The role of bidirectional communication between the adipokines and the endogenous opioid system in an experimental mouse model of colitis-associated colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of death globally. Multiple factors may contribute to the pathogenesis of CRC, including the abnormalities in the functioning of the endogenous opioid system (EOS) or adiponectin-related signaling. The aim of our study was to evaluate if differences in the expression of opioid receptors (ORs) influence the development of CRC and if modulation of adiponectin receptors using AdipoRon, a selective AdipoR1 receptor agonist, affects colorectal carcinogenesis. METHODS: Naltrexone, an opioid receptor antagonist, was injected intraperitoneally every second day for 2 weeks, at the dose of 1 mg/kg in healthy Balb/C mice to induce changes in ORs expression. CRC was induced by a single intraperitoneal injection of azoxymethane (AOM) and the addition of dextran sodium sulfate (DSS) into drinking water in three-week cycles. The development of CRC was assessed using macro- and microscopic scoring and molecular analysis (RT qPCR, ELISA) after 14 weeks. RESULTS: Naltrexone significantly increased the mRNA expression of Oprm1, Oprd1, and Oprk1 in the mouse colon and in the brain (non-significantly). The pretreatment of mice with naltrexone aggravated the course of CRC (as indicated by tumor area, colon thickness, and spleen weight). The level of circulatory adiponectin was lowered in mice with CRC and increased in the colon as compared with healthy mice. The ß-endorphin level was increased in the plasma of mice with CRC and decreased in the colon as compared to healthy mice. AdipoRon, AdipoR1 agonist, worsened the CRC development, and pretreatment with naltrexone enhanced this negative effect in mice. CRC did not affect the expression of the Adipor1 gene, but the Adipor1 level was increased in mice pretreated with naltrexone (AOM/DSS and healthy mice). AdipoRon did not influence the expression of opioid receptors at the mRNA level in the colon of mice with CRC. The mRNA expression of Ptgs2, Il6, Nos2, Il1b, Il18, Gsdmd, and Rela was increased in mice with CRC as compared to the healthy colon. AdipoRon significantly decreased mRNA expression of Ptgs2, Il6, Il1b, and Il18 as compared to CRC mice. CONCLUSION: EOS and adiponectin-related signaling may play a role in the pathogenesis of CRC and these systems may present some additivity during carcinogenesis.

Role of Adiponectin-Notch pathway in cognitive dysfunction associated with depression and in the therapeutic effect of physical exercise.

A substantial percentage of late-life depression patients also have an cognitive impairment, which severely affects the life quality, while the co-occurring mechanisms are still unclear. Physical exercise can ameliorate both depressive behaviors and cognitive dysfunction, but the molecular mechanisms underlying its beneficial effects remain elusive. In this study, we uncover a novel adipose tissue to hippocampus crosstalk mediated by Adiponectin-Notch pathway, with an impact on hippocampal neurogenesis and cognitive function. Adiponectin, an adipocyte-derived hormone, could activate Notch signaling in the hippocampus through upregulating ADAM10 and Notch1, two key molecules in the Notch signaling. Chronic stress inhibits the Adiponectin-Notch pathway and induces impaired hippocampal neurogenesis and cognitive dysfunction, which can be rescued by AdipoRon and running. Inhibition Notch signaling by DAPT mimics the adverse effects of chronic stress on hippocampal neurogenesis and cognitive function. Adiponectin knockout mice display depressive-like behaviors, associated with inhibited Notch signaling, impaired hippocampal neurogenesis and cognitive dysfunction. Physical exercise could activate Adiponectin-Notch pathway, and improve hippocampal neurogenesis and cognitive function, while deleting adiponectin gene or inhibiting Notch signaling blocks its beneficial effects. Together, our data not only suggest that Adiponectin-Notch pathway is involved in the pathogenesis of cognitive dysfunction associated with depression, but also contributes to the therapeutic effect of physical exercise. This work helps to decipher the etiology of cognitive impairment associated with depression and hence will provide a potential innovative therapeutic target for these patients.

Effects of exogenous adiponectin supplementation in early pregnant PCOS mice on the metabolic syndrome of adult female offspring.

OBJECTIVE: PCOS is a heterogeneous endocrine disorder with both reproductive and metabolic abnormalities. At present, PCOS has been confirmed to have a certain genetic background. Compared with healthy women, the vast majority of PCOS patients have hyperandrogenemia, and this excessive androgen exposure during pregnancy may affect the development of female fetuses. The aim of the current study was to investigate the effect of adiponectin intervention during early pregnancy of obese mice with PCOS on the metabolic phenotype of adult female offspring. METHODS: After the PCOS model was established, C57BL/6J mice were divided into maternal-control, maternal-PCOS, and maternal-PCOS + APN groups. DHEA-induced PCOS mice were supplemented with adiponectin (10 mg/kg/day) in the early pregnancy in order to eliminate adverse hormone exposure and then traced for endocrine indicators in their adult female offspring, which were observed for metabolism syndrome or endocrine disturbance and exhibited the main effects of APN. To further explore the underlying mechanism, the relative expressions of phosphorylated AMPK, PI3K, and Akt were detected in the ovaries of offspring mice. RESULTS: The serum testosterone level of the maternal-PCOS + APN group in early pregnancy was significantly lower than that of the maternal-PCOS group (p < 0.01). The serum testosterone level in the offspring-PCOS + APN group was significantly lower than in the offspring-PCOS group (p <0.05), the diestrus time characterized by massive granulocyte aggregation in the estrus cycle was significantly shorter than in the offspring-PCOS group (p<0.05), and the phenotypes of PCOS-like reproductive disorders and metabolic disorders, such as obesity, insulin resistance, impaired glucose tolerance, and hyperlipidemia, were also significantly improved in the offspring-PCOS + APN group (p < 0.05). Compared with the control group, the expression levels of phosphorylated AMPK, PI3K, and Akt in the offspring-PCOS group were significantly decreased (p < 0.05), while those in the offspring-PCOS + APN group were significantly increased (p < 0.05). CONCLUSIONS: APN intervention in early pregnancy significantly reduced the adverse effects of maternal obesity and high androgen levels during pregnancy on female offspring and corrected the PCOS-like endocrine phenotype and metabolic disorders of adult female offspring. This effect may be caused by the activation of the AMPK/PI3K-Akt signaling pathway in PCOS offspring mice.

Molecular Links between Central Obesity and Breast Cancer.

: Worldwide, breast cancer (BC) is the most common malignancy in women, in regard to incidence and mortality. In recent years, the negative role of obesity during BC development and progression has been made abundantly clear in several studies. However, the distribution of body fat may be more important to analyze than the overall body weight. In our review of literature, we reported some key findings regarding the role of obesity in BC development, but focused more on central adiposity. Firstly, the adipose microenvironment in obese people bears many similarities with the tumor microenvironment, in respect to associated cellular composition, chronic low-grade inflammation, and high ratio of reactive oxygen species to antioxidants. Secondly, the adipose tissue functions as an endocrine organ, which in obese people produces a high level of tumor-promoting hormones, such as leptin and estrogen, and a low level of the tumor suppressor hormone, adiponectin. As follows, in BC this leads to the activation of oncogenic signaling pathways: NFκB, JAK, STAT3, AKT. Moreover, overall obesity, but especially central obesity, promotes a systemic and local low grade chronic inflammation that further stimulates the increase of tumor-promoting oxidative stress. Lastly, there is a constant exchange of information between BC cells and adipocytes, mediated especially by extracellular vesicles, and which changes the transcription profile of both cell types to an oncogenic one with the help of regulatory non-coding RNAs.

Adiponectin: a therapeutic target in the antiphospholipid syndrome?

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of the IgG and/or IgM isotypes of the antiphospholipid antibodies, thrombosis and/or recurrent pregnancy losses. Various markers of inflammation are associated with clinical and/or laboratory features of APS. Adiponectin (Ad) is a member of the adipocytokines that exert its roles by binding to its receptors (AdR). Peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists induced Ad production. The aged Pparg null-mice represented the first animal model that spontaneously develops APS and this model emphasized the importance of PPAR-gamma signaling in the development of APS. Recombinant Ad (rAd) application was beneficial for the improvement of glucose, insulin and lipid levels in mice. Orally active AdR agonist exerted similar effects to Ad in mice. Due to the re-occurrence of thrombotic episodes in APS patients (despite life-long anticoagulation), administration of PPAR-gamma agonists, rAd, or AdR agonists should be further tested in experimental models of APS, which eventually, will provide more data for novel therapeutic strategies that will ameliorate clinical manifestations of the APS.

Adiponectina sérica en adultos normopeso, con sobrepeso u obesidad y su relación con el riesgo cardiovascular / Serum adiponectin in obese, overweight, and normal weight adults and its relationship with cardiovascular risk / Adiponectina sérica em adultos com peso normal, sobrepeso ou obesidade e sua relação com o risco cardiovascular

La adiponectina se ha relacionado con la resistencia a la insulina, la dislipemia y la enfermedad coronaria. El propósito del estudio fue evaluar la relación entre los niveles séricos de adiponectina y factores de riesgo cardiovascular (FRC) en adultos normopeso, con sobrepeso u obesidad. Se realizó un estudio descriptivo, correlacional y transversal en 73 adultos entre 20 y 40 años. Se determinó el perfil lipídico, los indicadores de resistencia a la insulina y la adiponectina sérica. Se midió el peso, talla y circunferencia de cintura y se determinó el Índice de Masa Corporal y la tensión arterial. Se relacionaron las variables en estudio. Los resultados mostraron que las concentraciones séricas de adiponectina para el total de la muestra fueron en promedio más bajas en los sujetos obesos respecto de los normopeso (p<0,01). Estas diferencias se encontraron tanto en el sexo masculino como en el femenino (p<0,01). Adicionalmente, los valores resultaron mayores en las mujeres en relación con los hombres (p<0,01). La adiponectina correlacionó significativamente con la resistencia a la insulina y la mayoría de los FRC estudiados (p<0,01), a excepción del colesterol total y del cLDH. Estos hallazgos sugieren la utilidad de la adiponectina sérica como un marcador potencial de riesgo cardiovascular en adultos.

Adiponectin has been linked to insulin resistance, dyslipidemia and coronary disease. The purpose of the study was to evaluate the relationship between serum adiponectin levels and cardiovascular risk factors (CRF) in obese, overweight, and normal weight adults. The study was descriptive, correlational and cross-sectional in 73 adults between 20 and 40 years of age. Lipid profile, indicators of insulin resistance and serum adiponectin were determined. Weight, height and waist circumference were measured and body mass index and blood pressure were determined. The variables studied were related. The results showed that serum adiponectin levels for the total sample were, on average, lower in obese subjects compared to normal weight (p<0.01). These differences were found both in males and females (p<0.01). Additionally, the values were higher in women compared to men (p<0.01). Adiponectin correlated significantly with insulin resistance and most of the CRFs studied (p<0.01), except for total cholesterol and LDL-c. These findings suggest the utility of serum adiponectin as a potential marker of cardiovascular risk in adults.

Adiponectina tem sido associada à resistência à insulina, dislipidemias e doença coronariana. A finalidade do estudo foi avaliar a relação entre os níveis séricos de adiponectina e factores de risco cardiovascular (FRC) em adultos com peso normal, excesso de peso ou obesidade. Um estudo descritivo, correlacional e transversal foi realizado em 73 adultos entre 20 e 40 anos de idade. Foi determinado o perfil lipídico, indicadores de resistência à insulina e a adiponectina sérica. Foi medido o peso, altura e circunferencia da cintura e se determinou o índice de massa corporal e a pressão arterial. As variáveis estudadas foram relacionadas. Os resultados mostraram que as concentrações séricas de adiponectina para o total da amostra foram em média, inferiores em indivíduos obesos em comparação com peso normal (p<0,01). Essas diferenças foram encontradas tanto no sexo masculino quanto no feminino (p<0,01). Além disso, os valores eram mais elevados em mulheres em comparação com homens (p <0,01). A adiponectina correlacionou-se significativamente com a resistência à insulina e a maioria dos FRC avaliados (p<0,01), com exceção do colesterol total e do LDL-c. Estes resultados sugerem a utilidade da adiponectina sérica como um marcador potencial de risco cardiovascular em adultos.

Central adiponectin acutely improves glucose tolerance in male mice.

Adiponectin, an adipocyte-derived hormone, regulates glucose and lipid metabolism. It is also antiinflammatory. During obesity, adiponectin levels and sensitivity are reduced. Whereas the action of adiponectin in the periphery is well established the neuroendocrine role of adiponectin is largely unknown. To address this we analyzed the expression of adiponectin and the 2 adiponectin receptors (AdipoR1 and AdipoR2) in response to fasting and to diet-induced and genetic obesity. We also investigated the acute impact of adiponectin on central regulation of glucose homeostasis. Adiponectin (1 µg) was injected intracerebroventricularly (ICV), and glucose tolerance tests were performed in dietary and genetic obese mice. Finally, the influence of ICV adiponectin administration on central signaling cascades regulating glucose homeostasis and on markers of hypothalamic inflammation was assessed. Gene expression of adiponectin was down-regulated whereas AdipoR1 was up-regulated in the arcuate nucleus of fasted mice. High-fat (HF) feeding increased AdipoR1 and AdipoR2 gene expression in this region. In mice on a HF diet and in leptin-deficient mice acute ICV adiponectin improved glucose tolerance 60 minutes after injection, whereas normoglycemia in control mice was unaffected. ICV adiponectin increased pAKT, decreased phospho-AMP-activated protein kinase, and did not change phospho-signal transducer and activator of transcription 3 immunoreactivity. In HF-fed mice, ICV adiponectin reversed parameters of hypothalamic inflammation and insulin resistance as determined by the number of phospho-glycogen synthase kinase 3 ß(Ser9) and phospho-c-Jun N-terminal kinase (Thr183/Tyr185) immunoreactive cells in the arcuate nucleus and ventromedial hypothalamus. This study demonstrates that the insulin-sensitizing properties of adiponectin are at least partially based on a neuroendocrine mechanism that involves centrally synthesized adiponectin.

Multifaceted roles of adiponectin in cancer.

Obesity is linked to increased cancer risk. Pathological expansion of adipose tissue impacts adipocyte function and secretion of hormonal factors regulating tissue homeostasis and metabolism. Adiponectin is an adipocyte-secreted, circulating hormone with pleiotropic functions in lipid and glucose metabolism, and beneficial roles in cardiovascular functions and inflammation. In obesity, decreased Adiponectin plasma levels correlate with tumor development and progression. The association of Adiponectin with potential tumor-limiting functions has raised significant interest in exploring this adipokine as a target for cancer-diagnostic and therapeutic applications. Recent studies, however, also implicate Adiponectin in supporting malignancy. This review highlights the evidence that links Adiponectin signaling to either cancer-protective or cancer-supporting functions. In this context, we discuss Adiponectin interactions with its receptors and associated signaling pathways. Despite significant advances in understanding Adiponectin functions and signaling mechanisms, its role in cancer remains multifaceted and subject to controversy.

Pro-inflammatory cytokine associated with somatic and pain symptoms in depression.

BACKGROUND: More than two-thirds of depressed patients complain of somatic and pain symptoms, which are frequently regarded as a psychological reaction. Although there is a growing body of evidence showing that depression is related to immune abnormalities, few studies have investigated the association between inflammatory cytokines and somatic/pain symptoms. METHOD: Patients with depressive disorder but without any medical disorders, and age/gender/body mass index (BMI)-matched healthy subjects were enrolled. All the subjects completed the self-rating scales of the Beck Depression Inventory-II and the Depression and Somatic Symptoms Scale, which was comprised of depressive, somatic, and pain subscales. Pro-inflammatory cytokines, including C-reactive protein (CRP), interleukin-2 receptor (sIL-2R), soluble interleukin 6 receptor (sIL-6R), soluble TNF-receptors (sTNF-R), soluble P-selectin (sP-selectin), monocyte chemotactic protein-1 (MCP-1), and adiponectin, were assessed by enzyme-linked immunosorbent assays. RESULTS: In all, 109 patients with depressive disorder and 126 normal controls were enrolled. The patients with depressive disorder had significantly more severe depression, somatic and pain symptoms (all p<0.001), and higher levels of sIL-2R (p<0.0001), sTNF-R (p<0.001), and sP-selectin (p=0.005) than the normal control group. Using multivariate regression analysis with controlling of age, gender, BMI, and other pro-inflammatory cytokines, sIL-2R was the most significant predictor for depressive symptoms (p<0.0001); with further controlling of severity of depressive symptom, sP-selectin was the only predictor for somatic (p=0.002) and pain (p=0.059) symptoms. CONCLUSION: The elevated sP-selectin associated with somatic symptoms in depression, may indicate early micro-vascular changes occur subtly, and provide neurobiological evidence for somatic and pain symptom in depression.

Equol, adiponectin, insulin levels and risk of breast cancer.

Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer death among women. Soy isoflavones have been widely studied and among all isoflavones equol has been gaining interest with regard to its relationship with breast cancer risk. Obesity has been revealed as one of the breast cancer risk factors, known to be associated with high levels of circulating insulin and decreased levels of adiponectin. Hence there have been many studies investigating relationships between insulin and adiponectin levels and breast cancer risk. Additionally recent findings have suggested that insulin and adiponectin themselves may have influence on breast cancer development, independent of obesity. In the present review, we discuss the relationships between breast cancer risk and equol, insulin and adiponectin levels, which are three important factors in our ongoing hospital-based case-control study. Herein these factors are reviewed not only from the clinical viewpoint but also from possible chemical and biological points of view which may explain clinical observations.

Human milk adiponectin affects infant weight trajectory during the second year of life.

OBJECTIVE: Serum adiponectin (APN) is associated with lower childhood obesity, and APN concentration in human milk is associated with slower growth during active breast-feeding. We examined infant weight gain in the second year of life after exposure to high or low levels of mother's milk APN. METHODS: Breast-feeding mother-infant pairs were recruited in Mexico City and studied for 2 years; 192 infants with at least 12 months' follow-up were analyzed. Monthly milk samples were assayed for APN; mothers were classified as producing high or low levels of milk APN. Infant and maternal serum APN were assessed during year 1. Infant anthropometry was measured monthly (year 1) or bimonthly (year 2), and World Health Organization z scores were calculated. Longitudinal adjusted models assessed weight-for-age and weight-for-length z score trajectories from 1 to 2 years. RESULTS: Maternal serum APN modestly correlated with milk APN (r=0.37, P<0.0001) and infant serum APN (r=0.29, P=0.01). Infants exposed to high milk APN experienced increasing weight-for-age and weight-for-length z scores between age 1 and 2 years in contrast to low milk APN exposure (P for group × time=0.02 and 0.054, respectively), adjusting for growth in the first 6 months and other covariates. In contrast, infant serum APN in year 1 was not associated with the rate of weight gain in year 2. CONCLUSIONS: High human milk APN exposure was associated with accelerated weight trajectory during the second year of life, suggesting its role in catch-up growth after slower weight gain during the first year of life.

Adiponectina, insulina y glicemia, en individuos con sobrepeso u obesidad sometidos a un régimen de alimentación rico en carbohidratos complejos / Adiponectin, insulin and glucose concentrations in overweight and obese subjects after a complex carbohydrates (fiber) diet

La adiponectina es una citoquina secretada por el tejido adiposo, que regula el metabolismo energético, estimula la oxidación de ácidos grasos, reduce los triglicéridos plasmáticos y mejora el metabolismo de la glucosa mediante aumento de la sensibilidad a la insulina. Se evaluaron niveles séricos de adiponectina, insulina y glicemia, y su relación con pérdida de peso en 56 individuos con diagnostico de sobrepeso y obesidad bajo un régimen de alimentación hipocalórico, basado en el consumo de carbohidratos complejos (cereal rico en fibra durante seis semanas). Se realizó antropometría y determinación de adiponectina e insulina (ELISA), glicemia (Colorimetrico-enzimático). Los datos se analizaron por pruebas no paramétricas para comparaciones de muestras independientes o relacionadas. Los participantes fueron (12 hombres, 44 mujeres, 20 a 55 años) 17 con diagnostico de sobrepeso y 39 con obesidad. La adiponectina se encontró significativamente baja al inicio del programa en todos los participantes (4,47 ±1,64µg/mL), mayor en mujeres que en hombres (4,62±1,57 vs 3,93±1,86µg/mL). Para la glicemia e insulina sérica, los valores estuvieron dentro del rango normal (82,46±26,51 µg/dL) y (14,12±10,15l µU/mL) respectivamente sin diferencias significativas por sexo. Los participantes con sobrepeso tuvieron concentraciones significativamente mayores de adiponectina que los obesos desde el inicio hasta el final del programa. El régimen de alimentación promovió cambios en la concentración de adiponectina sérica durante el período de evaluación, notables a la segunda y sexta semana, encontrándose un incremento significativo en sus niveles séricos, y correlación negativa con el IMC y sexo a medida que perdían peso corporal.

Adiponectin one of the cytokines secreted by the adipose tissue that regulates the energetic metabolism through glucose and insulin interactions., stimulates the oxidation of fatty acids, reduces the plasmatic triglycerides and improves glucose metabolism by increasing insulin sensibility. Serum concentrations of adiponectin, insulin and glucose were assessed in order to establish association to weight loss after a dietary regime based on consumption of complex carbohydrates (fiber) during six weeks. Overweight and obese subjects (n=56) were studied by anthropometry. Adiponectin and insulin were measured by ELISA and glucose by Colorimetry. Data was analyzed by non parametric tests to compare independent or related samples. 12 men and 44 women, aged 20 to 55 years, 17 overweight and 39 obese were assessed. Adiponectin concentration was significantly low at basal determination in all the subjects (4,47 ±1,64); being higher in women (4,62±1,57 vs 3,93±1,86 µU/mL in men), while glucose and insulin values were at normal range (82,46±26,51 µg/dL and 14,12±10,15 µU/mL) respectively with no significant differences for sex. Overweight subjects had significantly higher adiponectin concentrations than obese participants, at all measurements. Dietary regime promoted significant increase in adiponectin concentration at second and sixth week, with a negative correlation to body mass index and gender as they lost body weight.

Obesidade, adipocitocinas e gravidez: uma atualização da literatura / Obesity, adipocytokines and pregnancy: an update of the literature

Atualmente, a obesidade é considerada um dos maiores e mais visíveis, porém mais negligenciados, problemas de saúde pública em todo o mundo. A adiposidade visceral, mais do que a subcutânea, é determinante para o aparecimento de doenças como o diabetes mellitus, a hipertensão arterial e a doença vascular coronariana. Fisiologicamente, as alterações no metabolismo dos carboidratos e dos lipídios ocorrem na gravidez para garantir um fornecimento contínuo de nutrientes para feto em crescimento promovendo um estado de resistência à insulina (RI). Além dos hormônios placentários, citocinas pró-inflamatórias, as adipocitocinas, secretadas por células do tecido adiposo e pela placenta, desempenham um papel significativo na instalação e manutenção desta RI na gravidez. Nesta revisão, procuramos atualizar o conhecimento sobre as alterações promovidas pelas adipocitocinas e pela obesidade central no organismo da gestante, ressaltando o diagnóstico da adiposidade visceral na gravidez e o risco que envolve este tipo de obesidade para a gestante.

Currently, obesity is considered one of the largest and most visible, but most neglected, public health problems worldwide. The visceral adiposity, rather than subcutaneously, is crucial to the emergence of diseases such as diabetes mellitus, hypertension and coronary vascular disease. Physiologically, changes in the metabolism of carbohydrates and lipids occur in pregnancy to ensure a continuous supply of nutrients to the growing fetus by promoting a state of insulin resistance (IR). In addition to the placental hormones, proinflammatory cytokines, the adipocytokines, secreted by fat tissue and the placenta, play a significant role in the installation and maintenance of IR in pregnancy. In this review, we present the knowledge of the changes promoted by adipocytokines and obesity in the central body of the mother, emphasizing the diagnosis of visceral fat in pregnancy and the risks surrounding this type of obesity in pregnant women.

[The metabolic syndrome and type-2 diabetes mellitus as conditions predisposing for malignant tumors]. / A metabolikus szindróma és a 2-es típusú diabetes mellitus mint rosszindulatú daganatra hajlamosító állapotok.

Recently more and more evidences have emerged about the oncogenic effect of type 2 diabetes and metabolic syndrome. Among these evidences epidemiological data are in first line. There is a causal relationship according to gender, ethnicity and geographic situation between different tumors and type 2 diabetes/metabolic syndrome as well. Supposed pathomechanisms are obesity, cytokines, secreted excessively in adipose tissue, permanent and postprandial hyperglycemia, hyperinsulinism and insulin resistance, other growth factors, like proinsulin, insulin like growth factor-1, reactive oxygen species, angiogenesis, inflammation, and the multiple effects of inflammatory cytokines. It proved to be evident that both peroxisome-proliferator-activated receptors and the regulatory ubiquitin proteasome system have significant role in insulin sensitivity and in co-ordinating cell proliferation and angiogenesis. These mechanisms in metabolic syndrome are risk factors towards atherosclerosis and cancer diseases as well. This newly emerged knowledge may open new pathways in treating and preventing the above-mentioned pathologic processes.