Sleeve gastrectomy leads to weight loss in the Magel2 knockout mouse

Abstract

Background Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia, obesity, cardiopulmonary diseases, and increased mortality. While successful weight loss improves health in PWS, few treatments cause sustained weight loss in obese patients let alone obese individuals with PWS. Objectives The present study uses the Magel2 knockout (KO) mouse, an animal model of PWS, to conduct a preclinical study on the efficacy of Sleeve Gastrectomy (SG) in PWS. Setting Academic Research Laboratory, United States. Methods We performed sham or SG surgeries in 24-28 week old male Magel2 KO and wild-type littermate control mice (WT) who had been maintained on a high-fat diet for 10 weeks. We monitored body weight, food intake, and fat and lean mass pre- and post-operatively. Fasting glucose, glucose tolerance, and counterregulation were measured post-operatively. Results Magel2 KO animals had similar recovery and mortality rates compared to WT. SG resulted in similar weight loss, by specifically loss of fat but not lean mass, in both Magel2 KO and WT mice. SG also resulted in significantly lower fasting glucose levels and a reduction in fat intake in both Magel2 KO and WT mice. We also found that Magel2 KO mice failed to increase their food intake in response to the glucoprivic agent, 2-deoxy-D-glucose (2DG) suggesting impaired glucose counterregulation, but this occurred regardless of surgical status. All results were considered significant when P < 0.05. Conclusions We find in this mouse model of PWS, SG is a safe, effective strategy for weight and fat loss.

Sleeve gastrectomy rapidly enhances islet function independently of body weight

“…However, the GLP-1 receptor is not necessary for the glucose-lowering effect of surgery (40)(41)(42), and the GIP receptor has not been studied. Furthermore, in most studies with single gene KO models, the effect of surgery on glucose tolerance is retained (40,(42)(43)(44)(45)(46), with several exceptions (47)(48)(49). This suggests the mechanisms involved in enhanced insulin secretion after bariatric surgery are complex and likely multifaceted.…”

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

“…After weaning, mutant mice equaled the body weight of their WT littermates; however, KO mice were characterized by higher body fat percentage as well as decreased lean mass and muscle fibers. In addition, the bone mineral density was decreased [ 53 , 59 , 61 , 63 , 64 , 67 ]. When Magel2 KO mice were fed a standard diet for 12–14 weeks, a slight increase in body weight—compared to WT littermates—was observed [ 59 , 69 ].…”

The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways

“…Mice lacking Magel2 are obese with high levels of leptin, an adipose-derived hormone that regulates body weight by inhibiting hunger pathways in the brain (7)(8)(9)(10)(11). Consistent with their failure to decrease food intake in response to high endogenous leptin levels, Magel2-null mice fail to reduce their food intake when treated with exogenous leptin (12).…”