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Hungry Like PACAP Man:
The Role of PACAP and PACAP6-38 in Eating Behaviors
Greenfield SMART Team: Jessica Wallner, Andrew Braatz, Francis Deleon-Camacho, Dakota Alphin, Elena Groth,
Tahseen Shaik, Pratyusha Emkay, Katie Kelly, Jordon Piotrowski, Vincent Krenz, Karen Nakhla, L.I.am Granlund, Nicole Deleon-Camacho
Teachers: Julie Fangmann and Drew Rochon
Mentor: SuJean Choi, PhD, Marquette University
Greenfield High School: 4800 South 60th Street, Greenfield, WI 53220
Abstract:
A. Obesity and Related Health Concerns in the United States
According to the CDC, 34.9% of United States adults are obese, which is linked to premature death, heart disease,
cancer, respiratory disorders, fertility problems, Type 2 diabetes, and stroke. Over- and under-eating are related to
brain chemistry. A 38 amino acid peptide hormone in the hypothalamus, called pituitary adenylate cyclase-activating
peptide (PACAP), may be linked to weight gain and eating disorders. PACAP binds to PACAP type 1 receptor (PAC1R),
a G-protein coupled receptor. Seven hydrophobic transmembrane (TM) domains hold PAC1R in hypothalamic cell
membranes. PAC1R’s extracellular domain (ECD) contains a ligand binding site. PAC1R’s many negative residues
attract PACAP’s many positive ECD residues. PACAP’s V19, K20, and L27 affect PACAP binding to PAC1R. K20 forms a
possible salt bridge with PAC1R’s G104, allowing PACAP to align parallel to PAC1R so PACAP’s N-terminus interacts
with PAC1R’s TM domains. This activates PAC1R, sending a signal inside the cell. Too much PACAP may cause a
person to stop eating and lead to eating disorders. PACAP6-38 is an antagonist formed when a protease removes the
first five PACAP residues. When PACAP6-38 binds to PAC1R, eating increases, possibly leading to obesity. SuJean
Choi, PhD wants to determine how ratios of PACAP and PACA6-38 are regulated. The Greenfield SMART (Students
Modeling A Research Topic) Team modeled PAC1R’s ECD and its two ligands, PACAP and PACAP6-38, using 3D
printing technology to investigate their relationships. Studying PACAP and PACAP6-38 regulation and brain chemistry
involved in eating behaviors could improve people’s lives and decrease obesity-related US medical costs. Program
supported by a grant from NIH-CTSA.
B. Eating Behavior and Brain Chemistry
Eating and the Brain
Researchers know the
hypothalamus regulates eating
behaviors. However, more needs
to be studied regarding the specific
regions of the hypothalamus
involved in regulating eating. Two
possible areas of the
hypothalamus that regulate eating
and brain chemistry are the PVN
(Paraventricular Nuclei) and VMN
(Ventromedial Nuclei).
Obesity rates in the United States
• Obesity and eating disorders are a major health concern in the
United States. Over 39% of adults in the U.S. were obese and
69% were overweight as of 2012 (CDC).1
• Up to 24 million people
of all ages and genders
suffer from an eating
disorder (anorexia nervosa,
bulimia and binge eating)
in the U.S. (ANAD).2
Stroke
Some Cancers
Endometrium and
Breast
Heart
Disease
Obesity
Gall Bladder
Disease
Type 2
Diabetes
Sleep
Disorders
C. Applying PACAP to the Hypothalamic VMN
Decreases Food Intake in Rats
Not only does obesity lead to a variety of health
concerns, but there is also a link between obesity
and early death. As Body Mass Index (BMI)
increases, the mortality rate also increases.5
Osteoarthritis
E. Structures of PAC1R, PACAP, and PACAP6-38
PAC1R ECD
Extracellular
Domain (ECD)
Hydrophobic
Toward
C-terminus amino acids
Possible
PACAP
binding
site
Transmembrane
Domains
Intracellular
Domain
pdb file: 2JOD
Figure B1. The
hypothalamus.6
Toward
Disulfide
N-terminus bond
Figure B2. Regions of
the hypothalamus.7
Figure C1. A guide cannula
injector system was used to
administer chemicals to the VMN
to determine if they would alter
eating behavior.9
Comparing the
Hypothalamic PVN &
VMN Regions
Two regions within the hypothalamus
were examined to see if they produce
the PAC1R receptor, a protein involved
in eating and brain chemistry. White
dots appear where mRNA molecules
coding for PAC1R are expressed in the
hypothalamus. High concentrations of
PAC1R mRNA were found in the VMN,
and also in PVN. Due to the high
concentration of PAC1R mRNA in the
VMN, the VMN is a target for
administering chemicals related to
pituitary adenylate cyclase-activating
protein (PACAP) signaling in lab
animals.
The medical costs due to obesity in the U.S were over $105
billion in 2008, when obesity rates were lower.4 These high
healthcare bills are due to other health conditions related to
obesity.
Hypertension
• Obesity rates are increasing
in U.S. adults (see Figure
to the right). 3
Obesity and Morbidity
Obesity Health Concerns and Costs
Figure C2. PACAP alone decreased consumption
significantly, while PACAP6-38 (PACAP with the
first 5 amino acids removed) administered just
prior to PACAP administration) blocked PACAP’s
effects on feeding.10
D. How Different Ratios of PACAP and
PACAP6-38 Affect Eating Behaviors
PACAP
PACAP6-38
Figure E1. PAC1R has 7 transmembrane
domains, an extracellular domain (ECD) for
binding, and an intracellular domain.11
PACAP1-27
Amino
acids 1-5
Alpha helix
pdb file: 1GEA
Amino acids possibly
important in PAC1R
binding
Figure E1. The structure of PACAP1-27 (above)
and PACAP6-38 (right).
Figure B3. The top image
shows the location of the
PVN in the hypothalamus.
The bottom image
magnifies the PVN,
showing more detail.8
Figure B4. The top image
shows the location of the
VMN in the hypothalamus.
The bottom image shows
the VMN in more detail. 8
Beta Sheet
Alpha helix
Figure E2. The structure of PAC1R’s
extracellular domain, where PACP and
PACAP6-38 possibly binds.
PACAP6-38
Toward
C-terminus
Alpha helix
pdb file: 2JOD
Amino acids
possibly important
in PAC1R binding
Toward
N-terminus
F. The Future of PACAP and Eating Behaviors
Figure D1. If the ratio of
PACAP to PACAP6-38 is
balanced eating behavior
is balanced
1<http://www.cdc.gov/nchs/fastats/obesity-overweight.htm>2<http://www.anad.org/get-information/about-eating-disorders/eating-disorders-statistics>3<http://www.cdc.gov/obesity/data/prevalence-maps.html>4
< http://www.cdc.gov/chronicdisease/overview/>5<http://www.medscape.org/viewarticle/484768_2>6<http://www.upright-health.com/pituitarygland.html>7<http://ccforum.com/content/7/6/427/figure/F1?highres=y>8<(Choi, Marquette University)>9<http://www.leicabiosystems.com/pathologyleaders/stereotaxic/navigator-through-the-brain-stereotaxic-atlases-forneuroscience-research/>10<Resch et al., 2013 American Journal of Physiology>11<http://en.wikipedia.org/wiki/G_protein–coupled_receptor>
Figure D2. If the ratio of
PACAP to PACAP6-38 is
greater, then the person
will consume less food
Figure D3. If the ratio of
PACAP to PACAP6-38 is less,
then the person will feel the
urge consume more.
PACAP research can help can prolong lives by reducing eating disorders, such as binge-eating, obesity,
and anorexia. PACAP could help find a balance between over- and under-eating. PACAP can also help
solve many different types of disease, such as diabetes and heart disease, through controlling food
intake and ultimately excess weight gain. Some of the treatments for these diseases are expensive, so
if weight gain and some of these diseases are prevented by PACAP, the country will save money and be
more healthy overall. Additionally, this medical research can help researchers understand brain
signaling and know what is causing over- and under-eating.
The SMART Team Program is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number 8UL1TR000055. Its contents are solely the responsibility
of the authors and do not necessarily represent the official views of the NIH.