ABSTRACT
Bariatric surgery is an effective treatment that promotes sustained weight loss and remission of type 2 diabetes
(T2D) and fatty liver diseases. Although bariatric surgery produces the most dramatic metabolic improvements
of any obesity and T2D treatments available, it is invasive and has severe long-term side effects. Moreover,
the surgery is not routinely available to low-income populations, which are disproportionately affected by
obesity and T2D. Therefore, safer and more affordable therapies are urgently needed. Developing a greater
understanding of the molecular mechanisms that underlie the metabolic benefits of bariatric surgery may
provide a roadmap to develop innovative approaches to treat obesity, T2D, and other metabolic complications.
Our preliminary data and the experiments proposed in this application rely on vertical sleeve gastrectomy
(VSG) in mice as a model to interrogate the molecular consequences of bariatric surgery. VSG produces
prominent physiological effects and generally results in fewer complications than other bariatric surgeries. It
has thus become one of the most popular bariatric operations performed in clinical practice. After performing
VSG in obese mice, we observe dramatic changes in serum bile acid (BA) composition, as well as
downregulation of the enzyme CYP8B1. Specifically, we observe reduced ratios of 12a-hydroxylated (12a-OH)
BAs relative to non-12a-OH BAs. 12a-OH BAs require CYP8B1 for synthesis in the liver and have been
associated with insulin resistance and non-alcoholic fatty liver disease. Intestinal lipid absorption, which
contributes to weight gain, is also substantially lower in mice after VSG. Based on these exciting preliminary
results, we hypothesize that VSG alters specific BAs in enterohepatic circulation by downregulating CYP8B1,
thus restricting intestinal lipid absorption and changing the gut microbiome, which contributes to the metabolic
effects of the surgery. We propose three specific aims to test our hypothesis: (1) To characterize the
redistribution of BAs along the enterohepatic circuit after VSG; (2) To determine the extent to which CYP8B1
downregulation mediates the metabolic effects of VSG; and (3) To investigate the mechanisms by which
CYP8B1 downregulation contributes to the metabolic effects of VSG. We will compare the effects of VSG on
wild type, Cyp8b1 knockout (KO), CYP8B1 overexpressing, as well as Cyp2c70 KO mice that confer more
human-like BA pool composition. These studies will provide novel insights into the molecular mechanisms
underlying the beneficial effects of bariatric surgery. We anticipate that our findings will lead to the
development of safer, non-invasive, and more cost-effective therapies for obesity, T2D, and other metabolic
diseases.