Weight loss (WL) improves obesity-related co-morbidities such as type 2 diabetes mellitus (DM). Unfortunately, WL through life-style interventions has a high degree of recidivism and the paucity of safe, effective and affordable pharmacotherapy together with an increase in the prevalence of morbid obesity has led to a rise in bariatric procedures. Clinical trials in patients with DM show that improvements in glycemia vary between procedures and occur in the following order: Roux-en-Y gastric bypass (RYGB) > sleeve gastrectomy (SG) > laparoscopic adjustable gastric banding (LAGB) > medical/life-style therapy. This order mirrors the amount of WL with each intervention and is a major driver of glycemic improvement. We have shown profound changes unique to RYGB and SG in levels of hormones that make up the ?gut-brain? and ?enteroinsular? axes. The association of some of these hormones with insulin sensitivity (IS) and glycemia independent of WL strongly suggests that glycemic improvements after surgery occur in part through pathways that are distinct from just calorie restriction. A new direction of this application builds on our results showing that levels of fibroblast growth factor 19 (FGF19), a protein secreted by intestinal cells, are increased after RYGB and SG but not after low calorie diet (LCD). One of the effects of FGF19 is to improve IS, which in rodents occurs via suppression of agouti-related protein (AgRP) neurons in the hypothalamus. Another finding in rodents is that FGF19 ameliorates activation of the hypothalamic-pituitary-adrenal (HPA) axis, further adding to the growing evidence that operating on the gut changes brain activity. We have shown that measurement of plasma AgRP reflects central activity. Thus, in AIM ONE we will explore the ?gut-brain-HPA? axis in humans and test the hypothesis that diet-induced WL causes an increase in plasma AgRP and activation of the HPA axis whereas equivalent WL after RYGB or SG do not produce such an increase. These findings are of clinical significance as preventing activation of the HPA axis may control hunger and allow for long-term maintenance of WL.
In AIM TWO we will utilize proteomic analysis to further extend our investigations of WL dependent and independent mechanisms that may account for differences in metabolic outcomes between LCD, RYGB and SG. A number of experimental paradigms indicate that protein secreted from the proximal small intestine induces insulin resistance which provides a possible explanation as to why RYGB, which excludes this segment of the intestine, produces superior results compared with SG that are independent of WL. In the proposed Aims subjects will be carefully characterized with frequently sampled intravenous glucose tolerance tests and mixed meal tolerance tests. We expect results that will tease out mechanisms related to improvements in IS and beta-cell function that are independent of weight reduction and specific to RYGB or SG with the ultimate goal of optimizing surgical procedures and providing new non-surgical therapeutic targets for the treatment of DM and obesity.

Public Health Relevance

Together with an increase in morbid obesity and type 2 diabetes is an increase in the number of bariatric surgeries that are the most effective treatment for these chronic conditions. The objective of these studies is to gain an understanding of the mechanisms that promote weight loss and improved glucose control. The ultimate goal is to identify therapeutic pathways for obesity and diabetes as a way to optimize surgical procedures and discover novel non-surgical targets for safe and effective drug therapy.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Teff, Karen L
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Columbia University (N.Y.)
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Rao, Raghavendra; Roche, Alexander; Febres, Gerardo et al. (2017) Circulating Apolipoprotein A-IV presurgical levels are associated with improvement in insulin sensitivity after Roux-en-Y gastric bypass surgery. Surg Obes Relat Dis 13:468-473
Sachdev, Saachi; Wang, Qi; Billington, Charles et al. (2016) FGF 19 and Bile Acids Increase Following Roux-en-Y Gastric Bypass but Not After Medical Management in Patients with Type 2 Diabetes. Obes Surg 26:957-65
Nguyen, Kim T; Billington, Charles J; Vella, Adrian et al. (2015) Preserved Insulin Secretory Capacity and Weight Loss Are the Predominant Predictors of Glycemic Control in Patients With Type 2 Diabetes Randomized to Roux-en-Y Gastric Bypass. Diabetes 64:3104-10
Nguyen, Kim T; Korner, Judith (2014) The sum of many parts: potential mechanisms for improvement in glucose homeostasis after bariatric surgery. Curr Diab Rep 14:481
Nagareddy, Prabhakara R; Kraakman, Michael; Masters, Seth L et al. (2014) Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab 19:821-35
Jackness, Clifton; Karmally, Wahida; Febres, Gerardo et al. (2013) Very low-calorie diet mimics the early beneficial effect of Roux-en-Y gastric bypass on insulin sensitivity and ?-cell Function in type 2 diabetic patients. Diabetes 62:3027-32
Page-Wilson, Gabrielle; Wardlaw, Sharon L; Khandji, Alexander G et al. (2012) Hypothalamic obesity in patients with craniopharyngioma: treatment approaches and the emerging role of gastric bypass surgery. Pituitary 15:84-92
Plum, Leona; Ahmed, Leaque; Febres, Gerardo et al. (2011) Comparison of glucostatic parameters after hypocaloric diet or bariatric surgery and equivalent weight loss. Obesity (Silver Spring) 19:2149-57
Korner, Judith; Nandi, Anindita; Wright, Suzanne M et al. (2011) Implantable gastric stimulator does not prevent the increase in plasma ghrelin levels that occurs with weight loss. Obesity (Silver Spring) 19:1935-9
Korner, J; Inabnet, W; Febres, G et al. (2009) Prospective study of gut hormone and metabolic changes after adjustable gastric banding and Roux-en-Y gastric bypass. Int J Obes (Lond) 33:786-95

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