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Vertical Sleeve Gastrectomy: Mechanisms for Weight Loss and Lessons for Obesity Therapy

Stefater, Margaret
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1299619301

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Bariatric surgery has emerged as a superior treatment for obesity because of its ability to produce potent, durable weight loss. Vertical sleeve gastrectomy (VSG) is one bariatric procedure that is gaining popularity as an obesity therapy. It is less invasive and as effective as other bariatric procedures including the Roux-en-Y gastric bypass (RYGB). Here, we perform VSG in rats and demonstrate dramatic, long-term weight loss in rats following surgery. This weight loss was a specific loss of fat mass. Initial weight loss was due to early postsurgical reductions in food intake and was maintained a lack of compensatory hyperphagia in response to the postoperative weight loss. Ingestive behavior after the surgery was characterized by smaller, more frequent meals than in sham-operated controls. Importantly, we demonstrated that VSG does not impair ability to overeat in response to additional weight loss but instead appears to reduce motivation to overeat. Energy expenditure was unaffected by VSG, substantiating the idea that changes to food intake are primary determinants of a newly defended, postsurgical body fat level. Because leptin resistance is a feature of obesity that often precludes the maintenance of diet-induced weight loss, we initially hypothesized that enhanced leptin sensitivity contributes to defended body weight after VSG. Food intake reduction following an exogenous dose of leptin was greater in VSG- than sham-operated rats. However, because the response after VSG was comparable to the anorexia elicited in pair-fed rats, we concluded that behavioral sensitization to leptin after surgery is secondary to weight loss and is unlikely to drive reduced motivation of VSG-operated rats to overeat. This conclusion is supported by the absence of changes in the expression of genes in the mediobasal hypothalamus that regulate activity of the melanocortin axis. Highlighting the power of VSG as a treatment not only for obesity but also for obesity-related comorbidities, we show that the procedure produces significant, weight-independent improvements to lipid homeostasis. This benefit is primarily a postprandial phenomenon. Our data indicate that lower postprandial plasma lipid levels are due to reduced intestinal triglyceride secretion in the absence of any changes to hepatic triglyceride production. We did not detect any changes to the expression of genes regulating lipid transport and/or triglyceride production in either the proximal intestine or the liver. We hypothesize that changes to intestinal biology following VSG are not due to permanent, transcriptional changes but, rather, to altered patterns of intestinal nutrient delivery after surgery. Meal patterns and/or gastric emptying might elicit these changes. We also report weight-related enhancement of plasma bile acid levels, leading us to propose that bile acids may mediate some weight-dependent metabolic benefits to weight loss following VSG and potentially other bariatric procedures. Together, these data provide exciting promise for the use of VSG as a metabolic surgery for obese populations. Although it is unclear what mechanism(s) may suppress hyperphagic behavior and thus lower defended body fat level after VSG, our data contribute significantly to the understanding of the cascade of metabolic changes elicited by VSG. Additionally, we provide the first evidence that VSG induces weight-independent changes to lipid homeostasis. Therefore, VSG is a procedure that holds the potential to treat not only obesity, but obesity-related comobidities which may include atherosclerosis and hyperlipidemia. Further understanding the mechanisms for these improvements, including the role of intestinal nutrient sensing, is an important area for future research.
Randy Seeley, PhD (Committee Chair)
David D'Alessio, MD (Committee Member)
Sara Kozma, PhD (Committee Member)
A John MacLennan, PhD (Committee Member)
Silvana Obici, MD (Committee Member)
Stephen Woods, PhD (Committee Member)
165 p.
Surgery
Obesity; Bariatric Surgery; Vertical Sleeve Gastrectomy; Hypothalamus; Leptin; Triglyceride

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Citations

  • Stefater, M. (2011). Vertical Sleeve Gastrectomy: Mechanisms for Weight Loss and Lessons for Obesity Therapy [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1299619301

    APA Style (7th edition)

  • Stefater, Margaret. Vertical Sleeve Gastrectomy: Mechanisms for Weight Loss and Lessons for Obesity Therapy. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1299619301.

    MLA Style (8th edition)

  • Stefater, Margaret. "Vertical Sleeve Gastrectomy: Mechanisms for Weight Loss and Lessons for Obesity Therapy." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1299619301

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.