Transcript Integration of long-term adipostatic and short

MPB 333
The Molecular
Endocrinology of
Obesity and
Diabetes
Satiety and
Hunger
Meal Patterning
in Rodents
Behavioral Satiety Sequence
in Rodents
Terminology
Hunger
Food Seeking Behavior
Meal Initiation
Meal
Meal termination
Satiety
Satiate
Nausea
Inter-meal Interval
Reward
Reward Pathways
Reward Pathways – Sensory Inputs
Lessons on Reward and Satiety from the Sham
Feeding Model
Reward and Satiety
LH is Responsive to Oropharyngeal Sensory
Inputs
Sensory-Specific Satiety
Brain Regions Implicated in Hunger and Satiety
Brain Regions Implicated in Hunger and Satiety
Satiety Signals
• Gastric distension
• Gut peptides, hormones, and factors
• Ileal brake mechanism
Satiety Signals
• Most come from the GI tract.
• Secreted in response to food ingestion,
create a sensation of fullness or satiety.
• Reduce meal size without causing malaise.
• Act within the time frame of a single meal
• Interact with other controllers of meal size.
Satiety Signals
• Reduce meal size comparably
– In lean animals and
– In genetically obese animals
– In diet-induced obese animals
• Blocking their action leads to increased meal
size.
• But…body weight not effected after repeated
injections.
Assays for Proving Satiety
• Behavioral Satiety Sequence
• Aversive Conditioning
Anatomy of
Hunger and
Satiety
Factors
The effects of CCK and stomach
stretch are integrated in vagal
afferent fibers
CCK
Forebrain
Hindbrain
Stretch
Vagus
Nodose Ganglion
30-Minute
Food
Intake
DOSE
Gut-Brain Communication
Gut-Brain Communication
Satiety and Hunger Factors
Cholecystokinin (CCK) - A well-characterized
satiety factor acting on the NTS
 Released from I cells in the duodenum in response
to nutrients particularly fat and protein
 Enters the blood, acts on gut motility, gallbladder
contraction, and gastric and pancreatic enzyme
secretion
 Diffuses locally to activate CCK-A receptors present
on the vagal snsory nerves
 Reduces food intake in the short-term
PYY: a Gut Peptide Released in Response to Short Chain Fatty Acids
Ilial
Infusion
50mM
SCFA
Cherbut et al., Short-chain fatty acids modify motility through nerves and
polypeptide YY release. Am. J. Physiol. 275, G1415-G1422, 1998
Effect of CCK on Food Intake
Effects of Leptin
Vagotomy blocks inhibition of
food intake by CCK
Discovery of a Novel Satiety Factor: PYY3-36
PYY3-36
inhibits
feeding
under
carefully
controlled
conditions
PYY3-36 Inhibits Food Intake in MC4-R-/- Mice
Effect of Vagotomy on PYY3-36
action
3
Sham Saline n=12
Sham PYY n=13
BSDV Saline n=6
BSDV PYY n=6
**
2
1
PYY3-36 Inhibits
Food Intake in
Vagotomized Mice
0
2
4
6
8
Time (h)
Control:
Vagotomy blocks
inhibition of food
intake by CCK
PYY3-36 Inhibits
Firing of
Anorexigenic
POMC Neurons
PYY3-36 Activates
AP Neurons
A Conditioned-Taste Aversion Assay for PYY3-36
PYY3-36 Exhibits Aversive Activity
Other Satiety Factors
Amylin
Preproglucagon-derived
peptides
PYY
Apo A-IV
Bombesin
Meal
Initiation
1.Glucostatic
Theory
2. Gastric
Pressure
Receptors
3. Ghrelin
Glucostatic Theory
Ghrelin: a meal
initiation factor
acting at the
GHS-R
From: Cummings, D.E. et al.
Diabetes 50, 1714-1719, 2001
Ghrelin Increases Hunger and Food Intake in Humans
Wren, et al. JCEM. 86(12):5992-5, 2001.
Ghrelin Levels Rise With Weight Loss
Cumming, et al. NEJM. 2002 346:1623-30.
Ghrelin Acts on Vagal and
Hypothalamic Neurons to
Stimulate Food Intake
Ghrelin Acts on Vagal and
Hypothalamic Neurons to
Stimulate Food Intake
The Big Picture
Leptin Tonically Regulates a Multitude of
Circuits Involved in Acute Intake and
Expenditure
Behavioral
Endocrine
Autonomic
Regulation of CCK Response by Leptin
Synergy by CCK and Leptin to Inhibit Food Intake
Matson and Ritter. AJP. 45:R1038-45, 1999.
40
a
30
48-hour
chow
Intake
(g)
20
b
10
0
Saline
CCK
Leptin
CCK + Leptin
Leptin Regulates the
Responsiveness of
Vagal Afferent Nerves
to CCK
MC4-R impacts autonomic, endocrine, and behavioral
effector pathways to balance energy intake and
expenditure so as to maintain energy homeostasis.
The melanocortin system is an ideal neuroanatomical
substrate for the integration of long-term and short-term
energy needs – a second pathway for tonic effects of leptin
on satiety
Activation of c-Fos by CCK by in POMC NTS Neurons
MC4-R Blockade Inhibits CCK Action
Feeding-activated c-Fos in POMC NTS Neurons
A Majority of NTS POMC Neurons are LeptinResponsive