Numerous lines of evidence support a relationship between intestinal inflammation and cancer. Therefore, much attention has recently been focused on the identification of natural compounds with anti-inflammatory activities as a strategy to suppress the early stages of colorectal cancer. Because cocoa is a rich source of bioactive compounds, the present study investigated its anti-inflammatory properties in a rat model of azoxymethane (AOM)-induced colon carcinogenesis and in TNF-a-stimulated Caco-2 cells. A total of forty male rats were fed with control or cocoa-enriched diets (12 %) during 8 weeks and injected with saline or AOM (20 mg/kg body weight) during the third and fourth week (n 10 rats/group). At the end of the experiment, colon samples were evaluated for markers of inflammation. The anti-inflammatory activity of a cocoa polyphenolic extract (10 mg/ml) was examined in TNF-a-stimulated Caco-2 cells, an in vitro model of experimentally induced intestinal inflammation. The signalling pathways involved, including NF-kB and the mitogen-activated protein kinase family such as c-Jun NH 2 -terminal kinases (JNK), extracellular signal-regulated kinases and p38, were also evaluated. The results show that the cocoa-rich diet decreases the nuclear levels of NF-kB and the expression of pro-inflammatory enzymes such as cyclo-oxygenase-2 and inducible NO synthase induced by AOM in the colon. Additionally, the experiments in Caco-2 cells confirm that cocoa polyphenols effectively down-regulate the levels of inflammatory markers induced by TNF-a by inhibiting NF-kB translocation and JNK phosphorylation. We conclude that cocoa polyphenols suppress inflammation-related colon carcinogenesis and could be promising in the dietary prevention of intestinal inflammation and related cancer development.

Cocoa is a rich source of bioactive compounds with potential chemopreventive ability but up to date its effectiveness in animal models of colon carcinogenesis has not been addressed. Herein, we investigated the in vivo effect of a cocoa-rich diet in the prevention of azoxymethane (AOM)-induced colon cancer and the mechanisms involved. Our results showed that cocoa feeding significantly reduced AOM-induced colonic aberrant crypt foci formation and crypt multiplicity. Oxidative imbalance in colon tissues seems to be prevented by cocoa as indicated by reduced oxidation markers levels and increased enzymatic and non-enzymatic endogenous defences. Cocoa-rich diet also exhibited antiproliferative effects by decreasing the levels of extracellular regulated kinases, protein kinase B and cyclin D1 together with pro-apoptotic effects evidenced by reduced Bcl-x(L) levels and increased Bax levels and caspase-3 activity. Our findings provide the first in vivo evidence that a cocoa-rich diet may inhibit the early stage of colon carcinogenesis probably by preventing oxidative stress and cell proliferation and by inducing apoptosis

Catch-up growth has been associated with the appearance of metabolic dysfunctions such as obesity and type 2 diabetes in adulthood. Because the entero-insular axis is critical to glucose homeostasis control, we explored the relevance of the incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) in the development of these pathologies. Offspring of rat dams fed ad libitum (control [C]) or 65% food-restricted during pregnancy and suckling time (undernourished [U]) were weaned onto a high-fat (HF) diet (CHF and UHF, respectively) to drive catch-up growth. Both male and female UHF rats showed an obese phenotype characterized by hyperphagy, visceral fat accumulation, and adipocyte hypertrophy. High-fat diet induced deterioration of glucose tolerance in a sex-dependent manner. Female UHF rats experienced much more severe glucose intolerance than males, which was not compensated by insulin hypersecretion, suggesting insulin resistance, as shown by homeostatic model assessment of insulin resistance values. Moreover, female, but not male, UHF rats displayed enhanced GIP but not GLP-1 secretion during oral glucose tolerance test. Administration of the GIP receptor antagonist (Pro3)GIP to UHF female rats over 21 days markedly reduced visceral fat mass and adipocyte hypertrophy without variations in food intake or body weight. These changes were accompanied by improvement of glucose tolerance and insulin sensitivity. In conclusion, the exacerbated production and secretion of GIP after the catch-up growth seems to represent the stimulus for insulin hypersecretion and insulin resistance, ultimately resulting in derangement of glucose homeostasis. Overall, these data evidence the role of GIP as a critical link between catch-up growth and the development of metabolic disturbances. (Endocrinology 155: 3769 -3780, 2014)

Glucotoxicity (high levels of glucose) is a major factor in the pathogenesis of diabetic kidney disease. Cocoa has anti-diabetic effects by lowering glucose levels. However, whether cocoa exerts beneficial effects on the renal cortex glucose homeostasis and the molecular mechanisms responsible for this possible protective activity remain largely unknown. Thus, the potential anti-diabetic properties of cocoa on insulin signalling, glucose transporters and gluconeogenic enzymes were evaluated in the renal cortex of Zucker Diabetic fatty (ZDF) rats. Male ZDF rats were fed a control or cocoa-rich diet (10%), and Zucker Lean animals received the control diet. ZDF rats supplemented with cocoa (ZDF-Co) showed decreased body weight gain, glucose and insulin levels, improved glucose tolerance, insulin resistance and structural alterations in renal cortex. Moreover, cocoa-rich diet ameliorated insulin resistance by reverting decreased tyrosine-phosphorylated-insulin receptor levels and by preventing the inactivation of glycogen synthase kinase-3/glycogen synthase pathway (GSK-3/GS) in the renal cortex of ZDF-Co rats. Cocoa antihyperglycaemic effect also appeared to be mediated through the diminution of phosphoenolpyruvate-carboxykinase (PEPCK), glucose-6phosphatase (G-6-Pase), sodium-glucose-co-transporter-2 (SGLT-2), and glucosetransporter-2 (GLUT-2) levels in ZDF-Co rat´s renal cortex. These findings demonstrate that cocoa alleviates renal injury by contributing to maintain the glucose homeostasis in type 2 diabetic ZDF rats.

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