MPB 333 The Molecular
Endocrinology of Obesity and
Diabetes
Satiety and Hunger
Meal Patterningin Rodents
Behavioral Satiety Sequencein Rodents
Terminology
HungerFood Seeking Behavior
Meal InitiationMeal
Meal terminationSatietySatiateNausea
Inter-meal IntervalReward
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
Forebrain
Hindbrain
The effects of CCK and stomachstretch are integrated in vagal afferent fibers
CCK Stretch
Nodose GanglionVagus
DOSE
30-Minute Food Intake
Gut-Brain Communication
Gut-Brain Communication
Satiety and Hunger Factors
Cholecystokinin (CCK) - A well-characterized Cholecystokinin (CCK) - A well-characterized satiety factor acting on the NTSsatiety 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
Cherbut et al., Short-chain fatty acids modify motility through nerves and polypeptide YY release. Am. J. Physiol. 275, G1415-G1422, 1998
Ilial Infusion50mM SCFA
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
PYY3-36 Inhibits Food Intake in
Vagotomized Mice
Effect of Vagotomy on PYY3-36action
2 4 6 80
1
2
3Sham Saline n=12Sham PYY n=13
BSDV Saline n=6BSDV PYY n=6
**
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 HumansWren, et al. JCEM. 86(12):5992-5, 2001.
Ghrelin Levels Rise With Weight LossCumming, 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 IntakeMatson and Ritter. AJP. 45:R1038-45, 1999.
Saline CCK Leptin CCK + Leptin
10
0
20
30
40
48-hourchowIntake
(g)
b
a
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 Leptin-Responsive