1.Guanylin and uroguanylin stimulate lipolysis in human visceral adipocytes.
Rodríguez A1,2,3, Gómez-Ambrosi J1,2,3, Catalán V1,2,3, Ezquerro S1,2,3, Méndez-Giménez L1,2,3, Becerril S1,2,3, Ibáñez P2,3,4, Vila N2,3,4, Margall MA2,3,4, Moncada R2,3,5, Valentí V2,3,6, Silva C2,3,4, Salvador J3,4, Frühbeck G1,2,3,4. Int J Obes (Lond). 2016 Apr 25. doi: 10.1038/ijo.2016.66. [Epub ahead of print]
BACKGROUND/OBJETIVES: Uroguanylin and guanylin are secreted by intestinal epithelial cells as prohormones postprandially and act on the hypothalamus to induce satiety. The impact of obesity and obesity-associated type 2 diabetes (T2D) on proguanylin and prouroguanylin expression/secretion as well as the potential role of guanylin and uroguanylin in the control of lipolysis in humans was evaluated.
2.Obesity-Induced Colorectal Cancer Is Driven by Caloric Silencing of the Guanylin-GUCY2C Paracrine Signaling Axis.
Lin JE1, Colon-Gonzalez F1, Blomain E1, Kim GW1, Aing A1, Stoecker B1, Rock J1, Snook AE1, Zhan T2, Hyslop TM3, Tomczak M4, Blumberg RS4, Waldman SA5. Cancer Res. 2016 Jan 15;76(2):339-46. doi: 10.1158/0008-5472.CAN-15-1467-T.
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells restored GUCY2C signaling, eliminating intestinal tumors associated with a high calorie diet.
3.Cellular localization of guanylin and uroguanylin mRNAs in human and rat duodenal and colonic mucosa.
Brenna Ø1,2, Furnes MW3, Munkvold B3, Kidd M3, Sandvik AK4,3,5, Gustafsson BI4,3. Cell Tissue Res. 2016 Apr 5. [Epub ahead of print]
Guanylin (GUCA2A/Guca2a/GN) and uroguanylin (GUCA2B/Guca2b/UGN) are expressed in the gastrointestinal tract and have been implicated in ion and fluid homeostasis, satiety, abdominal pain, growth and intestinal barrier integrity. Their cellular sources are debated and include goblet cells, entero-/colonocytes, enteroendocrine (EE) cells and tuft cells. We therefore investigated the cellular sources of GN and UGN mRNAs in human and rat duodenal and colonic epithelium with in situ hybridization (ISH) to determine co-expression with Chromogranin A (CHGA/Chga/CgA; enterochromaffin [EC] cells), defensin alpha 6 (DEFA6/Defa6; Paneth cells), mucin 2 (MUC2/Muc2; goblet cells) and selected tuft cell markers. GUCA2A/Guca2a expression was localized to goblet cells and colonocytes in human and rat colon. In human duodenum, GUCA2A was expressed in Paneth cells and was scarce in villous epithelial cells. In rat duodenum, Guca2a was only localized to goblet cells.