Transcript Regulation of Food Intake and Body Weight

• Caloric Homeostasis:
Control of Energy
Homeostasis and Food
Intake
• Diabetic hyperphagia
The amount of food eaten varies
considerably
 from meal to meal and
 from day to day.
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Food availability
Time of day
Cost
Emotions
Social factors
Etc.
Energy expenditure may also vary from
day to day.
Over short time periods, energy intake may
not be correlated with Energy Expenditure.
 Despite short-term mismatches in
energy intake and expenditure,
body weight and stores of energy
are remarkably stable.
 Thus, over the long-term, the
cumulative energy intake must be
matched to energy expenditure.
Caloric Balance
Caloric Expenditure = Caloric Intake + Stored Calories
Caloric Homeostasis (stored calories
remain unchanged)
D Stored Calories = Caloric Intake + Caloric Expenditure = 0
Caloric Intake = Caloric Expenditure
Lipostatic Model of Feeding Behavior
Stored Calories = Caloric Intake + Caloric Expenditure
In order to ensure a continuous supply of metabolic fuels to cells
• food intake provides nutrients, and
• the amount of stored calories influences the size and/or
frequency meal intake indirectly.
• Recently ingested calories will be utilized during and
immediately after meals.
• At other times calories will be drawn from stored calories.
Energy, stored in the form of adipose tissue, leads to
the generation of inhibitory signals that decrease food
intake, primarily by decreasing meal size.
Stored Calories = Caloric Intake + Caloric Expenditure
Homeostatic mechanisms provide a continuous
supply of metabolic fuels to support cellular
metabolism.
• Increases in cellular activities increases the
demand for energy.
• Most cells have limited stored energy.
• Carbohydrates, lipids, and proteins provide usable
energy, but their use is varies with the tissue.
Most tissues can oxidize glucose and free fatty
acids, depending on their availability and the
levels of various hormones in the blood.
Exceptions:
Liver – requires lipids for proper functioning
Brain – large, continuous need for glucose,
despite the ability to oxidize lipids to
form ketone bodies.
Critical Goal for Homeostasis at the
Cellular Level:
• Maintenance of adequate fuel
supplies to all cells.
• Maintenance of blood [glucose] in
sufficient amounts to support
normal brain function.
• If the supply of glucose to the brain
is compromised, then neurons cease
to function, and consciousness is
quickly lost; death may ensue.
Two distinct metabolic states are defined
by the immediate source of calories used
in maintaining homeostasis at the cellular
level:
1. The Prandial State
2. The Postabsorptive State
1. The Prandial State
• Newly ingested and absorbed nutrients are available
in the blood.
• Ingested and absorbed food
• Generate “satiety” signals that limit meal size, and
• Inhibit “hunger” signals
• Nutrients are rapidly stored or sequestered to prevent
loss in the urine.
 Carbohydrates are stored as glycogen in liver and skeletal
muscle.
 Triglycerides are stored in adipose tissue
 Excess carbohydrate is largely converted to triglycerides
2. The Postabsorptive State
• Absence of calories entering the circulation from the
gastrointestinal tract.
• Absence of meal-generated “satiety” signals
• Generation of “hunger” signals
• Reliance on stored energy less recently consumed.
• Stored energy is released gradually into the blood.
 Glycogen in liver and skeletal muscle is converted back to
glucose.
 Triglycerides are mobilized from adipose tissue and free fatty
acids and glycerol enter the circulation.
 Fatty acids used by tissues or converted to ketone bodies
 Glycerol converted to glucose
 Muscle proteolysis
 Increased hepatic gluconeogenesis
In both the Prandial and the Postabsorptive
States:
• Tissues and cells take nutrients from the blood as
needed.
• The liver is the key organ in the trafficking of energy
• In the prandial state
• Lipogenesis (also in adipose cells)
• Glycogen formation
• In the postabsorptive state
• Glycogenolysis
• Ketogenesis
• Gluconeogenesis
An interplay among several hormones
and the autonomic nervous system
allows for the control of:
• Delivery of metabolic fuels from the
gastrointestinal tract.
• Storage of excess fuels
• Mobilization of stored energy
Insulin is the key hormone affecting the
maintenance of blood [glucose].
Pancreatic b-cell secretion of insulin is
influenced by the following:
Blood [glucose]
• Insulin secretion increases in direct proportion to blood
[glucose]
Autonomic Nervous System
• Cholinergic parasympathetic activity stimulates insulin
secretion.
• a-Adrenergic sympathetic activity inhibits insulin secretion.
Gastrointestinal Hormones
• Augment the pancreatic b-cell response to elevated blood
[glucose]
• Cholecystokinin (CCK)
• Incretins
• GLP-1 (glucagon-like peptide-1)
• GIP (gastric inhibitory peptide; aka, glucose-dependent
insulinotropic polypeptide).
In response to
meal-related
events, prandial
insulin secretion
is rapid and
appropriate for the
caloric load such
that, ingested
fuels are
efficiently used
and stored.
Insulin Secretion:
Cephalic phase
• Anticipation, aroma, taste, etc. initiate a long-loop neural reflex
via vagal cholinergic innervation of the pancreas.
• Insulin secreted during this phase helps reverse the
mobilization of fuels occurring during the post-absorptive state
in preparation for fuels from the gastrointestinal tract.
Gastrointestinal phase
• Food in the stomach and duodenum stimulates the release of
CCK, GLP-1, and GIP that stimulate insulin secretion.
• Insulin secreted during this phase ensures that the level of
insulin is high when nutrients are appearing in the blood from
the gastrointestinal tract.
Substrate phase
• Elevated blood glucose (aa’s, ketone bodies) further stimulates
insulin secretion
Circulating
insulin is the
most important
factor that
promotes energy
storage.
• Insulin enables
tissues to take
up glucose for
immediate
oxidation or for
storage during
the prandial
period.
During the
postabsorptive period,
insulin secretion is
reduced, but not
inhibited.
• In the absence of
insulin, stored
energy is
mobilized.
Insulin secretion is also influenced by body
adiposity
• Obese individuals have fewer active insulin
receptors on adipose tissue and skeletal muscle.
• Consequently, secretion of insulin is greater in
obese individuals than in lean individuals.
• This reciprocal relationship between insulin secretion
and insulin sensitivity of tissues ensures efficient storage
and use of fuels independent of body weight.
In healthy individuals, plasma insulin levels in
both the prandial and postabsorptive periods
are reliable correlates of adiposity.
Interactions
between
“Meal-Generated Satiety Signals,”
“Hunger Signals,”
and
Body Adiposity
in the
Control of Food Intake
and
Caloric Homeostasis
In the prandial state, the contents of individual
meals elicit satiety signals that limit meal size and
inhibit hunger signals.
• Gastric volume and distention provides a satiety
signal
• CNS receptors in vagal afferents
• Post-gastric effects of meals provide additional
satiety signals
• CCK
• Stimulate CNS receptors in vagal afferents
• Enteroglucagons (GLP-1 and OXM)
• Act in a manner analogous to CCK
• Hepatic vagal afferent sensory fibers
• Receptors for absorbed amino acids and glucose
• Post-gastric effects of meals also inhibit the hunger
signal
• Ghrelin secretion by the stomach is inhibited
Gastric volume and distention
• CNS stretch receptors in the stomach wall respond to distention
in proportion to volume.
• Vagal sensory afferents carry this sensory information to the
medulla.
• Meals usually end long before significant digestion and
absorption has occurred.
• Distention interacts with other satiety signals
In the prandial state, post-gastric effects of meals
provide additional satiety signals
• CCK
• Slows the rate of gastric emptying, prolonging gastric
distention
• Interacts with receptors on vagal sensory afferent nerve
endings
• Acts synergistically with gastric distention to convey
sensory information to the medulla
• Enteroglucagons (GLP-1 and oxyntomodulin or OXM)
• Act in a manner analogous to CCK
• Hepatic vagal afferent sensory fibers
• Absorbed nutrients (glucose, aa’s) in hepatic portal blood
stimulate vagal afferent nerve endings.
• Acts synergistically with gastric distention
In the post-absorptive state, “hunger” signals are
generated.
• Ghrelin
• Circulating levels increase with the duration of postabsorptive or fasting period
• Contributes to preprandial hunger
• Participates in meal initiation
• Ghrelin levels are suppressed within minutes of feeding.
• Suppression is dose-dependently related to the number
of ingested calories.
• The magnitude of the subsequent preprandial
recovery of ghrelin levels correlates with the number
of calories consumed in the following meal.
Body adiposity also influences food intake.
Long-term maintenance of body weight (adiposity)
• Periods of food deprivation are followed by periods of
increased food intake
• Periods of forced feeding are followed by periods of lower food
intake.
Adiposity indirectly influences food intake
• Modulation of the efficacy of gastric and postgastric satiety
signals
• Loss of body fat reduces the efficacy of meal-generated
“satiety” signals and increases the efficacy of “hunger”
signals.
• Larger meals consumed until body fat is restored.
• Gain of body fat increases the efficacy of meal-generated
satiety signals and reduces the efficacy of “hunger” signals
• Fewer meals are taken and meals end earlier, so less
calories are consumed until body fat is restored.
Hormones secreted in proportion
to body adiposity
Insulin
Leptin
Ghrelin
Leptin
 167-aa protein released from adipocytes
 Plasma [leptin] covaries with the degree of adiposity
 Plasma [leptin] falls with fasting and utilization and loss of
fat stores.
 Synthesis and secretion is stimulated by insulin
 Transported into the CNS by a saturable, receptor-mediated
process
 Chronic administration of leptin (i.c.v.) produces a decrease
in food intake and body weight
 Weight loss is due to loss of fat
 Decreased food intake
 Increased sympathetic nervous system activity
increases metabolic rate.
 Delay of several hours
• In the brain, leptin binds to specific leptin receptors
(Ob-R).
• Ob-R are expressed in discrete neuronal populations.
• Hypothalamic arcuate nucleus (ARC)
• Leptin acts to inhibit feeding and increase energy
expenditure
• Leptin increases the efficacy of meal-generated sensory
signals and satiety peptides to limit meal size.
Insulin
 Plasma [insulin] covaries with the degree of adiposity.
 Enters the CNS by a receptor-mediated, saturable transport
process across brain capillaries
CSF [insulin] reflects food intake and adiposity
 Fat experimental animals have higher CSF [insulin]
than lean animals.
 Fed experimental animals have higher CSF [insulin]
than fasted animal of equal adiposity.
 Chronic infusion of insulin (i.c.v.) produces a decrease
in food intake and body weight similar to leptin.
 Weight loss is due to loss of fat
 Decreased food intake
 Increased sympathetic nervous system activity
increases metabolic rate
 Insulin stimulates synthesis and secretion of leptin by
adipocytes and inhibits ghrelin.
• In the brain, insulin binds to specific insulin receptors.
• Insulin receptors are expressed within discrete
neuronal populations.
• Hypothalamic arcuate nucleus (ARC)
• Insulin acts to inhibit feeding and increase energy
expenditure
• Insulin increases the efficacy of meal-generated sensory
signals and satiety peptides to limit meal size.
Ghrelin
 188-aa peptide released from ghrelin cells (formerly called “X/Alike cells”) of the stomach
 Plasma [ghrelin] varies inversely with the degree of adiposity
 Plasma [ghrelin] increases with fasting and utilization and loss
of fat stores.
 Synthesis and secretion is inhibitedted by insulin
 Transported into the CNS by a saturable, receptor-mediated
process; also synthesized within the CNS
 Chronic administration of ghrelin (i.c.v.) produces an increase in
food intake and body weight
 Weight loss is due to gain of fat
 Icreased food intake
 Decreased sympathetic nervous system activity increases
metabolic rate.
 Food intake (and insulin) causes a rapid fall in ghrelin secretion.
• In the brain, ghrelin binds to specific ghrelin receptors
(formerly called “growth hormone secretogogue
receptors” or GHSRs)).
• Ghrelin receptors are expressed in discrete neuronal
populations.
• Hypothalamic arcuate nucleus (ARC)
• Ghrelin acts to increase appetitive (i.e., motivation to seek
out food and initiate feeding) feeding behaviors.
• Decrease in the latency to feed, leading to additional
meals.
• Elevated ghrelin levels decrease the efficacy of mealgenerated sensory signals and satiety peptides to increase
meal size.
• Ghrelin also stimulates:
• Gastrointestinal motility and acid secretion
• Pancreatic enzyme secretion
Summary of single meal generated satiety
signals that limit meal size.
• Gastric distention
• Post-gastric detection of calories via signals that
arise from the presence of chyme and arrival of
glucose and amino acids at the liver:
• CCK-, GLP-1-, and OXM-induced stimulation of
vagal nerve endings in the gastrointestinal
tract.
• Glucose- and amino acid-induced stimulation of
vagal nerve ending in liver.
• Elevated insulin inhibits ghrelin secretion
• Satiety is prolonged by integration of signals
Summary of the influence of body weight
(degree of adiposity) on food intake.
• Centrally-mediated effects of leptin, insulin, and
ghrelin can alter the sensitivity of the CNS to the
meal generated satiety signals
• When leptin and insulin are elevated and
ghrelin is suppressed, then smaller meals are
eaten.
• When leptin and insulin are decreased and
ghrelin is elevated, then larger meals are
eaten.
CNS
Control
of
Food
Intake
The hypothalamic arcuate nucleus (ARC)
mediates the effect of adiposity on food
intake and body weight.
Leptin and insulin exert the following actions within the
ARC:
• Activation of neurons that synthesize and release
a-melanocyte-stimulating hormone (a-MSH)
• Inhibition of neurons that synthesize and release
neuropeptide Y (NPY) and agouti-related peptide (AgRP)
Ghrelin exerts the following action with the ARC:
• Stimulation of neurons that synthesize and release NPY and
AgRP
a-MSH
• Potent catabolic peptide
• Act on melanocortin (MC) receptors
• MC3 and MC4 receptors on neurons in hypothalamic
paraventricular nucleus (PVN)
• ARC-a-MSH neurons project from ARC to PVN
• Leptin- or insulin-induced activation of ARC-a-MSH
neurons causes
• Decreased food intake
• Increased energy expenditure by increasing
sympathetic nervous system activity.
• a-MSH exerts a tonic catabolic effect to keep body
weight from increasing
NPY and AgRP
• Potent anabolic peptides
• ARC-NPY-AgRP neurons project to the PVN
• NPY acts at the PVN to increase food intake
and decrease energy expenditure.
• AgRP antagonizes the effects of a-MSH at
MC3/MC4 receptors in the PVN.
• Disinhibition of PVN neurons involved in
increasing food intake and decreasing
energy expenditure.
• Increased food intake and decreased energy
expenditure
• ARC monitors body
adiposity (leptin,
insulin, and ghrelin).
• Two groups of
neurons project from
the ARC to other
hypothalamic nuclei
(especially the PVN)
to modulate aspects
of caloric
homeostasis.
• ARC-a-MSH
neurons have a
net catabolic
effect.
• ARC-NPY-AgRP
neurons have a
net anabolic
effect.
SUMMARY
• In the post-absorptive state, in the absence of nutrients in the
upper gastrointestinal tract, “hunger” signals are generated and
“satiety” signals are diminished.
• In the prandial state, meal-generated “satiety” signals arise from
acute stimuli that elicit neural signals from the stomach,
intestines, and liver to the medulla, while “hunger” signals are
suppressed
• Gastric distention
• Delivery of calories to the small intestine
• Delivery of calories to the liver
• Increased insulin secretion
• Adiposity indirectly affects the efficacy of gastric, intestinal, and
hepatic satiety signals
• Hormones secreted in proportion to body adiposity enter the
brain and modulate the response of the brain to the acute
meal-generated satiety signals.
•Leptin
•Insulin
•Ghrelin
SUMMARY
• The CNS exerts control of eating at many levels.
• Autonomic nervous system efferent outflow
• Energy expenditure
• Behavior of the gastrointestinal tract
• Integration of information about:
• ingested food
• body adiposity
• Taste
• Memory
• Experience
• Other desires
• Aspects of the environment.
FOOD INTAKE IS A SIMPLE BEHAVIOR.
FOOD INTAKE IS INFLUENCED BY A
COMPLEX ARRAY OF STIMULI AND
SITUATIONAL VARIABLES.
Diabetic Hyperphagia
Characteristics of Type 1 Diabetes Mellitus:
• Effects of the lack of insulin
• Despite the ingestion of food, there is a continuous
post-absorptive metabolic state.
• At the liver
•Glycogenolysis
•Ketogenesis
•Gluconeogenesis
• At muscle
•Proteolysis
• At adipose tissue
•Lipolysis
• Hyperglycemia
• Weight loss
• Increased food intake.
Diabetic Hyperphagia
• Lack of insulin
• Hyperglycemia
• Weight loss
Decreased
adiposity
• Increased food intake.
Decreased
leptin
Increased
ghrelin