mpb 333 the molecular endocrinology of obesity and diabetes satiety and hunger
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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. - PowerPoint PPT PresentationTRANSCRIPT
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MPB 333 The Molecular
Endocrinology of Obesity and
Diabetes
Satiety and Hunger
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Meal Patterningin Rodents
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Behavioral Satiety Sequencein Rodents
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Terminology
HungerFood Seeking Behavior
Meal InitiationMeal
Meal terminationSatietySatiateNausea
Inter-meal IntervalReward
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Reward Pathways
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Reward Pathways – Sensory Inputs
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Lessons on Reward and Satiety from the Sham Feeding Model
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Reward and Satiety
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LH is Responsive to Oropharyngeal Sensory Inputs
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Sensory-Specific Satiety
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Brain Regions Implicated in Hunger and Satiety
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Brain Regions Implicated in Hunger and Satiety
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Satiety Signals
• Gastric distension
• Gut peptides, hormones, and factors
• Ileal brake mechanism
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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.
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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.
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Assays for Proving Satiety
• Behavioral Satiety Sequence
• Aversive Conditioning
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Anatomy of Hunger and
Satiety Factors
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Forebrain
Hindbrain
The effects of CCK and stomachstretch are integrated in vagal afferent fibers
CCK Stretch
Nodose GanglionVagus
DOSE
30-Minute Food Intake
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Gut-Brain Communication
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Gut-Brain Communication
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Satiety and Hunger Factors
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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
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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
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Effect of CCK on Food Intake
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Effects of Leptin
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Vagotomy blocks inhibition of food intake by CCK
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Discovery of a Novel Satiety Factor: PYY3-36
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PYY3-36 inhibits feeding under
carefully controlled conditions
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PYY3-36 Inhibits Food Intake in MC4-R-/- Mice
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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
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PYY3-36 Inhibits Firing of
Anorexigenic POMC Neurons
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PYY3-36 Activates AP Neurons
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A Conditioned-Taste Aversion Assay for PYY3-36
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PYY3-36 Exhibits Aversive Activity
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Other Satiety Factors
Amylin
Preproglucagon-derived peptides
PYY
Apo A-IV
Bombesin
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Meal Initiation
1.Glucostatic Theory
2. Gastric Pressure
Receptors
3. Ghrelin
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Glucostatic Theory
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Ghrelin: a meal initiation factor
acting at the GHS-R
From: Cummings, D.E. et al.Diabetes 50, 1714-1719, 2001
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Ghrelin Increases Hunger and Food Intake in HumansWren, et al. JCEM. 86(12):5992-5, 2001.
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Ghrelin Levels Rise With Weight LossCumming, et al. NEJM. 2002 346:1623-30.
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Ghrelin Acts on Vagal and Hypothalamic Neurons to
Stimulate Food Intake
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Ghrelin Acts on Vagal and Hypothalamic Neurons to
Stimulate Food Intake
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The Big Picture
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Leptin Tonically Regulates a Multitude of Circuits Involved in Acute Intake and
Expenditure
Behavioral
Endocrine
Autonomic
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Regulation of CCK Response by Leptin
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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
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Leptin Regulates the Responsiveness of
Vagal Afferent Nerves to CCK
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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
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Activation of c-Fos by CCK by in POMC NTS Neurons
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MC4-R Blockade Inhibits CCK Action
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Feeding-activated c-Fos in POMC NTS Neurons
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A Majority of NTS POMC Neurons are Leptin-Responsive