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Intestinal-derived FGF15 preserves muscle and bone mass following sleeve gastrectomy

03 Jun 2020-bioRxiv (Cold Spring Harbor Laboratory)-

TL;DR: Interestingly, ablation of intestinal FGF15 in adult mice results in little change to body weight or glucose regulation when challenged with a high-fat diet, and data point to an important role for intestinal F GF15 to protect the organism from deleterious effects of rapid weight loss that occurs after VSG.
Abstract: Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive, but provide the most effective long-term metabolic improvements in obese and Type 2 diabetic patients. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Preliminary data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma levels in humans and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2; Fgf15f/f) mice and controls, which were maintained on 60% high-fat diet. Interestingly, ablation of intestinal FGF15 in adult mice results in little change to body weight or glucose regulation when challenged with a high-fat diet. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG and this was a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density observed after VSG in control mice was increased in intestinal-specific FGF15 knock out mice. Finally the effect of VSG to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of rapid weight loss that occurs after VSG.

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Intestinal-derived FGF15 preserves muscle and bone mass following sleeve
gastrectomy
Nadejda Bozadjieva Kramer
1
, Jae Hoon Shin
1
, Yikai Shao
2
, Ruth Gutierrez-Aguilar
3
,
Ziru Li
4
, Kristy M. Heppner
5
, Samuel Chiang
1
, Sara G. Vargo
1
, Katrina Granger
4
,
Darleen A. Sandoval
1
, Ormond A MacDougald
4
, Randy J. Seeley
1
1
Department of Surgery, University of Michigan; Ann Arbor, MI.
2
Center for Obesity and Metabolic Surgery, Huashan Hospital of Fudan University,
Shanghai, China.
3
Divsión de Investigación, Facultad de Medicina, Universidad Nacional Autónoma de
México and Laboratorio de Enfermedades Metabólicas: Obesidad y Diabetes, Hospital
Infantil de México “Federico Gómez”, Mexico.
4
Department of Molecular & Integrative Physiology, University of Michigan; Ann Arbor,
MI
5
Novo Nordisk Research Center Seattle, Inc.; Seattle, WA.
Corresponding author:
Dr. Randy J. Seeley
University of Michigan
2800 Plymouth Rd.
NCRC Building 26-343N
Ann Arbor, MI 48109-2800
USA
Phone: (513) 549-7411
Fax: (734) 232-1223
Email: seeleyrj@med.umich.edu
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint

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Abstract
Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive, but
provide the most effective long-term metabolic improvements in obese and Type 2
diabetic patients. These powerful effects of manipulating the gastrointestinal tract point
to an important role of gastrointestinal signals in regulating both energy balance and
metabolism. To that end, we have used mouse models of VSG to identify key gut
signals that mediate these beneficial effects. Preliminary data from our rodent model of
VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth
Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many
aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal
enterocytes of the small intestine and is released postprandially. Like many other gut
hormones, postprandial plasma levels in humans and ileal FGF15 expression in mice
increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2;
Fgf15
f/f
) mice and controls, which were maintained on 60% high-fat diet. Interestingly,
ablation of intestinal FGF15 in adult mice results in little change to body weight or
glucose regulation when challenged with a high-fat diet. Unlike what we had predicted,
intestinal-specific FGF15 knock out mice lost more weight after VSG and this was a
result of increased lean tissue loss compared to control mice. Further, the loss of bone
mineral density observed after VSG in control mice was increased in intestinal-specific
FGF15 knock out mice. Finally the effect of VSG to reduce hepatic cholesterol was also
absent in intestinal-specific FGF15 knock out mice. These data point to an important
role for intestinal FGF15 to protect the organism from deleterious effects of rapid weight
loss that occurs after VSG.
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint

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Introduction
Obesity has become a growing epidemic, where associated complications such as
cardiovascular morbidity, type 2 diabetes and insulin resistance pose major health care
challenges worldwide (Afshin et al., 2017). Current pharmacological treatments for
obesity include less than ten FDA approved drugs, all of which demonstrate modest
effect sizes and substantial liabilities for patients including cardiac and gastrointestinal
distress (Saltiel, 2016). Although invasive, bariatric surgery is the most effective
treatment for sustained weight loss, and also improves glycemic control and other
comorbidities in patients better than conventional weight-loss therapies (Adams et al.,
2017; Schauer et al., 2017).
The effectiveness of bariatric surgery to reduce body weight and improve glucose
metabolism has highlighted the important role that the gastrointestinal tract has in
regulating a wide range of metabolic processes. One weight-independent effect of
bariatric surgery is the alteration of enterohepatic bile acid circulation resulting in
increased plasma bile levels as well as altered bile acid composition in rodents (Kohli et
al., 2010; Myronovych et al., 2014) and humans (Patti et al., 2009; Pournaras et al.,
2012). While it remains unclear why both VSG and RYGB can alter bile acids, it is
possible that these changes are important mediators of the effects of surgery. We have
previously identified bile acid signaling through the nuclear ligand-activated farnesoid X
receptor (FXR) as a potential link for mediating the beneficial effects of elevated bile
acids following bariatric surgery. We have shown that bile acids are increased after
VSG and that FXR is essential for the positive effects of bariatric surgery on weight loss
and glycemic control (Myronovych et al., 2014; Ryan et al., 2014). Unlike wild-type
mice, FXR-/- mice do not maintain body weight loss and do not have improved glucose
tolerance after VSG or after bile diversion to the ileum (Albaugh et al., 2019; Ryan et al.,
2014). These studies have highlighted the importance of the enterohepatic circulation in
the metabolic effects following bariatric surgery.
Downstream of FXR is the gut-derived hormone Fibroblast Growth Factor 15 (the
human ortholog is termed FGF19). Pharmacological administration of FGF15/19 has
potent effects to reduce bile acid secretion at the level of both the liver and the
gallbladder (Kir et al., 2011; Potthoff et al., 2011) and has potent effects on body weight
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint

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and glucose maintenance (Lan et al., 2017). In the ileum, bile acids activate intestinal
FXR and its downstream target FGF15/19. FGF15/19 is expressed in ileal enterocytes
of the small intestine and is released postprandially in response to bile acid absorption
(Inagaki et al., 2005). Once released from the ileum, FGF15/19 enters the portal venous
circulation and travels to the liver where FGF15/19 binds to its receptor FGFR4 and
represses de novo bile acid synthesis and gallbladder filling (Inagaki et al., 2005).
Therefore, bile acids and FGF15/19 both act as ligands to regulate bile acid synthesis
and facilitate communication between the liver and small intestine. The actions of
FGF15/19 resemble that of insulin in stimulating protein and glycogen synthesis and
reducing gluconeogenesis. However, unlike insulin, FGF15/19 decreases hepatic
triglycerides and reduces cholesterol. This notable difference has made FGF19 a
potential therapeutic target to aid insulin’s actions while avoiding some pitfalls of insulin
therapy (DePaoli et al., 2019; Harrison et al., 2018).
Consistent reports demonstrate that pharmacologically elevating Fibroblast
Growth Factor FGF15/19 levels in preclinical models of metabolic disease results in
multiple metabolic benefits including increased energy expenditure, reduced adiposity,
and improved lipid and glucose homeostasis (Fu et al., 2004; Miyata et al., 2011;
Morton et al., 2013; Ryan et al., 2013; Tomlinson et al., 2002). Circulating FGF19 levels
are reduced in individuals with metabolic disorders and nonalcoholic fatty liver disease
(NAFLD). FGF19 levels are lower in obese patients, without strong association to
glucose metabolism or insulin sensitivity (Gallego-Escuredo et al., 2015; Gomez-
Ambrosi et al., 2017; Haluzikova et al., 2013; Mraz et al., 2011; Renner et al., 2014).
Other studies report that basal FGF19 levels are inversely correlated to glucose
metabolism or insulin sensitivity (Barutcuoglu et al., 2011; Sonne et al., 2016) and
nonalcoholic fatty liver disease (NAFLD) (Eren et al., 2012; Jiao et al., 2018). Most
importantly, fasting and postprandial plasma FGF19 levels in humans (Belgaumkar et
al., 2016; DePaoli et al., 2019; Gomez-Ambrosi et al., 2017; Haluzikova et al., 2013;
Mulla et al., 2019; Sachdev et al., 2016) and ileal FGF15 expression in mice (as shown
in these studies) increase after VSG. These data point to FGF15/19 as a potential target
to mediate the effects of weight loss and improved glucose tolerance following VSG. To
test the hypothesis of whether FGF15 plays a role in the metabolic improvements after
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint

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bariatric surgery, we used a mouse model of VSG, which has increased ileal expression
of FGF15 in VSG compared to Sham mice. We generated a novel mouse model of
intestinal-specific FGF15 knock out (VilCreERT2; Fgf15
f/f
) and controls, which were
maintained on 60% high-fat diet before and after undergoing Sham or VSG surgery.
Intestinal-derived FGF15 is necessary for the improvement in peripheral blood glucose
regulation, to preserve muscle mass and bone mass, and for the decrease in hepatic
cholesterol after VSG-induced weight loss. These finding point to an important role for
FGF15 in the regulation of multiple metabolic parameters following VSG.
was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission.
The copyright holder for this preprint (whichthis version posted June 3, 2020. ; https://doi.org/10.1101/2020.06.02.130278doi: bioRxiv preprint

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