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Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.

Roux-en-Y gastric bypass (RYGB) may improve beta cell function by mechanisms other than caloric restriction and body weight loss. We aimed to assess the impact of anatomical and hormonal alterations specific to RYGB on glucose homeostasis, β cell function and morphology.Male Zucker(fa/fa) rats underwent either RYGB (n = 11) or sham surgeries (n = 10). Five of the shams were then food restricted and body weight matched (BWM) to the RYGB rats. Six male Zucker(fa/+) rats underwent sham surgery and served as additional lean controls. Twenty-seven days after surgery, an oral glucose tolerance test (OGTT) was performed and plasma levels of glucose, insulin and glucagon-like peptide-1 (GLP-1) were measured. Immunohistological analysis of pancreatic islets was performed, and GLP-1 receptor and PDX-1 mRNA content were quantified.Shams consumed more food and gained more weight compared to both RYGB and BWM (p 0.001). Hyperglycaemia was evident in ad libitum-fed shams, whilst postprandial glucose levels were lower in RYGB compared to the BWM sham group (p 0.05). During the OGTT, RYGB rats responded with2.5-fold increase of GLP-1. Histology revealed signs of islet degeneration in ad libitum-fed shams, but not in RYGB and sham BWM controls (p 0.001). GLP-1 receptor and PDX-1 mRNA content was similar between the RYGB and BWM shams but higher compared to ad libitum shams (p 0.05).Combined molecular, cellular and histological analyses of pancreatic function suggest that weight loss alone, and not the enhancement of GLP-1 responses, is predominant for the short-term β cell protective effects of RYGB.

Background Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zuckerfa/fa and lean Zuckerfa/+ to investigate the association between obesity, oxidative stress and genomic damage after weight loss induced either by Roux-en-Y gastric bypass surgery (RYGB) or caloric restriction. Methods Male Zuckerfa/fa rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zuckerfa/+ rats served as lean controls. Body weight and food intake were measured daily. An oral glucose tolerance test was performed on day 27. DHE staining and western blots of HSP70 and HO-1 were used to evaluate oxidative stress and anti-3-nitrotyrosine antibody staining for nitrative stress detection in colon and kidney. Lipid peroxidation products in urine were quantified by TBARS assay. LC/MS/MS was applied to measure urinary excretion of 8-oxoGua (oxidized DNA derived base), 8-oxodG (oxidized DNA derived nucleoside) and 8-oxoGuo (oxidized RNA derived nucleoside). DNA double strand breaks (DSBs) and cell proliferation (PCNA) were detected by immunohistochemistry. Results Sham-operated rats showed impaired glucose tolerance, elevated plasma insulin levels as well as elevated oxidative stress and nitrative stress markers, which were less severe after weight loss by RYGB or caloric restriction. Cell proliferation showed similar trends but no significant alteration. DNA DSBs were more frequent in sham-operated compared to all other groups. DNA damage in Zuckerfa/fa rats positively correlated with basal plasma insulin values (Spearman's correlation coefficient for colon, 0.634 and for kidney, 0.525). Conclusions RYGB and caloric restriction were sufficient to significantly reduce elevated oxidative/nitrative stress and genomic damage in obese Zuckerfa/fa rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects.