The functional impact of adiponectin on pancreatic beta cells is so far poorly understood. Although adiponectin receptors (AdipoR1/2) were identified, their involvement in adiponectininduced signaling and other molecules involved is not clearly defined. Therefore, we investigated the role of adiponectin in beta cells and the signaling mediators involved. MIN6 beta cells and mouse islets were stimulated with globular (2.5 g/ml) or full-length (5 g/ml) adiponectin under serum starvation, and cell viability, proliferation, apoptosis, insulin gene expression, and secretion were measured. Lysates were subjected to Western blot analysis to determine phosphorylation of AMP-activated protein kinase (AMPK), Akt, or ERK. Functional significance of signaling was confirmed using dominant negative mutants or pharmacological inhibitors. Participation of AdipoRs was assessed by overexpression or siRNA. Adiponectin failed to activate AMPK after 10 min or 1-and 24-h stimulation. ERK was significantly phosphorylated after 24-h treatment with adiponectin, whereas Akt was activated at all time points examined. 24-h stimulation with adiponectin significantly increased cell viability by decreasing cellular apoptosis, and this was prevented by dominant negative Akt, wortmannin (PI3K inhibitor), and U0126 (MEK inhibitor). Moreover, adiponectin regulated insulin gene expression and glucose-stimulated insulin secretion, which was also prevented by wortmannin and U0126 treatment. Interestingly, the data also suggest adiponectin-induced changes in Akt and ERK phosphorylation and caspase-3 may occur independent of the level of AdipoR expression. This study demonstrates a lack of AMPK involvement and implicates Akt and ERK in adiponectin signaling, leading to protection against apoptosis and stimulation of insulin gene expression and secretion in pancreatic beta cells.Type 2 diabetes is characterized by both a loss of insulin sensitivity and beta cell dysfunction in the pancreas. Adiponectin is an adipocyte-derived hormone that shows a strong negative correlation with insulin resistance and obesity (1, 2). Studies show that whereas adiponectin knock-out mice develop insulin resistance and glucose intolerance when challenged with a high fat diet, adiponectin-overexpressing mice are highly insulin-sensitive and are resistant to diet-induced diabetes (3-6). Adiponectin is reported to stimulate fatty acid oxidation and glucose uptake and reduce gluconeogenesis in myocytes and hepatocytes, thus increasing peripheral insulin sensitivity (7). Reduced adiponectin levels are also correlated with reduced vascular function and an increase in coronary artery disease (8).Adiponectin forms trimers or higher order complexes including hexamers and oligomers (9). These higher order complexes of full-length adiponectin (fAd) 4 are the primary circulating forms, and localized proteolytic cleavage of fAd has been shown to produce globular adiponectin (gAd) (10). Two proposed homologous adiponectin receptors (AdipoR1 and AdipoR2) were cloned and shown to be wi...

Post-translational modification pathways such as SUMOylation are integral to all cellular processes and tissue homeostasis. We investigated the possible involvement of SUMOylation in the epithelial signalling in Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD). Initially in a murine model of IBD, induced by dextran–sulfate–sodium (DSS mice), we observed inflammation accompanied by a lowering of global SUMOylation of colonic epithelium. The observed SUMOylation alteration was due to a decrease in the sole SUMO E2 enzyme (Ubc9). Mass-spectrometric analysis revealed the existence of a distinct SUMOylome (SUMO-conjugated proteome) in DSS mice with alteration of key cellular regulators, including master kinase Akt1. Knocking-down of Ubc9 in epithelial cells resulted in dramatic activation of inflammatory gene expression, a phenomenon that acted via reduction in Akt1 and its SUMOylated form. Importantly, a strong decrease in Ubc9 and Akt1 was also seen in endoscopic biopsy samples (N = 66) of human CD and UC patients. Furthermore, patients with maximum disease indices were always accompanied by severely lowered Ubc9 or SUMOylated-Akt1. Mucosal tissues with severely compromised Ubc9 function displayed higher levels of pro-inflammatory cytokines and compromised wound-healing markers. Thus, our results reveal an important and previously undescribed role for the SUMOylation pathway involving Ubc9 and Akt1 in modulation of epithelial inflammatory signalling in IBD.

Highlights d The deSUMOylase SENP7 contributes to IBD pathophysiology d SENP7 function and interactome modulate epithelial-immune crosstalk d SIAH2 negatively regulates SENP7 by ubiquitination in healthy, but not inflamed, cells d Epithelial SENP7 upregulation triggers proinflammatory mechanisms via gd T cells

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