MPB 333 The Molecular Endocrinology of Obesity and Diabetes Satiety and Hunger.

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