CNS control of food intake and body weight

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CNS control of food intake and body weight

• Randy J. Seeley
• Department of Psychiatry
• Genome Research Institute
• University of Cincinnati

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Energy Balance Equation
Intake
Expenditure
Metabolic Rate Thermogenesis Activity
Hunger Satiety Nutrient Absorption
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Accuracy!
Energy Intake in a Year 912500 calories
Error of 0.4 Or 11 calories/day
Gaining 1 pound (0.45 kg) in a year 4050 calories
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MW Schwartz, et al., Nature, 2000
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Meal Size Regulation
FOOD INTAKE
SENSOR
GUT
METABOLIC EFFECTS
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Meal Size Regulation
FOOD INTAKE
SENSOR
(-)
GUT
METABOLIC EFFECTS
()
GASTROINTESTINAL PEPTIDES SATIETY FACTORS
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CCK DECREASES MEAL SIZE
PERCENT OF CONTROL
MEAL SIZE
100
50
CONTROL CCK
West et al., AJP 246R776 1984
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CCK INCREASES THE NUMBER OF MEALS
PERCENT OF CONTROL
MEAL SIZE
100
50
CONTROL CCK
West et al., AJP 246R776 1984
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CCK, GIVEN ALONE, HAS NO NET EFFECT ON FOOD
INTAKE OR BODY WEIGHT IN FREELY FEEDING RATS
PERCENT OF CONTROL
MEAL SIZE
DAILY INTAKE
100
100
50
50
CONTROL CCK
CONTROL CCK
West et al., AJP 246R776 1984
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MW Schwartz, et al., Nature, 2000
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Humoral Regulation
CNS Regulatory Mechanisms
Caloric Intake
Humoral Signal
Energy Balance Stored Calories
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Humoral Regulation
CNS Regulatory Mechanisms
Caloric Intake
Leptin
Energy Balance Stored Calories
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Serum Leptin is Increased in Obesity
100
80
60
Serum Leptin (ng/mL)
40
20
0
10
20
30
40
50
60
70
Body Fat ()
Considine RV, N Engl J Med 1996334292-5
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Humoral Regulation
CNS Regulatory Mechanisms
Caloric Intake
Leptin
Energy Balance Stored Calories
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Alphabet Soup

• Leptin
• Insulin
• Amylin
• NPY
• CRH
• UCN
• UCN II
• Galanin
• Neurotensin
• CART
• Oxytocin
• ?-MSH

• Corticosterone
• Serotonin
• Dopamine
• MCH
• Orexins
• Histamine
• Ghrelin
• GLP-1
• GLP-2
• AgRP
• Beacon
• Cannabinoids

• TNFa
• Beta-Endorphin
• Dynorphin
• BDNF
• PYY
• IL-6
• IL-1
• IL-1RA
• Norepinephrine
• Amino Acids
• PRL-RL
• GAL-LP

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Humoral Regulation
CNS Regulatory Mechanisms
Caloric Intake
Leptin
Energy Balance Stored Calories
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Melanocortin System

• Ligands
• ACTH
• ?-MSH

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Melanocortin System

• Ligands
• ACTH
• ?-MSH

• Receptors
• MC1 (skin and hair)
• MC2 (adrenal)
• MC3 (hypothalamus)
• MC4 (CNS)

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Melanocortin System

• Ligands
• ACTH
• ?-MSH
• AgRP

• Receptors
• MC1 (skin and hair)
• MC2 (adrenal)
• MC3 (hypothalamus)
• MC4 (CNS)

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MELANOCORTIN REGULATION OF FEEDING BEHAVIOR
AGONIST
AgRP
?-MSH
MC4-R
REDUCED FEEDING AND BODY WEIGHT
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MELANOCORTIN REGULATION OF FEEDING BEHAVIOR
ANTAGONIST
AGONIST
AgRP
AgRP
?-MSH
MC4-R
MC4-R
INCREASED FEEDING AND BODY WEIGHT
REDUCED FEEDING AND BODY WEIGHT
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POMC Mutation
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Negative Energy Balance
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Adiposity Signals and Melanocortins
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Leptin and Neuropeptides
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A Simple Model
Energy Balance
Negative
Low Leptin

-
AgRP
POMC
Increased Food Intake and Weight Gain
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Positive Energy Balance
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A Simple Model
Energy Balance
Negative
Positive
Low Leptin
High Leptin


-
-
POMC
AgRP
POMC
AgRP
Increased Food Intake and Weight Gain
Decreased Food Intake and Weight Loss
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Model
Arcuate
PVN
Increased Weight
AgRP
Y1 or Y5 Receptor
Decreased Weight
POMC
MC4 Receptor
WHITE FAT
Leptin
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Model
Arcuate
PVN
Increased Weight
AgRP
Y1 or Y5 Receptor
POMC
MC4 Receptor
WHITE FAT
Leptin
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Model
Arcuate
PVN
Increased Weight
AgRP
Y1 or Y5 Receptor
POMC
MC4 Receptor
WHITE FAT
Leptin
Leptin
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Model
Arcuate
PVN
Increased Weight
AgRP
Y1 or Y5 Receptor
Decreased Weight
POMC
MC4 Receptor
WHITE FAT
Leptin
Leptin
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Negative Energy Balance
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MW Schwartz, et al., Nature, 2000
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Ghrelin
MW Schwartz, et al., Nature, 2000
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Ghrelin is secreted by enteroendocrine (a-) cells
in the stomach into circulation
Kojima M et al. Nature. 1999402656-60.
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Ghrelin
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ghrelin correlates negatively with body fat mass
and adipocyte size
r -0.45, p 0.018
Ravussin E, Tschöp M et al. J Clin Endocrinol
Metab. 2001 864547-51.
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Ghrelin
n 20, p0.0001
4
3
ghrelin
cumulative weight gain g
2
1
control
0
0
2
4
6
8
10
12
14
ghrelin
control
treatment day
Tschöp et al. Nature. 2000407908-13.
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Ghrelin AGRP decrease spontaneous physical
activity (SPA)
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Ghrelin-couch potato hormone?
Appetite Physical Activity
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Ghrelin
MW Schwartz, et al., Nature, 2000
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Treatments for Obesity

• Behavioral Therapy
• Bariatric Surgery

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Roux-en-Y Gastric Bypass
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Potential causes of weight loss in bariatric
surgery

• Gastric restriction
• Malabsorption
• Changes in satiety signals

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Roux-en-Y Gastric Bypass
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Cummings, et al. NEJM 3461623
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Treatments for Obesity

• Behavioral Therapy
• Bariatric Surgery
• Pharmacotherapy

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Pharmacotherapy for Obesity

• Lipase inhibitors--Orlistat
• Reduce fat absorption from the GI tract
• Modest reductions in body weight
• Use limited by side effects

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Pharmacotherapy for Obesity

• CNS Appetite Suppressant -- Meridia
• Reuptake inhibitor for norepinephrine and
  serotonin
• Modest effects on body weight
• Use is complicated by increases in blood pressure
  in some patients

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Future Pharmacotherapy

• Cannabinoid receptor antagonists

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Alphabet Soup

• Leptin
• Insulin
• Amylin
• NPY
• CRH
• UCN
• UCN II
• Galanin
• Neurotensin
• CART
• Oxytocin
• ?-MSH

• Corticosterone
• Serotonin
• Dopamine
• MCH
• Orexins
• Histamine
• Ghrelin
• GLP-1
• GLP-2
• AgRP
• Beacon
• Cannabinoids

• TNFa
• Beta-Endorphin
• Dynorphin
• BDNF
• PYY
• IL-6
• IL-1
• IL-1RA
• Norepinephrine
• Amino Acids
• PRL-RL
• GAL-LP