Caloric Homeostasis: Control of Energy Homeostasis and Food IntakeCaloric Homeostasis: Control of Energy Homeostasis and Food Intake Diabetic hyperphagia.

• Caloric Homeostasis: Caloric Homeostasis: Control of Energy Control of Energy Homeostasis and Food Homeostasis and Food IntakeIntake

• Diabetic hyperphagia

The amount of food eaten varies considerably

from meal to meal and from day to day.

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 Expenditure = Stored Calories+Caloric Intake

Caloric BalanceCaloric Balance

Caloric Homeostasis (stored calories Caloric Homeostasis (stored calories remain unchanged)remain unchanged)

Caloric Expenditure = 0Stored Calories += Caloric Intake

Caloric Intake Caloric Expenditure=

Lipostatic Model of Feeding BehaviorLipostatic Model of Feeding Behavior

Caloric Expenditure=Stored Calories +Caloric Intake

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.

Caloric Expenditure=Stored Calories +Caloric Intake

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 -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.

• -Adrenergic sympathetic activity inhibits insulin secretion.

Gastrointestinal Hormones• Augment the pancreatic -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 post-

absorptive 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/A-

like 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 meal-generated 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 -melanocyte-stimulating hormone (-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

-MSH

• Potent catabolic peptide• Act on melanocortin (MC) receptors

• MC3 and MC4 receptors on neurons in hypothalamic paraventricular nucleus (PVN)

• ARC--MSH neurons project from ARC to PVN• Leptin- or insulin-induced activation of ARC--MSH

neurons causes

• Decreased food intake

• Increased energy expenditure by increasing sympathetic nervous system activity.

• -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 -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--MSH neurons have a net catabolic effect.

• ARC-NPY-AgRP neurons have a net anabolic effect.

• 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.

SUMMARY

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

• Increased food intake.

• Lack of insulin• Hyperglycemia• Weight loss

Decreased adiposity Increased

ghrelin

Decreased leptin