SLIDE 1 Growth factor regulation of development and function of vagal sensory innervation
Edward Fox Purdue University
Growth factor regulation of development and function of vagal sensory innervation
Edward Fox Purdue University
SLIDE 2
Intraganglionic laminar endings IGLEs
SLIDE 3 “Advances in contraception and industrialized food production allowed modern couples to have fewer offspring while leaving the total weight of families constant”
SLIDE 4
SLIDE 5
- Vagus Nerve
- Neurotrophins & Vagal GI afferents
- Neurotrophin knockouts in the GI tract
=> development of vagal GI afferents => feeding behavior
SLIDE 6 Yi, Zeltser, & Tschop
SLIDE 7
Woods et al., Science 280:1378 1998
Vagal afferents signal satiation
SLIDE 8 There are many types of GI vagal afferents
Powley et al., 2011 Fox et al., 2002 Berthoud et al., 1995 Fox et al., 2001 Netter
IMAs IGLEs crypt villus
SLIDE 9
Growth factors: neuron survival neuron differentiation axon growth / guidance
SLIDE 10
Brain-derived neurotrophic factor (BDNF) Evidence for Role in Development of Vagal Sensory Innervation of the GI Tract
SLIDE 11
TrkB is expressed in vagal sensory neurons
Wiklund & Ekstrom J Neurobiol, 45:142 2000 Michael & Priestley J Neurosci, 19:1844 1999
protein (IHC) mRNA (ISH)
SLIDE 12
BDNF KO mice have 59% loss of vagal sensory neurons
Elshamy & Ernfors J Neurosci 17: 8667 1997
Wild type BDNF -/-
SLIDE 13 BDNF is present in embryonic and early postnatal GI tract
lumen sm bv mes att E17 E17
Stomach Intestine
bv sm
Fox & Murphy 2008
SLIDE 14 Global BDNF KO P0 50% decrease IGLE number
initial formation (+/+) P0 immature
*
n=12 n=12 n=11
genotype:
near mature (+/+) P8
Murphy & Fox 2008
SLIDE 15 Sites of BDNF Expression that Influence Vagal Development
3 2 1
Modified from Lawrence & Luckman, Trends in Endocrinol Metabol,14, 60, 2003
SLIDE 16 Neurotrophic Hypothesis
Oppenheim 1991:
- neurons are overproduced during development
- neurons compete for limiting amounts of
target-derived neurotrophic factors
- neurotrophic factors support neuron survival by
preventing apoptosis
SLIDE 17 Sites of BDNF Expression that Influence Vagal Development
3 2 1
Modified from Lawrence & Luckman, Trends in Endocrinol Metabol,14, 60, 2003
SLIDE 18 Predictions: SM-BDNF KO Effects
- decreased numbers of vagal sensory neurons
- decreased survival of IGLE innervation of GI tract
- decreased vagal satiation signaling (increased meal size)
SLIDE 19 Smooth-muscle specific BDNF KO
Modified from Mak et al., Nat Rev Immunol, 1:11. 2001
SLIDE 20 BDNF Expression Compared with SM-BDNF KO INTESTINE (E14-15)
BDNF Expression SM-BDNF KO
Fox et al., Neurosci 229, 176, 2013
SLIDE 21 SM-BDNF KO Reduced BDNF mRNA in the Intestine
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 22 SM-BDNF KO does not Alter Gastric IGLEs
control SM-BDNF KO
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 23 SM-BDNF KO Increases Intestine IGLE Density
control
SM-BDNF KO
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 24 SM-BDNF KO Increases Vagal Sensory Neuron Number
SM-BDNF KO Control
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 25 SM-BDNF KO has No Effect on Body Weight or Daily Food Intake
Body weight Body fat Food Intake
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 26 SM-BDNF KO Reduces Meal Duration and Meal size => Suggests Increased Satiation Signaling
meal duration eating rate meal size
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 27 5 10 15 20 25 30 0.0000 0.0025 0.0050 0.0075 0.0100 control BDNF SM -/- minutes grams (g)
Total food intake min 6-30 initial early decay late decay
control BDNF SM -/- 0.000 0.025 0.050 0.075 0.100 grams (g)
*
SM-BDNF KO Increases Suppression of Feeding => Consistent with Increased Satiation Signaling
Biddinger & Fox, J Neurosci 34, 10379, 2014
SLIDE 28 Yi, Zeltser, & Tschop
SLIDE 29 Summary: SM-BDNF KO Effects
- increased intestinal IGLE innervation
- meal analyses suggest increased satiation signaling
- increased numbers of vagal sensory neurons
- suggests BDNF in GI smooth muscle normally
decreases survival of IGLEs
- not consistent with neurotrophic hypothesis
- may be mediated by BDNF activation of trkB-p75
SLIDE 30 NT-3 Expression Compared with SM-NT-3 KO Mesenteric Blood Vessels NT-3 Expression SM-NT-3 KO SM-NT-3 KO
Fox et al., Am J Physiol 305, R1307, 2013
(E15-17)
SLIDE 31 Fox et al., Am J Physiol 305, R1307, 2013
NT-3 Expression Compared with SM-NT-3 KO (E15-17) stomach intestine NT-3 Expression SM-NT-3 KO SM-NT-3 KO
SLIDE 32 SM-NT-3 KO Reduces Vagal Activation by Consumption of a Large Meal
Fox et al., Am J Physiol 305, R1307, 2013
SLIDE 33 SM-NT-3 KO has no Effect on Body Weight or Daily Food Intake
Fox et al., Am J Physiol 305, R1307, 2013
SLIDE 34 SM-NT-3 KO Increases Meal Duration => Suggests Decreased Satiation Signaling meal duration eating rate meal size
Fox et al., Am J Physiol 305, R1307, 2013
SLIDE 35 SM-NT-3 KO Reduces Suppression of Feeding => Consistent with Decreased Satiation Signaling
meal size
initial early decay late decay
eating rate
Fox et al., Am J Physiol 305, R1307, 2013
Total food intake all 30 min
SLIDE 36 Summary: SM-NT-3 KO Effects
- decreased vagal activation of brainstem by large meal
- increased meal duration
- increased 1st meal size
=> suggests decreased satiation signaling
SLIDE 37 Yi, Zeltser, & Tschop
SLIDE 38
- Effects of smooth muscle KO’s of BDNF & NT-3:
- SM-BDNF KO: increased intestinal innervation & satiation
- SM-NT-3 KO: decreased vagal signaling & satiation
- Implications?
- selective pharmacological or electrophysiological
activation (or inhibition) of intestinal IGLE pathway could reduce (or increase) meal size.
- in conjunction with other treatments may help treat obesity
and eating disorders such as anorexia and bulimia
Conclusions
SLIDE 39
Acknowledgements
Jessica Biddinger Mardi Byerly Michelle Murphy Elizabeth Ayres Jennifer McAdams Amber Worman Phyllis Zickmund Talal Karam Tammy Dilden Kevin Jones, Univ Colorado Guoping Fan, UCLA NIH NS46716
