# The role of intestinal-derived FGF15/19 during obesity and rapid weight loss

> **NIH VA IK2** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

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...

## Key facts

- **NIH application ID:** 10364480
- **Project number:** 1IK2BX005715-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Nadejda Bozadjieva Kramer
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-03-01 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364480

## Citation

> US National Institutes of Health, RePORTER application 10364480, The role of intestinal-derived FGF15/19 during obesity and rapid weight loss (1IK2BX005715-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10364480. Licensed CC0.

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