Factores reguladores del balance energético en la obesidad. Estudio de los mecanismos de adaptación histológicos y funcionales tras restricción calórica impuesta o inducida mediante cirugía bariátrica (gastrectomía tubular)

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Regulatory factors of energy balance in obesity. Study of adaptive histological and functional mechanisms after caloric restriction induced by diet or bariatric surgery (sleeve-gastrectomy) Marina Martín Rodríguez. School of Sciences. University of Navarra. 2011. Obesity is the result of a disruption in energy balance. Food intake is controlled by peripheral and central, orexigenic and anorexigenic signals, integrated in the hypothalamus to regulate appetite and satiety. Nowadays, bariatric surgery is considered an effective therapy in the treatment of morbid obesity in carefully selected patients. Recent data show that bariatric surgery exerts its beneficial metabolic effects by inducing changes in the levels of factors regulating appetite and satiety. The hypothesis of the present study is based on the probable existence of differences in the response to caloric restriction induced by diet compared to that induced by sleeve gastrectomy (SG). It is established that the histological and functional gastrointestinal adaptive mechanisms may involve changes in the expression of factors regulating energy balance in imposed caloric restriction against the surgery. We try to probe this hypothesis in 2 animal models: 1) A model of diet-induced obesity (DIO) and caloric restriction (40 male Wistar rats), 2) A model of sleeve gastrectomy (SG) (56 male Wistar rats). In both animal models we studied body weight evolution, food intake, weight of different organs and circulating levels of ghrelin, GLP-1 and PYY. Furthermore, we determined the number of ghrelin-, GLP-1- and PYY-immunoreactive (IR) cells in the gastrointestinal tract and the expression of hypothalamic neuropeptides. 3) We also studied the number of immunoreactive ghrelin cells in 64 human gastric biopsies in order to determine its relation with body mass index (BMI). In summary, caloric restriction, induced by diet or by SG, leads to weight loss, even in the worst situation of continuous feeding on a high fat diet. SG is more effective, as its benefits go beyond mere food restriction. Both types of restriction imply a decrease in adiposity index and leptinemia, insulinemia and triglyceridemia. These effects result in improved insulin-sensitivity and lipid metabolism. The most significant changes in gastrointestinal hormones affect ghrelin and PYY. In the SG model the resection of a large part of the gastric mucosa producing ghrelin, leads to a significant decrease in the circulating concentrations of this hormone. Dietary restriction leads to an increase in serum ghrelin, which agrees with the increase of this cell type in the colon, but not with its decrease in the gastric mucosa. The intake of high fat diet decreases both serum and the number of PYY-producing cells in the ileum, while the SG promotes the increase of this hormone circulating levels. PYY modifications may contribute both to the obesogenic effect of high-calorie diet and the beneficial effects of SG. Together, the decrease in ghrelin and the increase in PYY after the SG seem to play a key role in the better evolution of the bariatric surgery groups. This study supports the effectiveness of SG in weight control and resolution of comorbidities in carefully selected morbid obese patients. We also determine that the number of ghrelin IR cells in human gastric mucosa depends on the BMI of the patient and the part of the gastric mucosa studied. These findings confirm the important role of ghrelin in the etiopathology of obesity.