Mechanisms of Weight Regain following Weight Loss.

Obesity is a world-wide pandemic and its incidence is on the rise along with associated comorbidities. Currently, there are few effective therapies to combat obesity. The use of lifestyle modification therapy, namely, improvements in diet and exercise, is preferable over bariatric surgery or pharmacotherapy due to surgical risks and issues with drug efficacy and safety. Although they are initially successful in producing weight loss, such lifestyle intervention strategies are generally unsuccessful in achieving long-term weight maintenance, with the vast majority of obese patients regaining their lost weight during followup. Recently, various compensatory mechanisms have been elucidated by which the body may oppose new weight loss, and this compensation may result in weight regain back to the obese baseline. The present review summarizes the available evidence on these compensatory mechanisms, with a focus on weight loss-induced changes in energy expenditure, neuroendocrine pathways, nutrient metabolism, and gut physiology. These findings have added a major focus to the field of antiobesity research. In addition to investigating pathways that induce weight loss, the present work also focuses on pathways that may instead prevent weight regain. Such strategies will be necessary for improving long-term weight loss maintenance and outcomes for patients who struggle with obesity.

GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.