or H6D) of the NAG-1 protein is associated with lower human prostate cancer incidence. The objective of the current study is to investigate the activity of NAG-1 H6D variant in prostate cancer tumorigenesis in vivo. Human prostate cancer DU145 cells expressing the H6D NAG-1 or wild-type (WT) NAG-1 were injected subcutaneously into nude mice and tumor growth was monitored. Serum and tumor samples were collected for subsequent analysis. The H6D variant was more potent than the WT NAG-1 and inhibited tumor growth significantly compared to control mice. Mice with tumors expressing the WT NAG-1 have greater reduced both body weight and abdominal fat than mice with H6D variant tumors suggesting different activities of the WT NAG-1 and the H6D NAG-1. A significant reduction in adiponectin, leptin, and IGF-1 serum levels was observed in the tumor-bearing mice with a more profound reduction observed with expression of H6D variant. Cyclin D1 expression was suppressed in the tumors with a dramatic reduction observed in the tumor expressing the H6D variant. Our data suggest that the H6D variant of NAG-1 inhibits prostate tumorigenesis by suppressing IGF-1 and cyclin D1 expression but likely additional mechanisms are operative.

Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling

The adipocyte-derived hormone adiponectin signals from the fat storage depot to regulate metabolism in peripheral tissues. Inversely correlated with body fat levels, adiponectin reduction in obese individuals may play a causal role in the symptoms of metabolic syndrome. Adiponectin lowers serum glucose through suppression of hepatic glucose production, an effect attributed to activation of AMPK. Here, we investigated the signaling pathways that mediate the effects of adiponectin by studying mice with inducible hepatic deletion of LKB1, an upstream regulator of AMPK. We found that loss of LKB1 in the liver partially impaired the ability of adiponectin to lower serum glucose, though other actions of the hormone were preserved, including reduction of gluconeogenic gene expression and hepatic glucose production as assessed by euglycemic hyperinsulinemic clamp. Furthermore, in primary mouse hepatocytes, the absence of LKB1, AMPK, or the transcriptional coactivator CRTC2 did not prevent adiponectin from inhibiting glucose output or reducing gluconeogenic gene expression. These results reveal that whereas some of the hormone's actions in vivo may be LKB1 dependent, substantial LKB1-, AMPK-, and CRTC2-independent signaling pathways also mediate effects of adiponectin.

Improvement in insulin sensitivity by weight loss does not affect hyperinsulinemia-mediated reduction in total and high molecular weight adiponectin: a MONET study

Acute hyperinsulinemia reduces total and high molecular weight (HMW) adiponectin levels in humans. Whether an increase in insulin sensitivity (IS) is accompanied by a greater suppressive effect of hyperinsulinemia on adiponectin levels is unknown, however. To clarify the inhibitory role of insulin on adiponectin, total and HMW adiponectin levels were measured during acute hyperinsulinemia before and after an improvement in insulin sensitivity in response to weight loss. Forty-six overweight and obese postmenopausal women were randomized to either 6-month caloric restriction (CR) alone (n= 22), or CR with resistance training (CR+RT, n = 24). IS (hyperinsulinemic-euglycemic clamp) was assessed before and after weight loss. Total and HMW adiponectin levels were measured by ELISA at baseline, 90, 160, and 180min of each clamp. Relative mean body weight loss was-8.0%± 4.4% for both groups (CR:-7.7% ± 3.8%; CR+RT:-8.2%± 5.0%). IS increased significantly, by 18.4%± 25.3% (CR: 19.3%± 29.7%; CR+RT: 17.7%± 21.0%). Before each intervention, total and HMW adiponectin levels in both groups significantly decreased in response to hyperinsulinemia (total:-8.4%± 19.4%; HMW:-3.2%± 13.2%). Despite the improvement in IS seen after each intervention, a similar pattern of reduction to that before weight loss was observed in total and HMW adiponectin levels during hyperinsulinemia. These results establish that total and HMW adiponectin levels decline during a hyperinsulinemic-euglycemic clamp. Also, the insulin-sensitizing effect of weight loss via caloric restriction alone or with resistance training does not amplify the reduction in adiponectin levels observed during hyperinsulinemia in healthy postmenopausal women.

Serum Adiponectin in Relation to Body Mass Index and Other Correlates in Black and White Women

Adiponectin is a promising biomarker linking obesity and disease risk; however, limited data are available regarding adiponectin in black women among whom obesity is highly prevalent. A cross-sectional analysis was conducted to assess racial differences and correlates of serum adiponectin measured in 996 black and 996 white women enrolled in the Southern Community Cohort Study through Community Health Centers in 12 southeastern states from 2002 to 2006. Black subjects had significantly lower adiponectin levels than white subjects (median 10.9 vs 14.9 μg/mL, Wilcoxon p < .0001). Among black subjects, adiponectin was lower among overweight and obese women compared with healthy weight women but showed no clear decreasing trend with increasing severity of obesity; adjusted geometric means (95% confidence interval) were 15.0 [13.8-16.4], 11.5 [10.6-12.5], 9.7 [9.0-10.6], 11.4 [10.3-12.6], and 10.9 [9.5-12.6] μg/mL for body mass index [BMI] categories of 18.5-24.9, 25-29.9, 30-34.9, 35-39.9, and 40-45, p for trend <.0001). In contrast, among whites there was a monotonic reduction in adiponectin over increasing BMI (adjusted geometric means = 19.9 [18.3-21.7], 15.1 [13.9-16.4], 14.3 [13.2-15.5], 12.5 [11.2-13.9], and 11.0 [9.7-12.5] μg/mL, p for trend <.0001). BMI, age, high-density lipoprotein cholesterol, and hypertension were important correlates of adiponectin in both groups. Among women, racial differences exist in both the magnitude and form of the adiponectin-BMI association.

Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome

Background It is not elucidated if liver fat deposits associated to metabolic syndrome (MS) aggravate the atherogenic state. We evaluated, in MS patients, if the presence of non-alcoholic hepatic steatosis (HS) determines differences in inflammatory markers and VLDL characteristics. Methods Seventy-five patients with MS were divided into 2 groups depending on the presence or absence of HS, assessed by ultrasound. Lipid profile, free fatty acids (FFA), VLDL composition, adiponectin, tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP), and soluble adhesion molecules (sVCAM-1 and sICAM-1) were measured. Results HS patients presented increased triglycerides levels, HOMA-IR and FFA. Patients with HS showed a reduction in adiponectin ( p = 0.04) and increase in hs-CRP ( p = 0.02), independently of insulin-resistance (IR). FFA correlated positively with TNF-α ( p = 0.04) and inversely with adiponectin ( p = 0.01). hs-CRP correlated with all inflammatory markers, independently of IR: TNF-α ( r = 0.34, p = 0.02), sVCAM-1 ( r = 0.29 p = 0.03), sICAM-1 ( r = 0.56, p = 0.01), adiponectin ( r = −0.34, p = 0.04). HS patients presented higher VLDL mass and number of particles. Adiponectin correlated with VLDL cholesterol content ( r = −0.47, p = 0.04), independently of IR. VLDL, once secreted, would suffer from changes, becoming more atherogenic. Conclusions Simple HS would play an important role increasing cardiovascular risk, independently of IR. hs-CRP may represent a useful biomarker of this condition.

Weight gain by hyperalimentation elevates C-reactive protein levels but does not affect circulating levels of adiponectin or resistin in healthy subjects

Increase of resistin and/or reduction of adiponectin have been implicated in the development of insulin resistance following weight gain. We aimed to study this prospectively in humans. Prospective and interventional with parallel control group. Twelve healthy men and six healthy women (age 26 ± 6.6 years) and an age-matched control group were recruited. Subjects in the intervention group aimed for a bodyweight increase of 5-15% by doubling the baseline caloric intake by eating at least two fast food-based meals a day in combination with adoption of a sedentary lifestyle for 4 weeks. Bodyweight increased from 67.6 ± 9.1 to 74.0 ± 11 kg, P<0.001, by the intervention. Insulin levels increased (before: 27.4 ± 12 pmol/l, after: 53.0 ± 22 pmol/l, P=0.004), while plasma levels of adiponectin (before: 5038 ± 3736 ng/ml, after: 6739 ± 7949 ng/ml, P=0.18) and resistin (before: 21.8 ± 19 ng/ml, after: 14.4 ± 6.8 ng/ml, P=0.074) remained unchanged by the weight gain and were similar as in controls. On the other hand, leptin levels increased about threefold following the intervention (before: 5.7 ± 7.4, after: 16 ± 20 ng/ml, P=0.008), and also the inflammatory marker C-reactive protein (CRP) increased from 0.34 ± 0.44 to 0.71 ± 0.87 mg/l, P=0.03, when two outliers >10 mg/l were disregarded. Hyperalimentation reduces insulin sensitivity when weight gain of 9% was combined with reduction of exercise. However, the levels of resistin and adiponectin were unaffected by the intervention, while CRP levels increased within this short time period suggesting that low-grade inflammation can occur early in the process of developing a metabolic syndrome.

Mechanical Loading Regulates NFATc1 and β-Catenin Signaling through a GSK3β Control Node

Mechanical stimulation can prevent adipogenic and improve osteogenic lineage allocation of mesenchymal stem cells (MSC), an effect associated with the preservation of beta-catenin levels. We asked whether mechanical up-regulation of beta-catenin was critical to reduction in adipogenesis as well as other mechanical events inducing alternate MSC lineage selection. In MSC cultured under strong adipogenic conditions, mechanical load (3600 cycles/day, 2% strain) inactivated GSK3beta in a Wnt-independent fashion. Small interfering RNA targeting GSK3beta prevented both strain-induced induction of beta-catenin and an increase in COX2, a factor associated with increased osteoprogenitor phenotype. Small interfering RNA knockdown of beta-catenin blocked mechanical reduction of peroxisome proliferator-activated receptor gamma and adiponectin, implicating beta-catenin in strain inhibition of adipogenesis. In contrast, the effect of both mechanical and pharmacologic inhibition of GSK3beta on the putative beta-catenin target, COX2, was unaffected by beta-catenin knockdown. GSK3beta inhibition caused accumulation of nuclear NFATc1; mechanical strain increased nuclear NFATc1, independent of beta-catenin. NFATc1 knockdown prevented mechanical stimulation of COX2, implicating NFATc1 signaling. Finally, inhibition of GSK3beta caused association of RNA polymerase II with the COX2 gene, suggesting transcription initiation. These results demonstrate that mechanical inhibition of GSK3beta induces activation of both beta-catenin and NFATc1 signaling, limiting adipogenesis via the former and promoting osteoblastic differentiation via NFATc1/COX2. Our novel findings suggest that mechanical loading regulates mesenchymal stem cell differentiation through inhibition of GSK3beta, which in turn regulates multiple downstream effectors.

Acute Hyperinsulinemia Differentially Regulates Interstitial and Circulating Adiponectin Oligomeric Pattern in Lean and Insulin-Resistant, Obese Individuals

Hyperinsulinemia emerges as a negative modulator of the circulating high-molecular-weight adiponectin multimers. Here we asked whether, in vivo, acute hyperinsulinemia regulates adiponectin formation and oligomeric complex distribution at the transcriptional or posttranslational level. Nine lean and nine uncomplicated obese males were studied in the postabsorptive state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Subcutaneous abdominal adipose tissue biopsies and interstitial and serum samples were taken at baseline and after the hyperinsulinemia. Adiponectin complexes were characterized by nonheating/nonreducing SDS-PAGE. At baseline, serum and interstitial total adiponectin levels were lower (P < 0.01) in obese than in lean subjects primarily due to a reduction of the high-molecular-weight isoforms. After hyperinsulinemia, serum and interstitial total adiponectin was reduced in both groups. The degree of adiponectin reduction was more prominent in interstitial fluid than in serum. Lean individuals showed an equal suppression of the high-, low-, and middle-molecular-weight adiponectin complexes both in serum and in situ (P < 0.01 vs. basal). In obese subjects, despite the lower interstitial adiponectin subfractions, insulin challenge reduced significantly the circulating middle-molecular-weight forms only. At the mRNA level, adiponectin and its receptors 1 and 2, as well as the abundance of the endoplasmic reticulum chaperone proteins ERp44 and Epsilonro1-Lalpha were similar within the groups, before and after the clamp. In human obesity, the impaired adiponectin oligomeric pattern in the circulation is mimicked at the tissue level, and hyperinsulinemia may differentially affect the compartmental distribution of the adiponectin complexes.

Enhanced Expressions of mRNA for Neuropeptide Y and Interleukin 1 Beta in Hypothalamic Arcuate Nuclei during Adjuvant Arthritis-Induced Anorexia in Lewis Rats

Objective: Food intake is activated by hypothalamic orexigenic neuropeptide Y (NPY), which is mainly under the dual control of leptin and ghrelin. Rat adjuvant arthritis (AA), similarly as human rheumatoid arthritis, is associated with cachexia caused by yet unknown mechanisms. The aim of our study was to evaluate NPY expression in hypothalamic arcuate nuclei (nARC) under the conditions of AA-induced changes in leptin, ghrelin and adiponectin. Since IL-1β is involved in the central induction of anorexia, we studied its expression in the nARC as well. Methods: AA was induced to Lewis rats using complete Freund’s adjuvant. On days 12, 15 and 18 after complete Freund’s adjuvant injection, the levels of leptin, adiponectin, ghrelin and IL-1β were determined by RIA or ELISA. The mRNA expressions for NPY, leptin receptor (OB-R), ghrelin receptor (Ghsr) and IL-1β were determined by TaqMan RT-PCR from isolated nARC. Results: In AA rats, decreased appetite, body mass and epididymal fat stores positively correlated with reduced circulating and epididymal fat leptin and adiponectin. Ghrelin plasma levels were increased. In nARC, mRNA for OB-R, Ghsr and NPY were overexpressed in AA rats. AA rats showed overexpression of mRNA for IL-1β in nARC while circulating, and spleen IL-1β was unaltered. Conclusion: During AA, overexpression of orexigenic NPY mRNA in nARC along with enhanced plasma ghrelin and lowered leptin levels occur. Decreased food intake indicates a predominant effect of the anorexigenic pathway. Activated expression of IL-1β in nARC suggests its role in keeping AA-induced anorexia in progress. The reduction in adiponectin may also contribute to AA-induced anorexia.

Chagas disease, adipose tissue and the metabolic syndrome

Trypanosoma cruzi infection of the adipose tissue of mice triggers the local expression of inflammatory mediators and a reduction in the expression of the adipokine adiponectin. T. cruzi can be detected in adipose tissue by PCR 300 days post-infection. Infection of cultured adipocytes results in increased expression of cytokines and chemokines and a reduction in the expression of adiponectin and the peroxisome proliferator-activated receptor gamma, both of which are negative regulators of inflammation. Infection also results in the upregulation of cyclin D1, the Notch pathway, and extracellular signal-regulated kinase and a reduction in the expression of caveolin-1. Thus, T. cruzi infection of cultured adipocytes leads to an upregulation of the inflammatory process. Since adiponectin null mice have a cardiomyopathic phenotype, it is possible that the reduction in adiponectin contributes to the pathogenesis of chagasic cardiomyopathy. Adipose tissue may serve as a reservoir for T. cruzi from which parasites can become reactivated during periods of immunosuppression. T. cruzi infection of mice often results in hypoglycemia. In contrast, hyperglycemia as observed in diabetes results in increased parasitemia and mortality. Adipose tissue is an important target tissue of T. cruzi and the infection of this tissue is associated with a profound impact on systemic metabolism, increasing the risk of metabolic syndrome.

Perspectives on Adipose Tissue, Chagas Disease and Implications for the Metabolic Syndrome

The contribution of adipose tissue an autocrine and endocrine organ in the pathogenesis of infectious disease and metabolic syndrome is gaining attention. Adipose tissue and adipocytes are one of the major targets of T. cruzi infection. Parasites are detected 300 days postinfection in adipose tissue. Infection of adipose tissue and cultured adipocytes triggered local expression of inflammatory mediators resulting in the upregulation of cytokine and chemokine levels. Adipose tissue obtained from infected mice display an increased infiltration of inflammatory cells. Adiponectin, an adipocyte specific protein, which exerts antiinflammatory effects, is reduced during the acute phase of infection. The antiinflammatory regulator peroxisome proliferator activated receptor-γ (PPAR-γ) is downregulated in infected cultured adipocytes and adipose tissue. T. cruzi infection is associated with an upregulation of signaling pathways such as MAPKs, Notch and cyclin D, and reduced caveolin-1 expression. Adiponectin null mice have a cardiomyopathy and thus we speculate that the T. cruzi-induced reduction in adiponectin contributes to the T. cruzi-induced cardiomyopathy. While T. cruzi infection causes hypoglycemia which correlates with mortality, hyperglycemia is associated with increased parasitemia and mortality. The T. cruzi-induced increase in macrophages in adipose tissue taken together with the reduction in adiponectin and the associated cardiomyopathy is reminiscent of the metabolic syndrome.

Emerging role of adipose tissue hypoxia in obesity and insulin resistance

Recent studies consistently support a hypoxia response in the adipose tissue in obese animals. The observations have led to the formation of an exciting concept, adipose tissue hypoxia (ATH), in the understanding of major disorders associated with obesity. ATH may provide cellular mechanisms for chronic inflammation, macrophage infiltration, adiponectin reduction, leptin elevation, adipocyte death, endoplasmic reticulum stress and mitochondrial dysfunction in white adipose tissue in obesity. The concept suggests that inhibition of adipogenesis and triglyceride synthesis by hypoxia may be a new mechanism for elevated free fatty acids in the circulation in obesity. ATH may represent a unified cellular mechanism for a variety of metabolic disorders and insulin resistance in patients with metabolic syndrome. It suggests a new mechanism of pathogenesis of insulin resistance and inflammation in obstructive sleep apnea. In addition, it may help us to understand the beneficial effects of caloric restriction, physical exercise and angiotensin II inhibitors in the improvement of insulin sensitivity. In this review article, literatures are reviewed to summarize the evidence and possible cellular mechanisms of ATH. The directions and road blocks in the future studies are analyzed.