Body Mass Index
BMI = [weight in pounds/height in inches2] x 703
BMI = [weight in kilograms/height in meters 2]
BMI
Below 18.5
18.5 – 24.9
25.0 – 29.9
30 & above
Weight Status
Underweight
Normal weight
Overweight
Obese
Obesity
• excessive energy intake (food)
• insufficient energy output (exercise, low resting metabolic rate)
• genetic predisposition
• low fat oxidation rate, low sympathetic activity
• low plasma leptin level
• environment favoring weight gain, psychologic stressors, lower socioeconomic status
Energy Balance - input needs to
equal output to maintain idea
weight
• An extra 100 calories per
day = 7.2 lb weight gain in
Control of Body Weight
A. Is determined by the interplay of several factors, including inheritanceone
andyear
environment
B. A physiologic system exists that maintains homeostatis of energy stores in reponse to feeding and energy
expenditure.
C. The afferent limb of this system includes several kinds of signals.
• Short term signals regulate onset and termination of individual meals. They originate in the GI tract
and include cholecystokinin (CCK), peptide YY (PYY) and ghrelin (Ghr).
• Long term signals monitor body energy stores. A major signal is leptin, which is produced by fat
cells.
D. These signals converge in the CNS where they are integrated and the magnitude and direction of the
efferent responses determined. These include the intensity of hunger and subsequent food seeking
behavior, the level of energy expenditure and the levels of key hormones such as insulin and glucagon.
E. The hypothalamus plays a significant role in this integrative function. The arcuate nucleus (ARC or ARN)
contains two sets of neurons with opposing action.
• Stimulation of orexigenic neurons increases food intake and reduces metabolism. These neurons
release the peptide neurotransmitters neuropeptide Y (NPY) and agouti-related protein (AgRP)
• Stimulation of anorexigenic neurons inhibits food intake and stimulates metabolism. These
neurons expression pro-opiomelanocortin (POMC), which releases the neurotransmitter  MSH,
and the cocaine-amphetamine regulated transcript (CART).
The goal of obesity treatment is to exert a negative energy
balance on the system by reducing energy input or increasing
energy output, or both to reach ideal weight.
Satiety is regulated by the balance of stimulation vs.
inhibition of neurons in arcuate nucleus of the
hypothalamus.
•
•
•
Neurons that label with and release AgRP and NPY
are orexigenic promoting food intake and slowing
metabolism.
Neurons that label with POMC and release the
neurotransmitters  MSH and CART are
anorexigenic promoting reduced food intake and
increasing metabolism.
These signals are interpreted by the “Satiety Center”
of the nuclear tractus solitarus.
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Becky Stepan
Rose-Hellekant – Appetite Control
Hypothalamic Orexigenic Mediators are neurons that produce NPY and AgRP
Neuropeptide Y (NPY) - Orexigenic
• It is a 36 AA neuropeptide, which is one of the most
potent orexigenic agents known.
• Levels of NPY in the PVN increase before mealtime
and stimulate food intake by activating Y1 and Y5 receptors.
• NPY release is inhibited by leptin and stimulated
by ghrelin.
• The anorexigenic effect of PYY is partially due to its
interaction with the Y2 receptor, a presynaptic inhibitory
receptor, on NPY neurons.
Agouti-related peptide (AgRP) - Orexigenic
• It is coexpressed in NPY/AgRP neurons in ARC and
inhibits the action of the anorexigenic agonist
a-melanocyte-stimulating hormone (a-MSH), which
is the neurotransmitter released from POMC/CART neurons.
• Antagonizes action of -MSH a neuropeptide
of POMC/CART
Anorexigenic hypothalamic mediators are the POMC/CART neurons
• /b-Melanocyte-Stimulating Hormone (/bMSH)
• It is the product of POMC cleavage
• It is an agonist for MC4 receptor
• Melanocortin-4 Receptor Mutations
• Account for up to 5% of cases of severe
childhood obesity and 0.5-2.5 of adult obesity
• Mutational frequency of 1/1000 estimated
• Hyperphagia, increase in fat and lean mass
• Its release is stimulated by leptin
• Its release is inhibited by ghrelin
• Feeding behavior is reduced
•
Cocaine and amphetamine
regulated transcript
(CART) - anorexigenic
− It is a 47 AA neuropeptide
that is coexpressed with
POMC,
− May explain the
anorexigenic effect of
cocaine and
amphetamine.
− CART deficiency does not
affect energy balance
Short-term regulation
of appetite
\
INCREASE and DECREASE
Stomach
Ghrelin
CCK: cholescystokinin
Intestine
GLP-1: glucagon like peptide-1
PYY: peptide YY
Endocrine organs
T4, Cortisol
Insulin
GI hormones provide short term signals
regulate onset and termination of each meal
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Becky Stepan
Rose-Hellekant – Appetite Control
GI Tract Mediators
• CCK - anorexigenic
• Secreted in duodenum in response to f.a.
• Stimulates vagus
• Causes contraction of the gallbladder,
• relaxation of the sphincter Oddi
• inhibition of gastric emptying
• PYY - anorexigenic
• Released after a meal from intestinal cells
in small intestine and colon
• Endogenous PYY influences motility
• When injected, inhibits NPY/AgRP neurons
• Ghrelin - orexigenic (The ONLY mediator which
stimulates appetite)
• 28 AA from the stomach
• Increases before spontaneous feeding
• Stimulates NPY/AgRP neurons
• Decreases after gastric bypass but is low in most obese individuals
Long-term control of appetite monitors energy stores: Leptin is the Anorexigenic Mediator from Adipose
• 146 AA secreted from adipocytes and positively correlated w/adiposity
• Circadian rhythm of secretion
• Secretion not affected directly by meals
• Levels in brain act as an indicator of energy stores
• Receptors in hypothalamus, midbrain, brain stem
• Inhibits NPY/AgRP (inhibits orexigenic pathway)
• stimulates POMC/CART (promotes anorexigenic pathways)
• Increases energy expenditure
• Monogenic mutations that lead to hyperphagia and obesity are present in the leptin-hypothalamic
system
Proband: Individual that forms a starting point for genetic study of family or pedigree
Congenital Leptin Deficiency Due to Homozygosity for the {Delta}133G Mutation….
Hypothesized hormones which regulate eating….
Inhibitory
CCK
Leptin
Glucagon
Glucagon-like peptide 1
Glucagon-like peptide 2
Peptide YY
Insulin
Amylin
Apoliprotein AIV
Gastrin Releasing Peptide
Neuromedin B
Somatostatin
Neurotensin
Enterostatin
Estradiol
Ghrelin
Excitatory
Ghrelin
Testosterone
Leptin
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Becky Stepan
Rose-Hellekant – Appetite Control
Pharmacotherapy
• Peripheral regulation of food intake/GI uptake: Orlistat
• Central regulation of appetite: Sibutramine
• Long term use is more effective
• Once drug is withdraw weight gain usually occurs
• Better outcome when coupled with diet, exercise, behavior modification
Orlistat (Xenical)
• Pancreatic lipase inhibitor which prevents the absorption of dietary fats.
− long chain fatty acids, cholesterol and fat-soluble vitamins
− Lipophilic medications
− Available over the counter
• <1% absorbed from GI (so non GI lipases fully functional)
• Average weight loss of 2.5-3 kg compared to placebo over 2 yrs.
• Reduction of serum cholesterol (LDL)
• Initially GI disturbances that subsides
− ~20%: flatulence with discharge, fatty stool, fecal urgency or incontinence
− after high fatty diet intake which is associated with high incidence of drug discontinuance.
• Vitamin supplement recommended due to decreases in absorption of fat soluble vitamins.
Sibutramine (Meridia)
• Noradrenalin, serotonin and to a lesser extent, dopamine, reuptake inhibitor
• Originally used as an antidepressant
• Targets hypothalamus and enhances satiation (level of fullness during meal consumption)* and
thermogenesis
• Average weight loss of an average of 4kg and ~ 10 kg if together with lifestyle modification ( over 2 yrs).
• Metabolized by CYP3A4 to two active metabolites
• Should not use with patients with cardiovascular disease as side effects including:
 Increased BP and HR in some;
 Dry mouth
 Insomnia, Constipation
• Should not be taken with other serotonergic drugs (e.g. selective serotonin reuptake inhibitors, SSRIs)
Surgery for patients with BMI > 40 or >35+ one or more obestiy related co-morbidity
• Gastric bypass
• Mean loss of excess weight: 65-75%
• Resolution or improvement of diabetes: 90%, hyperlipidemia 95%, hypertension: 90%.
• Estimate reduction in overall mortality: 40%
• Gastric banding
• Nonadjustable and adjustable combined data:
• Mean loss of xs weight (combined banding procedures): 50-65%
• Resolution or improvement rates for diabetes: ~80%, hypertension ~70% and hyperlipidemia ~
60%
• Obesity and diabetes:
• Remission rate of diabetes 73% vs. 13% on medical treatment.
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Becky Stepan
Rose-Hellekant – Appetite Control