Transcript Feeding Behavior/Obesity

Feeding Behavior/Obesity
Stefany Primeaux, PhD
Dept of Internal Medicine-Endocrinology
Office: MEB, 7159D
Phone:568-2733
Email: [email protected]
Reading for this lecture
Physiol Rev 85: 1131-1158; 2005
Why are we interested in learning
about Feeding Behavior and Obesity?
• The overconsumption of diets high in
calories and fat are major contributors
to the current rate in obesity.
• Approximately 75 million adult
Americans are considered OBESE.
• In 2009, 33% of adults in Louisiana
were considered OBESE.
• Obesity is a major risk factor for
cardiovascular disease, certain types of
cancers and Type II Diabetes.
Medical costs approximately $147 billion/year
Outline
I. Background
I.
Energy Balance
Equation
II. Obesity rates
III. Health Consequences
II. Peripheral
Mechanisms
I. Adiposity Factors
II. Gut Hormones
III. Central Mechanisms
I.
Hypothalamic Circuitry
Energy Balance Equation
Energy IN
Energy OUT
Energy Intake
Food/calories
Consumed
Energy
expenditure
Physical Activity
Resting
Metabolic Rate
• ENERGY IN (calories consumed) = ENERGY OUT (calories burned) = weight same
• Energy IN > Energy OUT= weight gain
• Energy IN < Energy OUT = weight loss
Estimated Daily Calorie Requirements
Sedentary
Moderately
Active
Active
2000 kcal
2000-2200 kcal
2400 kcal
2400 kcal
2600-2800 kcal
3000 kcal
Female
19-30 years old
Male
19-30 years old
• Sedentary means a lifestyle that includes only the light physical activity
associated with typical day-to-day life.
• Moderately active means a lifestyle that includes physical activity
equivalent to walking about 1.5 to 3 miles per day at 3 to 4 miles per hour
• Active means a lifestyle that includes physical activity equivalent to
walking more than 3 miles per day at 3 to 4 miles per hour
HHS/USDA Dietary Guidelines for Americans, 2005
Obesity is a chronic metabolic disease resulting
from an imbalance between energy intake and
energy output
•Obesity is caused by the interaction of multiple genetic
and environmental factors.
•Among these are:
• Excessive calorie and food intake
• Insufficient physical activity
• Genetic predisposition
• Family history of obesity
• Individual metabolism
• Behavioral factors
The defining feature is excess body fat
Percentage of individuals that are considered
overweight or obese.
Overweight =
Body Mass
Index (BMI) >25
Obesity = BMI
>30
= 5’5” and
180lbs
Louisiana: 1990 (10-14%) 1999 (20-24%) 2009 ( > 30%)
Health Consequences of Obesity
•
•
•
•
•
•
•
•
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Coronary heart disease
Type 2 Diabetes
Cancer (endometrial, breast, colon)
Hypertension
Dyslipidemia
Stroke
Liver & gallbladder disease
Sleep apnea & respiratory problems
Gynecological problems
– (abnormal menses, infertility)
Regulation of Food Intake
• Due to the numerous health consequences of obesity, there
is an emphasis on determining causes of and potential
treatments for obesity.
In order to understand and provide treatments for
obesity and its comorbidities, we must
understand the mechanisms which regulate
feeding behavior.
Control of Food Intake
Brain
Many factors control appetite and influence food intake
Absorptive vs. Post-Absorptive State
Gastrointestinal Tract
• Absorptive State
– Ingested nutrients enter the
blood from the GI tract
– Break down of food provides
nutrients
– Some nutrients provide
energy (carbohydrates)
– Up to 4 hours after a meal
• Post-absorptive State
– GI tract is empty of food and
nutrients
– Body’s cells must supply
energy (liver, adipose tissue)
– When are we in the postabsorptive state?
We eat for energy!
Nutrient Metabolism During the
Absorptive Period
 Absorbed carbohydrate is primary energy source (converted to
glucose)
 Net uptake of glucose by the liver.
 Some carbohydrate stored as glycogen in liver and muscle
 Excess carbohydrate stored as fat in adipose tissue
 Fat is stored in adipose tissue.
 Some amino acids used to synthesize body protein.
 Excess amino acids converted to fat.
What is the primary source of energy during the absorptive period?
Excess carbohydrates, fat and amino acids are stored as????
Nutrient Metabolism During the Postabsorptive Period
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




Glycogen, fat, and protein synthesis slow, net breakdown occurs
Formation of glucose in the liver
Gluconeogenesis in kidneys with prolonged fast.
Utilization of glucose by muscle and other non-neural tissues is reduced
Fatty acids released (lipolysis).
Fatty acids and ketones provide most of the body’s energy supply.
Brain uses glucose and starts using ketones as they build up in the blood.
What is the primary source of energy during the post-absorptive period?
Major goal is to maintain blood glucose levels
We might ask ourselves….
- Why do we feel hungry?
- How do we know when to start eating?
-How do we know when to stop eating?
- Does being overweight/obese alter our eating
behavior?
How is feeding behavior regulated?
Central and Peripheral mechanisms regulating feeding behavior
Peripheral Mechanisms regulating
Feeding Behavior
• Energy balance is regulated
by central and peripheral
signals
• The central nervous system
responds to signals from the
periphery…adipose tissue,
pancreas, liver and
gastrointestinal tract
What do these peripheral signals
communicate?
Energy homeostasis is controlled by peripheral signals.
Peripheral signals have a
positive (+) or negative (-)
effect on energy balance
What does a negative effect mean? How do these
signals affect feeding behavior? Positive effect?
Figure 1
Stanley S et al. Physiol Rev 2005;85:1131-1158
Peripheral Signals-Adiposity signals
Leptin
• One of the most important
hormones is leptin.
• Leptin is expressed
predominately in adipocytes
• Leptin levels are highly
correlated with adipose
tissue mass
• Food restriction decreases
circulating leptin
Considine, 2002
Leptin signals energy stores
Leptin
KO Mice do not express the leptin gene
• The more fat the more
circulating leptin!
Leptin
Food Intake
Wildtype
ob/ob
Ob/ob mice are hyperphagic and obese
White et al., 2009
Leptin Resistance
• The majority of obese
animals and humans have
raised plasma leptin.
Leptin resistance occurs when there is
no response to leptin
• Administration of leptin in
rats with high fat dietinduced obesity does not
reduce food intake
• Circulating levels of leptin are
higher in rats eating high fat
diet
Low fat diet
High fat diet
White et al., 2009
Leptin Deficiency in Humans
• Congenital leptin
deficiency
–
–
–
–
Hyperphagia
Severe obesity
Hypogonadism
Impaired immunity
Leptin treatment
reduced food
intake up to 80%
Farooqi & O’Rahilly, 2009
Peripheral Signals: Gut Hormones
Ghrelin
• Endogenous agonist of the
growth hormone receptor
• Produced and released
primarily by the stomach
• Orexigenic hormone
• Regulated by diurnal
rhythms and food intake
The only orexigenic gut hormone!
What does this mean???
Ghrelin
• Plasma ghrelin levels are highest
during fasting and fall after a
meal
• Postprandial reduction in ghrelin
is regulated by caloric intake and
circulating nutritional signals
(glucose)
• Circulating ghrelin is inversely
related to adiposity.
Obese < ghrelin
• Ghrelin administration increases
food intake in rodents and
humans
Humans
Druce et al., 2005
Energy homeostasis is controlled by peripheral signals.
Peripheral signals have a
positive (+) or negative (-)
effect on energy balance
How do these peripheral signals influence the brain???
Central Control of Feeding Behavior
• Brain plays a critical role in the regulation of energy
homeostasis
• CNS circuits instantly assess and integrate peripheral
metabolic, endocrine and neuronal signals
• CNS coordinates a response that modulates both
behavioral patterns and peripheral metabolism according
to acute and chronic requirements
• Two main types of afferent inputs to the brain from the
peripheral organs that are relevant for energy
homeostasis: Hormones & Neurons
Communication between the
peripheral signals and the brain
Brain
Neuronal
Vagus
Nerve
Fig. 4
Periphery—Hormones in circulation
Stanley et al. 2005
The central control of appetite and
feeding behavior
• Hypothalamus is
considered the main
integrator and processor
of peripheral metabolic
information
• Brain stem plays an
important role in these
processes
• Other brain regions that
influence feeding
Interconnected regions
Lesions of specific regions of the
hypothalamus induce starvation (LH) or
obesity (VMH)
J Endocrinol. 2005 Feb;184(2):291-318
Hypothalamic Lesion Studies
Lateral Hypothalamus Lesions
Rat decreased food intake, also
have sensory and motor deficits
Ventromedial Nucleus of the Hypothalamus
Rat continues to eat as long as it is
provided with palatable food
Arcuate Nucleus of the Hypothalamus
PYY
Insulin
Leptin
Ghrelin
Stanley S et al. 2005
• Arcuate Nucleus plays pivotal role in integration of signals
regulating appetite
• Contains receptors for peripheral hormones
• Contains two key peptidergic systems: Neuropeptide Y and
POMC (α-MSH)
Central Signals: Neuropeptide Y
• One of the most abundant
and widely distributed
neuropeptides in the CNS
• NPY mRNA and release
increase with fasting and
decrease with feeding
• Binds to g-protein coupled
receptors Y1—Y6, which are
located throughout the
brain
1.5
Neuropeptide Y/cyclophilin
mRNA (A.U.)
• ARC is the major site of NPY
expression
Ventromedial /Arcuate Nucleus
*
1
0.5
0
Fed
Fast
Refed
Primeaux, unpublished
Neuropeptide Y
• Most potent orexigen
known!!
• Administration of NPY
increases food intake,
inhibits thermogenesis,
suppresses sympathetic
nerve activity, reduces
energy expenditure
• Also involved in alcohol
intake, anxiety, seizure
activity
Rhesus monkeys
Larsen et al., 1999
Central Signals: Melanocortin System
• Comprised of the peptide
products of POMC cleavage,
their receptors
– α-MSH is one of the most potent
anorexigenic brain signals.
– AgRP is an endogenous ligand of
melanocortin receptors, acts as an
inverse agonist
• MC3R and MC4R play a role in
energy balance
• POMC gene mutations or
abnormal POMC peptide
processing result in early-onset
obesity and red hair
• Approximately 4% of cases of
genetic obesity in humans
Arcuate N.
Melanocortin System
Notice
Yellow
Coat
Daily energy intake in male mice
receiving normal or high fat chow
-/- POMC KO mouse
This 5-yr-old boy is heterozygous for a mutation in MC4R.
In addition to early-onset obesity and hyperphagia, this
child has increased lean mass, accelerated linear growth,
and severe hyperinsulinemia.
We have discussed:
1. Peripheral Regulation of
feeding behavior
1. Adiposity Signals: Leptin
2. Gut Hormones: Ghrelin
2. Central Regulation of feeding
behavior
1. How peripheral signals
affect the brain
2. Hypothalamus
3. Major Neuropeptides
involved in feeding
1. NPY
2. POMC
What other factors influence Feeding
Behavior?
Visual, olfactory, auditory
Modulatory Factors
Genetic &
Epigenetic
Taste
Non-homeostatic consumption
Morrison & Berthoud, 2007
Outline
I. Background
I.
Energy Balance
Equation
II. Obesity rates
III. Health Consequences
II. Peripheral
Mechanisms
I. Adiposity Factors
II. Gut Hormones
III. Central Mechanisms
I.
Hypothalamic Circuitry