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Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.

Ginkgo biloba extract (GbE) has been indicated as an efficient medicine for the treatment of diabetes mellitus type 2. It remains unclear if its effects are due to an improvement of the insulin signaling cascade, especially in obese subjects. The aim of the present study was to evaluate the effect of GbE on insulin tolerance, food intake, body adiposity, lipid profile, fasting insulin, and muscle levels of insulin receptor substrate 1 (IRS-1), protein tyrosine phosphatase 1B (PTP-1B), and protein kinase B (Akt), as well as Akt phosphorylation, in diet-induced obese rats. Rats were fed with a high-fat diet (HFD) or a normal fat diet (NFD) for 8 weeks. After that, the HFD group was divided into two groups: rats gavaged with a saline vehicle (HFD+V), and rats gavaged with 500 mg/kg of GbE diluted in the saline vehicle (HFD+Gb). NFD rats were gavaged with the saline vehicle only. At the end of the treatment, the rats were anesthetized, insulin was injected into the portal vein, and after 90s, the gastrocnemius muscle was removed. The quantification of IRS-1, Akt, and Akt phosphorylation was performed using Western blotting. Serum levels of fasting insulin and glucose, triacylglycerols and total cholesterol, and LDL and HDL fractions were measured. An insulin tolerance test was also performed. Ingestion of a hyperlipidic diet promoted loss of insulin sensitivity and also resulted in a significant increase in body adiposity, plasma triacylglycerol, and glucose levels. In addition, GbE treatment significantly reduced food intake and body adiposity while it protected against hyperglycemia and dyslipidemia in diet-induced obesity rats. It also enhanced insulin sensitivity in comparison to HFD+V rats, while it restored insulin-induced Akt phosphorylation, increased IRS-1, and reduced PTP-1B levels in gastrocnemius muscle. The present findings suggest that G. biloba might be efficient in preventing and treating obesity-induced insulin signaling impairment.

We have previously shown that adult female rats exposed to intra-uterine malnutrition were normophagic, although obese and resistant to insulininduced hypophagia. The present study aimed at examining aspects of another important catabolic component of energy homeostasis control, the hypothalamic serotonergic function, which inhibits feeding and stimulates energy expenditure. Pregnant dams were fed ad libitum or were restricted to 50 % of ad libitum intake during the first 2 weeks of pregnancy. Control and restricted 4-month-old progeny were studied. The restricted rats had increased body adiposity with normal daily food intake but failed to respond with hypophagia to an intracerebroventricular injection of serotonin (5-hydroxytryptamine; 5-HT). Stimulation, by food ingestion, of extracellular levels of serotonin in medial hypothalamus microdialysates was more pronounced and lasted longer in the restricted than in the control rats. In the restricted group, hypothalamic levels of 5-HT 2C receptor protein tended to be reduced (P¼ 0·07) while the levels of 5-HT 1B receptor and serotonin transporter proteins were significantly elevated (36 and 79 %, respectively). In conclusion, female rats undernourished in utero had normophagic obesity as adults but had an absence of serotonininduced hypophagia and low hypothalamic levels of the 5-HT 2C receptor. Compensatory adaptations for the functional serotonergic impairment were evidenced, such as an enhanced release of serotonin in response to a meal allied to up-regulated hypothalamic 5-HT 1B and transporter expression. Whether these compensations will persist in later life warrants further investigation. Moreover, it cannot be ruled out that the serotonergic component of energy expenditure was already impaired, thus contributing to the observed body-fat phenotype.Intra-uterine malnutrition: Serotonin: Hypothalamus: Obesity: Control of feeding The hypothalamus is the major centre of interaction of the numerous anabolic and catabolic factors involved in the control of energy balance. The serotonergic system plays a key role in these mechanisms, inhibiting food intake and stimulating energy expenditure (1 -4) . Serotonin (5-hydroxytryptamine; 5-HT) release is stimulated by the ingestion of food in hypothalamic sites related to feeding control, a finding that points to the physiological relevance of the system (5 -10) . Moreover, several investigations indicate that alterations of central serotonergic activity are present in obese rodents and humans (6,10 -12) and drugs that act as serotonin receptor agonists or serotonin reuptake inhibitors are used in the treatment of obesity (13,14) . Obesity, with its associated conditions, such as CVD, hypertension, insulin resistance, type 2 diabetes and the metabolic syndrome, represents nowadays a major health issue worldwide. Malnutrition during intra-uterine life has been linked to the development of obesity in later life.The 'thrifty phenotype' hypothesis suggests that the adaptive strategies developed during the period of poor nu...

The rapid increase in the number of individuals with obesity, over the past four decades, is triggered by a number of complex interactions among factors. Despite the plethora of treatments available, side effects are commonly observed and, in this context, herbal medicines have been employed as an alternative form of therapy. Ginkgo biloba extract (GbE) has been described as a promising new pharmacological approach to treat obesity. In order to better comprehend the mechanisms involved with this potential effect, the present study evaluated the effects of GbE treatment on diet-induced obese rats, focusing on the proteome and the oxidative stress defense system of visceral adipose tissue. After 14 days treatment, GbE significantly modulated 25 proteins. Retroperitoneal adipose tissue of treated animals exhibited higher amounts of proteins associated with adipogenesis (decorin), carbon metabolism and mitochondrial function (citrate synthase), and a concomitant reduction in adipocyte hypertrophy. In parallel, GbE down-regulated proteins involved in oxidative stress (peroxiredoxin) and the inflammatory response (complement C3, mast cell protease 1, and Ig gamma-2B chain C region). Moreover, also related to oxidative stress defense, GbE stimulated catalase activity, reduced malondialdehyde levels (lipid peroxidation indicator), and increased lactoylglutathione lyase levels. It was concluded that GbE acts as an antioxidant agent, and improved the proteome profile and oxidative stress response in the adipose tissue of diet-induced obese rats.