Feeding Behavior/Obesity

Stefany Primeaux, PhD

Dept of Internal Medicine-EndocrinologyOffice: MEB, 7159D

Phone:568-2733Email: sprime@lsuhsc.edu

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. BackgroundI. Energy Balance EquationII. Obesity ratesIII. Health Consequences

II. Peripheral MechanismsI. Adiposity FactorsII. Gut Hormones

III. Central MechanismsI. Hypothalamic Circuitry

• ENERGY IN (calories consumed) = ENERGY OUT (calories burned) = weight same • Energy IN > Energy OUT= weight gain

• Energy IN < Energy OUT = weight loss

Energy Balance Equation

Energy Intake

Food/calories Consumed

Energy expenditure

Physical Activity Resting

Metabolic Rate

Energy IN Energy OUT

Estimated Daily Calorie Requirements

• 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

Sedentary Moderately Active

Active

Female

19-30 years old 2000 kcal 2000-2200 kcal 2400 kcal

Male19-30 years old 2400 kcal 2600-2800 kcal 3000 kcal

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.

Louisiana: 1990 (10-14%) 1999 (20-24%) 2009 ( > 30%)

Overweight = Body Mass Index (BMI) >25

Obesity = BMI >30 = 5’5” and 180lbs

Health Consequences of Obesity• 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

• 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 post-

absorptive state?We eat for energy!

Gastrointestinal Tract

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 Post-absorptive Period

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

How is feeding behavior regulated?

- 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?

We might ask ourselves….

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.

Stanley S et al. Physiol Rev 2005;85:1131-1158

Figure 1

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?

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• The more fat the more

circulating leptin!

KO Mice do not express the leptin gene

Wildtype ob/ob

Ob/ob mice are hyperphagic and obese

Leptin Food Intake

White et al., 2009

Leptin Resistance

• The majority of obese animals and humans have raised plasma leptin.

• Administration of leptin in rats with high fat diet-induced obesity does not reduce food intake

• Circulating levels of leptin are higher in rats eating high fat diet

White et al., 2009

Low fat diet High fat diet

Leptin resistance occurs when there is no response to leptin

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

Ghrelin• Endogenous agonist of the

growth hormone receptor

• Produced and released primarily by the stomach

• Orexigenic hormone

• Regulated by diurnal rhythms and food intake

Peripheral Signals: Gut Hormones

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

Druce et al., 2005

Humans

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

Stanley et al. 2005

Fig. 4

Brain

Periphery—Hormones in circulation

NeuronalVagus Nerve

J Endocrinol. 2005 Feb;184(2):291-318

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)

Hypothalamic Lesion StudiesVentromedial Nucleus of the Hypothalamus

Rat continues to eat as long as it is provided with palatable food

Lateral Hypothalamus Lesions

Rat decreased food intake, also have sensory and motor deficits

Arcuate Nucleus of the Hypothalamus

• 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)

Stanley S et al. 2005

PYYInsulinLeptin

Ghrelin

Central Signals: Neuropeptide Y• One of the most abundant and

widely distributed neuropeptides in the CNS

• ARC is the major site of NPY expression

• 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

Ventromedial /Arcuate Nucleus

Fed Fast Refed0

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Neu

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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

Larsen et al., 1999Rhesus monkeys

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

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.

Daily energy intake in male mice receiving normal or high fat chow

Notice Yellow Coat

-/- POMC KO mouse

1. Peripheral Regulation of feeding behavior1. Adiposity Signals: Leptin2. Gut Hormones: Ghrelin

2. Central Regulation of feeding behavior1. How peripheral signals

affect the brain2. Hypothalamus3. Major Neuropeptides

involved in feeding1. NPY2. POMC

We have discussed:

What other factors influence Feeding Behavior?

Morrison & Berthoud, 2007

Modulatory Factors

Genetic & Epigenetic

Visual, olfactory, auditory

Taste

Non-homeostatic consumption

Outline

I. BackgroundI. Energy Balance EquationII. Obesity ratesIII. Health Consequences

II. Peripheral MechanismsI. Adiposity FactorsII. Gut Hormones

III. Central MechanismsI. Hypothalamic Circuitry