Pancreatitis is a potentially life-threatening inflammation of the pancreas. It can have many causes, including heavy, long-term alcohol
drinking, gallstones, and certain hereditary conditions.
United States residents are hospitalized with acute pancreatitis annually, suggested the National Institutes of Health's National Institute of
Diabetes and Digestive and Kidney Diseases.
‘The mechanism by which the stress hormone FGF21 keeps digestive enzymes from damaging the pancreas has been uncovered by researchers.’
mechanism by which the stress hormone FGF21 keeps digestive enzymes from
damaging the pancreas has been uncovered by UT Southwestern Medical Center researchers.The research, published online this month in Cell Metabolism
, points to the possibility of new therapies for pancreatitis.
Dr. David Mangelsdorf and Dr. Steven Kliewer - who have run a joint laboratory
at UT Southwestern since 2002 - earlier reported that the liver hormone
FGF21, or fibroblast growth factor 21, acts via the brain's reward
pathway to reduce the desire for sugar and alcohol in mammals.
November, they published a collaborative study
with European researchers comparing the genomes of more than 105,000
light and heavy social drinkers. That investigation identified a gene
variant for the brain's FGF21 receptors that suppresses the desire to
They then turned their attention from FGF21's effects in the central
nervous system to the digestive system, where another mystery awaited.
"Previous studies had shown that FGF21 protected the pancreas, but it
was unknown how or by what mechanism," said Dr. Mangelsdorf, Chair of
Pharmacology and a Howard Hughes Medical Institute Investigator. "We
found that FGF21 has a novel, unexpected role in stimulating the
pancreas to secrete digestive enzymes into the intestine."
The work may someday lead to new therapies for pancreatitis, said Dr.
Kliewer, Professor of Molecular Biology and Pharmacology and holder of
the Nancy B. and Jake L. Hamon Distinguished Chair in Basic Cancer
Research. Drs. Mangelsdorf and Kliewer are corresponding authors of the
The study reveals yet another surprising effect of FGF21. When
produced in the liver, FGF21 works on the central nervous system like a
hormone - a substance created in one part of the body that exerts
effects on other parts. In contrast, FGF21 made in the pancreas acts
locally, affecting only that organ, the researchers found.
The researchers report that the same FGF21 receptor complex found in
the brain is also present in the pancreas, the organ located behind the
stomach that makes enzymes used in digestion. Under normal conditions,
the pancreas makes enzymes that remain inactive (known as zymogen
granules) until they travel through the pancreatic ducts and arrive in
the intestine, where they become activated and help digest food. When
the pancreatic ducts become blocked, the powerful enzymes can activate
while still inside the pancreas and begin to digest the glandular organ
itself, they explained.
In one experiment, the researchers observed that mice genetically
unable to make FGF21 overproduced zymogen granules (the enzyme
precursors) in the pancreas. This effect was reversed when the mice
received FGF21 infusions.
"There was no evidence of pancreatitis in those mice, only a
significant increase in the amount of pancreatic enzymes, and
indications that having FGF21 helps clear those enzymes from the
pancreas," Dr. Kliewer said.
In another experiment, they found that mice genetically engineered to
overproduce FGF21 were protected from injury when exposed to a
pancreatic toxin. Conversely, mice lacking FGF21 were more susceptible
to damage from the toxin.
"Pancreatic FGF21 is a digestive enzyme secretion stimulator whose
function is to maintain enzyme balance in the pancreas," said Dr.
Mangelsdorf, who also holds the Alfred G. Gilman Distinguished Chair in
Pharmacology, and the Raymond and Ellen Willie Distinguished Chair in
Molecular Neuropharmacology in Honor of Harold B. Crasilneck.
"One of the big inducers of pancreatitis is alcohol consumption. So,
this hormone might someday be used to treat one of the key adverse
effects of alcoholism," Dr. Mangelsdorf said.
FGF21 was first described in association with dietary stresses such
as starvation and high-fat diets. It is also produced when mammals
consume carbohydrates and alcohol. Because of FGF21's unique effects,
drug forms of the protein are being evaluated for the treatment of
obesity and type 2 diabetes.
The researchers stressed that any potential therapeutics will need to
address some unusual side effects seen in their previous mouse studies,
such as bone loss, increased levels of the so-called fight-or-flight
hormones called glucocorticoids, and suppressed fertility in female
mice. Because FGF21's hormonal effects on the central nervous system
work via the brain's reward pathway, there is also concern about
possible adverse effects on mood, they said.
"FGF21 has remarkable pharmacologic effects," Dr. Mangelsdorf said.
"This study suggests an intriguing role in the body's reaction to
stresses in the digestive system, but there is more work to be done."
UT Southwestern co-authors, all in Pharmacology, include: co-lead
authors Dr. Katie Coate, a former postdoctoral researcher, and graduate
student Dr. Genaro Hernandez; Assistant Instructor Dr. Curtis Thorne; postdoctoral researcher Dr. Shengyi Sun; undergraduate researcher Thao D.V. Le; and research technician Kevin Vale.
The research was supported by the National Institutes of Health, the
Robert A. Welch Foundation, a National Science Foundation Graduate
Research Fellowship, and the Howard Hughes Medical Institute. Novo
Nordisk provided the recombinant FGF21 used in the experiments.
Dr. Mangelsdorf is a founder and member of the scientific advisory
board of Metacrine, a biotech company that seeks to develop anti-obesity