PROJECT SUMMARY The prevalence of obesity among US Veterans is high and associated with a substantial healthcare burden. The US Department of Veteran Affairs (VA) estimated 78% of Veterans are obese or overweight, which is much higher than the estimated 35% of the non-Veteran US adult population. Bariatric surgery is currently the most effective treatment for sustained weight loss. Bariatric surgery interventions, such as Vertical Sleeve Gastrectomy (VSG), also improve glycemic control and other comorbidities in patients more effectively than conventional weight loss therapies. However, with the rising use of bariatric surgery, there is also greater awareness of its complications, such as the development of osteopenia (loss in bone mass) and liver disease for a subset of patients. Preliminary data from our rodent model of VSG led us to hypothesize the gut hormone Fibroblast-Growth Factor 15/19 (FGF15/19, mouse/human ortholog) as a potent mediator for VSG effects. FGF15/19 is expressed in ileal enterocytes of the small intestine and is released postprandially in response to bile acid absorption. Plasma FGF19 levels in humans and ileal FGF15 expression in mice greatly increased after VSG. We sought to test whether FGF15 is also required for the effects of VSG using our novel inducible intestine-specific FGF15 (FGF15INT-KO) mouse model. To our surprise, FGF15INT-KO VSG mice develop bone and muscle loss after VSG. Additionally, FGF15INT-KO mice do not show improved glucose tolerance and have increased hepatic cholesterol after VSG. The lack of FGF15 after VSG also results in markedly elevated plasma bile acid levels, including significant increase in toxic hydrophobic bile acids. Thus, our data suggest that increased FGF15 is essential to limit the deleterious effects of VSG by keeping bile acids within a physiologically healthy range. The overall goal of this project is to test the hypothesis that FGF15 is a critical regulator of enterohepatic circulation that impacts lean muscle and bone mass, hepatic lipids and glucose metabolism after VSG. These studies propose a novel mechanism for regulating bile acid signaling in patients who have undergone VSG and develop bone and muscle loss and liver damage. Understanding the etiology of these complications and developing potential treatment options will improve care for VSG patients. Dr. Bozadjieva Kramer is a Postdoctoral Research Fellow in the Department of Surgery at the University of Michigan. She has extensive experience working with in vitro, ex vivo and in vivo models of obesity and type 2 diabetes. Dr. Randy Seeley and Dr. Robert O’Rourke at the University of Michigan will provide primary basic science and clinical science mentorship, respectively, during the award. The career development activities will take advantage of the exceptional research environment and resources at the University of Michigan and Ann Arbor VA Medical Center. Dr. Bozadjieva Kramer’s career and research development will also be facilitated by highly motivated Mentoring Committee, which includes Drs. Amy Rothberg, Ormond A. MacDougald, Charles F. Burant and Rohit Kohli. Dr. Bozadjieva Kramer will use various training activities to strengthen her experience, knowledge, and skills in several areas, including technical and conceptual knowledge in clinical research and metabolomics, research skills in rodent models of bariatric surgery, enterohepatic physiology, leadership, lab management, effective communication, and mentoring young scientists. The training and knowledge from execution of this proposal will lay the foundation for Dr. Bozadjieva Kramer’s future research directions in dissecting the role of enterohepatic axis in the metabolic effects of bariatric surgery, as well as providing training for starting her own independent research program.

PROJECT NARRATIVE Obesity and associated metabolic disease, including type 2 diabetes, are a public health crisis; the risks of which are elevated in military Veterans. Although invasive, bariatric surgery is the most effective treatment for sustained weight loss, and it also improves glycemic control and other comorbidities in obese patients. This innovative research project will examine the novel role of intestinal-derived Fibroblast Growth Factor 15 (FGF15) in the regulation of body composition and glucose metabolism following bariatric surgery. The findings from these studies have high potential to identify new interventions in targeting obesity, metabolic disease, and for the preservation of lean mass and bone density after weight loss surgery.