Leptin Receptors Are Not Required for Roux-en-Y Gastric Bypass Surgery to Normalize Energy and Glucose Homeostasis in Rats.

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 surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss.

Mechanisms of Roux-en-Y gastric bypass (RYGB) surgery are not fully understood. This study aimed to investigate weight loss-independent bacterial and metabolic changes, as well as the absorption of bacterial metabolites and bile acids through the hepatic portal system following RYGB surgery. Three groups of obese Zucker (fa/fa) rats were included: RYGB (n = 11), sham surgery and body weight matched with RYGB (Sham-BWM, n = 5), and sham surgery fed ad libitum (Sham-obese, n = 5). Urine and feces were collected at multiple time points, with portal vein and peripheral blood obtained at the end of the study. Metabolic phenotyping approaches and 16S rRNA gene sequencing were used to determine the biochemical and bacterial composition of the samples, respectively. RYGB surgery-induced distinct metabolic and bacterial disturbances, which were independent of weight loss through caloric restriction. RYGB resulted in lower absorption of phenylalanine and choline, and higher urinary concentrations of host-bacterial co-metabolites (e.g., phenylacetylglycine, indoxyl sulfate), together with higher fecal trimethylamine, suggesting enhanced bacterial aromatic amino acid and choline metabolism. Short chain fatty acids (SCFAs) were lower in feces and portal vein blood from RYGB group compared to Sham-BWM, accompanied with lower abundances of Lactobacillaceae, and Ruminococcaceae known to contain SCFA producers, indicating reduced bacterial fiber fermentation. Fecal γ-amino butyric acid (GABA) was found in higher concentrations in RYGB than that in Sham groups and could play a role in the metabolic benefits associated with RYGB surgery. While no significant difference in urinary BA excretion, RYGB lowered both portal vein and circulating BA compared to Sham groups. These findings provide a valuable resource for how dynamic, multi-systems changes impact on overall metabolic health, and may provide potential therapeutic targets for developing downstream non-surgical treatment for metabolic disease.

Impact of weight loss induced by gastric bypass or caloric restriction on oxidative stress and genomic damage in obese Zucker rats.

BACKGROUND: Evidence on bariatric surgery induced weight loss and its possible impact on cancer risk is limited, but also controversial. We used obese Zucker(fa/fa) and lean Zucker(fa/+) 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 Zucker(fa/fa) rats underwent RYGB (n=15) or sham surgery (n=17). Five shams were food restricted and body weight matched (BWM) to RYGB. Twelve Zucker(fa/+) 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 Zucker(fa/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 Zucker(fa/fa) rats. Further investigations are needed to elucidate the underlying mechanism of these genome protective effects.

Gastric Bypass-Related Effects on Glucose Control, ß Cell Function and Morphology in the Obese Zucker Rat.

BACKGROUND: 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, ß cell function and morphology. METHODS: 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. RESULTS: 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 with >2.5-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). CONCLUSIONS: 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 ß cell protective effects of RYGB.