Endocrine and Physiological Changes in Response ...

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Mar 12, 2010 - Alexander M. Owyang, Kathrin Maedler, Lisa Gross, Johnny Yin, Lin Esposito, ... disorders, ranging from depression to Cushing's syndrome.
Endocrine Reviews, April 2010, 31(2):254 –263

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XOMA 052, an Anti-IL-1␤ Monoclonal Antibody, Improves Glucose Control and ␤-Cell Function in the Diet-Induced Obesity Mouse Model Alexander M. Owyang, Kathrin Maedler, Lisa Gross, Johnny Yin, Lin Esposito, Luan Shu, Jaaee Jadhav, Erna Domsgen, Jennifer Bergemann, Steve Lee, and Seema Kantak (Endocrinology, 10.1210/en.2009-1124) ABSTRACT Recent evidence suggests that IL-1␤-mediated glucotoxicity plays a critical role in type 2 diabetes mellitus. Although previous work has shown that inhibiting IL-1␤ can lead to improvements in glucose control and ␤-cell function, we hypothesized that more efficient targeting of IL-1␤ with a novel monoclonal antibody, XOMA 052, would reveal an effect on additional parameters affecting metabolic disease. In the diet-induced obesity model, XOMA 052 was administered to mice fed either normal or high-fat diet (HFD) for up to 19 wk. XOMA 052 was administered as a prophylactic treatment or as a therapy. Mice were analyzed for glucose tolerance, insulin tolerance, insulin secretion, and lipid profile. In addition, the pancreata were analyzed for ␤-cell apoptosis, proliferation, and ␤-cell mass. Mice on HFD exhibited elevated glucose and glycated hemoglobin levels, impaired glucose tolerance and insulin secretion, and elevated lipid profile, which were prevented by XOMA 052. XOMA 052 also reduced ␤-cell apoptosis and increased ␤-cell proliferation. XOMA 052 maintained the HFDinduced compensatory increase in ␤-cell mass, while also preventing the loss in ␤-cell mass seen with extended HFD feeding. Analysis of fasting insulin and glucose levels suggests that XOMA 052 prevented HFD-induced insulin resistance. These studies provide new evidence that targeting IL-1␤ in vivo could improve insulin sensitivity and lead to ␤-cell sparing. This is in addition to previously reported benefits on glycemic control. Taken together, the data presented suggest that XOMA 052 could be effective for treating many aspects of type 2 diabetes mellitus.

Endocrine and Physiological Changes in Response to Chronic Corticosterone: A Potential Model of the Metabolic Syndrome in Mouse Ilia N. Karatsoreos, Sarah M. Bhagat, Nicole P. Bowles, Zachary M. Weil, Donald W. Pfaff, and Bruce S. McEwen (Endocrinology, published March 8, 2010, 10.1210/en.2009-1436) ABSTRACT Numerous clinical and experimental studies have linked stress to changes in risk factors associated with the development of physiological syndromes, including metabolic disorders. How different mediators of the stress response, such as corticosterone (CORT), influence these changes in risk remains unclear. Although CORT has beneficial short-term effects, long-term CORT exposure can result in damage to the physiological systems it protects acutely. Disruption of this important physiologic signal is observed in numerous disparate disorders, ranging from depression to Cushing’s syndrome. Thus, understanding the effects of chronic high CORT on metabolism and physiology is of key importance. We explored the effects of 4-wk exposure to CORT dissolved in the drinking water on the physiology and behavior of male mice. We used this approach as a noninvasive way of altering plasma CORT levels, whereas retaining some integrity in the diurnal rhythm present in normal animals. This approach has advantages over methods involving constant CORT pellets, CORT injections, or adrenalectomy. We found that high doses of CORT (100 ␮g/ml) result in rapid and dramatic increases in weight gain, increased adiposity, elevated plasma leptin, insulin and triglyceride levels, hyperphagia, and decreased home-cage locomotion. A lower dose of CORT (25 ␮g/ml) resulted in an intermediate phenotype in some of these measures, whereas having no effect on others. We propose that the physiological changes observed in the high-CORT animals approximate changes observed in individuals suffering from the metabolic syndrome and that they potentially serve as a model for hypercortisolemia and stress-related obesity.

Direct Action through the Sertoli Cells Is Essential for Androgen Stimulation of Spermatogenesis P. J. O’Shaughnessy, G. Verhoeven, K. De Gendt, A. Monteiro, and M. H. Abel (Endocrinology, published March 12, 2010, 10.1210/en.2009-1333) ABSTRACT Androgens act to stimulate spermatogenesis through androgen receptors (ARs) on the Sertoli cells and peritubular myoid cells. Specific ablation of the AR in either cell type will cause a severe disruption of spermatogenesis. To determine whether androgens can stimulate spermatogenesis through direct action on the peritubular myoid cells alone or whether action on the Sertoli cells

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