Energy Homeostasis

Internal hunger cues

Stomachs begin to rumble / growl Low blood glucose levels

Orexins / hypocretins

A peptide neurochemical produced in the lateral hypothalamus that stimulates eating Injection = increased eating in rats High levels following food deprivation (similar to NPY) Cells releasing ____ are influenced by leptin levels - High leptin levels = indicates sufficient fat is stored, ___ cells are inhibited, feeding is reduced - Low leptin levels = indicates fat stores are low, ___ cells are active and release ____, and feeding is stimulated Also stimulated by ghrelin - should lead to feeding Neurons that release ____ (similar to those releasing MCH) - Project widely in cerebral cortex & regulatory centers in midbrain and pons - play a more general role in linking internal homeostatic states to complex feeding behaviors Narcolepsy - the discovery that ___ play an important role in the sleep disorder narcolepsy has led to interest in the connection between feeding, activity levels, and sleep

neuropeptide Y (NPY)

A peptide neurochemical secreted by the arcuate nucleus of the hypothalamus that initiates eating.

adrenocorticotropic hormone (ACTH)

A pituitary hormone that stimulates release of cortisol from the adrenal glands.

thyroid-stimulating hormone (TSH)

A pituitary hormone that stimulates the growth and function of the thyroid gland, which in turn increases metabolic rate.

paraventricular (around the ventricle) nucleus (PVN)

A portion of the hypothalamus involved with the regulation of hunger.

agouti-related protein (AgRP)

A small protein secreted by the arcuate nucleus that initiates eating

Neural circuits in hindbrain

CAN affect behaviors controlled by motor neurons caudal to the transection Accomplished by transecting the brain stem (forebrain cannot communicate with hindbrain)

Neural circuits in forebrain

CANNOT affect behaviors controlled by motor neurons caudal to the transection Accomplished by transecting the brain stem (forebrain cannot communicate with hindbrain)

aMSH and CART (both)

Cause pituitary gland to release TSH and ACTH, raising body metabolic rates Activate sympathetic NS, increasing metabolism and body temp and inhibits feeding behavior

Fuel detectors in the brain

Cells that monitor available glucose are in the hindbrain, not the forebrain demonstrated control of muscles involved in ingestive behavior

Glucose hypothesis

Cellular glucose availability determines hunger In a healthy person, circulating glucose is the same as available glucose, and hunger will occur when blood glucose levels are low However, in the person with diabetes, circulating glucose is not available to cells due to reduced insulin functioning. - As a result, hunger occurs in spite of ample supplies of glucose. - An injection of insulin drives circulating blood glucose into cells, reducing the amount of available glucose and producing sensations of hunger.

Insulin release phases

Cephalic: mediated by brain in response to seeing, smelling or tasting food Digestive: insulin is released when food enters the digestive tract Absorptive: specialized liver cells - glucoreceptors - signal the pancreas to release even more insulin

Fuel detectors in the periphery - hormonal signals

Cholecystokinin (CCK): hormone released from intestine in response to nutrients Receptors for CCK in periphery (CCK-A) and in brain (CCK-B) In periphery - receptors on vagus nerve afferents fibers

Glycogen

Complex, insoluble carbohydrate used to store energy in the liver Acted on by glucagon to produce glucose If the body requires more energy than can be supplied by the glucose circulating in the blood, such as during a period of fasting, the liver converts stored ___ back into readily available glucose

arcuate nucleus pathway

arcuate nucleus neurons travel to PVN, LH and ANS control centers in brainstem and spinal cord

Liver

can metabolize glucose and fatty acids; receptors detect level of both nutrients

Ketones

chemicals produced from stored fat by the liver Energy for when stores of glycogen are depleted Ex. People following extremely low-carbohydrate diets, such as the Atkins diet, often rely on ____ for energy.

Nutrients

chemicals required for function, maintenance and growth of the body

Lateral hypothalamic neurons

communicate using MCH (melanin-concentrating hormone) project widely throughout the cerebral cortex might provide the necessary link between the hypothalamus' recognition of hunger and higher-order motivated behaviors that lead to eating and the storage of nutrients - Mice genetically modified to be incapable of producing MCH burned energy faster, ate less, and had less body fat (more likely to die of starvation)

aMSH in lateral hypothalamus

competes directly with AgRP for activation of the MC4 receptors AgRP initiates feeding behavior by blocking these receptors - When the MC4 receptors are blocked by AgRP, feeding is stimulated____ serves as an agonist at the MC4 receptor - When the MC4 receptors are activated by _____, feeding is inhibited

BMI - Associated Disease Risk

computed by dividing a person's weight in kilograms by the square of his or her height in meters Underweight <18.5 BMI Increased risk Normal 18.5 - 24.9 Normal risk Overweight 25 - 29.9 Increased risk Obese: Obese 1 30 - 34.9 High risk Obese 2 35 - 39.9 Very high risk Obese 3 > 40 BMI Extremely high risk

High levels of circulating leptin

discourage feeding by directly inhibiting the synthesis and release of NPY and AgRP

Basal metabolism

energy used for heat production, maintenance of membrane potentials, and life-sustaining processes

feeding cycle tapers off when...

fat stores return to normal levels - more leptin is released - NPY and AgRP are less active

Hedonic feeding

food intake driven by sensory perception or pleasure Has led a lot of research investigating relationship between food intake and reward neural systems

Ob/Ob Mice

Spontaneous genetic mutation Hyperphagic mice at early age Grossly obese by adulthood (>50% avg BW) Obese even when not permitted to overeat Had multiple metabolic disorders

Other Ways to Inhibit Feeding Behavior

Projections from the ARC travel to the PVN, LH, and NTS (brainstem) In the LH, aMSH competes with AgRP for activation of MC4 receptors- aMSH is an agonist of MC4 receptors -> decreases intake

Obesity

Rapid change - approximately 35 percent of American adults have BMIs greater than 30 - No state reported an obesity rate of less than 20 percent in 2015, whereas no state reported an obesity rate above 15 percent in 1988 Diet & exercise - When at rest, the average human body uses only about 12 calories (actually kcals) per pound per day Factors for increased rates: (1) Social factors = acceptance of large body size - reflected in the fact that having obese friends increases your risk of obesity by 57 percent, and having an obese spouse increases your risk of obesity by 37 percent (2) Stress alone and a high-fat diet alone do not necessarily lead to obesity, but the combination of the two appears to increase the release of NPY, which in turn increases appetite (3) Sleep deprivation, common among American adults, is also linked to disturbances in energy metabolism leading to obesity (4) Genetics - play an important role in a person's vulnerability to obesity - explain part of the reason why some people exposed to current lifestyles continue to maintain a healthy weight while others become obese - Large numbers of gene variations have been associated with obesity, each having small effects. (5) Gut bacteria types influence fat storage and obesity - When bacteria from obese mice were transplanted into typical mice, the typical mice increased their body fat 47 percent in two weeks - Manipulations of bacteria through the use of probiotics and antibiotics to promote weight gain in farm animals have been a staple in livestock management for decades. - Frequent exposure to antibiotics early in life is associated with a much higher risk of overweight and obesity in children - Different types of bacteria are found in humans who are lean and in those who consume high-fat diets and are obese - It is possible that future treatments for obesity might involve methods that influence the relative frequency of various types of gut bacteria

Obese gene (ob)

Rats Without ___ - Unable to produce leptin - Become fat

Insulin & glucose levels

normally released in response to eating or even to the anticipation of eating Tied to glucose levels (not positive relationship because...) - Injections produce feelings of hunger - Diabetes patients experience hunger and high levels of glucose

TSH & ACTH

release of NPY and AgRP in the lateral hypothalamus and PVN suppresses release of _____ raises body metabolic rates Both - originate in pituitary - Increase metabolic rate

hindbrain

where fuel detectors (cells that monitor available glucose) are located in the brain demonstrated control of muscles involved in ingestive behavior

Parasympathetic activity, feeding behavior, and TSH/ACTH suppression

work together to allow an animal to find, eat, and store nutrients

nucleus of the solitary track, arcuate nucleus

(1) Information is relayed from the _________ to the hypothalamus (2) Organization of appetite control neurons occur here in the ________ (3) Gets input from hormones and other areas of the brain to stimulate or inhibit feeding

Other Ways to Stimulate Feeding Behavior

(1) One specialized mechanism -> AgRP acts as an antagonist at a special receptor site in the LH - MC4 receptor - When MC4 receptors are blocked, feeding is initiated (2) Release of NPY and AgRP in the LH and PVN suppresses release of 2 pituitary hormones: - Thyroid-stimulating hormone (TSH) - Adrenocorticotropic hormone (ACTH) Suppressing TSH and ACTH helps allow the body to replenish fat stores LH neurons communicate with melanin-concentrating hormone (MCH), which then projects throughout the cortex - Might be link between hunger and higher-order motivated behaviors The hormone ghrelin (pancreas/stomach) stimulates hunger and acts on brain circuits involved with memory and reward Orexins (aka hypocretins) stimulate food intake - Influenced by leptin levels - Also involved in sleep -> current research on connection between feeding, activity, and sleep

Feeding stimulatory circuit

1) Leptin and insulin communicate with neurons in the arcuate nucleus of the hypothalamus 2) When leptin and insulin levels are low, these cells release neuropeptide Y (NPY) and agouti-related protein (AgRP) to communicate with the LH and with the paraventricular nucleus (PVN) of the hypothalamus 3) In response to these signals, the parasympathetic division of the ANS is activated, and feeding behavior is stimulated

arcuate nucleus

A cluster of neurons involved with feeding located within the hypothalamus.

Cholecystokinin (CCK)

A gut hormone released in response to the consumption of fats that also acts as a central nervous system (CNS) neurochemical that signals satiety. Receptors in periphery (CCK-A) (on vagus nerve afferents fibers) and in brain (CCK-B)

ghrelin

A hormone produced primarily in the pancreas and in the stomach lining - Receptors have been found in arcuate nucleus and ventromedial hypothalamus (VMH) Levels: - Highest during fasting - Decrease following a meal Functions: - Acts as a short-term circulating hormone that stimulates hunger - affects feeding by acting on brain circuits involved with memory and reward (might contribute to the rewarding feeling that is associated with feeding, especially when food deprivation has been more severe)

melanin-concentrating hormone (MCH)

A hormone that interacts with leptin and plays a role in the regulation of eating.

alpha melanocyte stimulating hormone (αMSH or alpha-MSH)

A neurochemical originating in the arcuate nucleus, believed to inhibit feeding behavior.

cocaine- and amphetamine-regulated transcript (CART)

A neurochemical, originating in the arcuate nucleus, believed to inhibit feeding behavior.

Glucagon

A pancreatic hormone that converts stored glycogen back into glucose Levels of ____ increase during periods of fasting, as the body taps into its glycogen stores to maintain blood glucose levels.

Leptin

A substance secreted by fat cells that helps the body regulate its fat stores Low levels of fat storage - When fat stores are low, levels of circulating leptin will also be low. - administering additional leptin to obese rodents reduced their weight Obese humans - already produce large amounts of leptin, but they seem to be resistant to its effects - Providing more leptin is unlikely to help them lose weight

Glucose

A type of sugar found in foods that is a major source of energy for living organisms. exclusive source of energy for the brain, whereas the rest of the body can use both glucose and fatty acids Excess is stored as fat by adipose tissue or converted by the liver into a complex carbohydrate called glycogen for storage

Mechanisms of Satiety STEPS

ACTIVATION 1) High fat stores 2) High levels of leptin 3) Activation of aMSH and CART EATING BEHAVIOR inhibited AUTONOMIC NERVOUS SYSTEM (ANS) Sympathetic nervous system is activated: Body expends nutrients PITUITARY GLAND TSH and ACTH are activated: Higher metabolic activity HYPOTHALAMUS aMSH stimulates MC4 receptors in lateral hypothalamus: Suppresses eating behavior RESULT 4) Body fat levels decrease, leading to hunger

Mechanisms of Hunger STEPS

ACTIVATION 1) Low fat stores 2) Low levels of leptin 3) Activation of NPY, AgRP, ghrelin and orexins EATING BEHAVIOR Initiated AUTONOMIC NERVOUS SYSTEM (ANS) Parasympathetic nervous system is activated: Body stores nutrients PITUITARY GLAND TSH and ACTH are suppressed: Lower metabolic activity HYPOTHALAMUS AgRP blocks MC4 receptors in lateral hypothalamus: Stimulates eating behavior RESULT 4) Body fat levels increase, leading to satiety

Fuel detectors in the periphery - neural signals

Absorbed nutrients pass through liver, which can monitor levels of nutrients - Liver can metabolize glucose and fatty acids; receptors detect level of both nutrients Send info to the brain via vagus cranial nerve - Brain cannot metabolize fatty acids; receptors detect only glucose levels Where it goes once it gets to the brain - Nucleus of the solitary tract via vagus nerve input

Decerebration

Accomplished by transecting the brain stem (forebrain cannot communicate with hindbrain) Neural circuits in hindbrain: CAN affect behaviors controlled by motor neurons caudal to the transection Neural circuits in forebrain: CANNOT affect behaviors controlled by motor neurons caudal to the transection Hindbrain: demonstrated control of muscles involved in ingestive behavior

ventromedial hypothalamus (VMH)

An area within the hypothalamus that participates in satiety - might serve as a satiety center Lesions = ___ syndrome, characterized by large weight gains and picky eating habits - Will eat much less bitter food (mixed with quinine) than normal control rats - Do not continue to eat indefinitely, instead seem to establish a much higher set point, which is defended in a somewhat normal manner RESULTS of lesions: - can damage important adjacent fiber pathways, such as fibers connecting the PVN to the NST in the brainstem (NST receives information from glucoreceptors and taste receptors and participates in energy storage; Disruption of this pathway could easily produce abnormal eating patterns) - Can result in excess insulin production (Chronically low-circulating glucose levels due to excess insulin produce constant hunger and feeding)

$117b

Cost of obesity per year

Leptin levels

Fat stores determine... (triggers a cascade of events leading to either hunger or satiety)

Digestion

Fats, proteins, and carbs are absorbed into the blood supply and circulated to waiting tissues Fats are either used for immediate energy or stored by adipose tissue (fat cells) CCK released when large amounts of food are consumed. Proteins are broken down into amino acids and used by muscles and other tissues for growth and protein synthesis Carbohydrates are broken into simple sugars, including glucose Excess glucose can be converted into glycogen for storage

Impaired insulin function consequences

Glucose cannot enter cells, so it stays in the blood and causes hyperglycemia (high blood sugar) Type 1 & 2 diabetes mellitus

Following a meal

Healthy person - experiences a large spike in insulin levels in the circulation Person w Type 2 diabetes - much slower and less dramatic release of insulin - will not be able to move glucose out of the blood into cells requiring nutrients- appetite -suppressing action is less effective

Blood glucose levels

High = just following a meal Low = when someone feels hungry

Second set of neurons in arcuate nucleus

Interact with high levels of circulating leptin Distinct from neurons that respond to low levels of leptin Source of two neuropeptides: (1) Alpha melanocyte stimulating hormone (aMSH or alpha-MSH) (2) Cocaine and amphetamine-regulated transcript (CART)

The Dual Center Hypothesis

Introduced by Eliot Stellar Lateral hypothalamic (LH) "feeding center" which stimulates hunger - Lesions in LH = rats become aphagic (stop eating) LH inhibited by "satiety center" in VMH (ventromedial hypothalamus) - Lesions of VMH = rats become hyperphagic (can't stop eating) CRITICS - Harvey Grill showed that the caudal brainstem could control many functions that were previously attributed to the hypothalamus - The system was more complex than originally thought

Additional risks for obesity related disease

Large waist circumference Poor aerobic fitness

Leptin Revolution

Led to the discovery of numerous peptides and circuits working in the brain to regulate food intake Also got people thinking about other tissues in the periphery that might function as endocrine organ Sparked the "peptide boom" in food intake research

Ob/Ob Kid (Child with mutation of leptin gene)

Leptin replacement worked in children - Increases doses are necessary to maintain effects Leptin treatment in obese adults doesn't work well - "Leptin resistant"

Major Structures of Digestive Tract

Oral cavity Tongue Esophagus Liver Gallbladder Duodenum Large intestine Small intestine Anal cavity Pancreas Stomach Rectum

Food Intake Factors

Social factors Stress Sleep Deprivation Genetics Gut microbiome Reinforcement

MC4 receptor

Special receptor site in the lateral hypothalamus When blocked, feeding is initiated AgRP acts as an antagonist

glucagon and insulin

The body's supply of energy from glucose is regulated mostly by ______ and ________ (produced in pancreas)

Satiety

The sensation of being full, cessation of eating occurs long before sufficient nutrients make their way into cells Early warning Signals for overeating: (1) Stomach fullness (2) Duodenum - joins the stomach and the small intestines - When glucoreceptors sense sugars, eating generally stops quickly - The arrival of foods containing fats and proteins at the duodenum signals the release of the peptide cholecystokinin (CCK) (3) cholecystokinin (CCK) - promotes the release of insulin by the pancreas and contracts the gallbladder to release bile to help break down fats - clearly contributes to feelings of satiety - injection with CCK antagonists increases eating - limits meals by activating pathways connecting the gastrointestinal tract and the hindbrain

External hunger cues

Time of day Sights and smells of food Social setting which food is presented in

Brain Mechanisms for Hunger (initiation and cessation of feeding behavior)

WITHIN THE HYPOTHALAMUS: LH (lateral hypothalamus) - Participates in initiating eating (Previously thought of as a hunger center) - Lesion = rats starve to death in presence of food, wouldn't initiate eating (CRITICISM: when force fed, rats eventually began initiating feeding on their own again) - Stimulation = immediate feeding VMH (ventromedial hypothalamus) Arcuate nucleus PVN (paraventricular nucleus)

Treatment of Obesity

Weight loss diet - Work by reducing the number of calories consumed Long term weight loss - Requires lifestyle changes that are sustainable indefinitely Popular diets - tend to allow too few calories, triggering physiological responses aimed at avoiding starvation - body lowers its metabolic rate, and the dieter might actually gain weight while eating less than before Medications - Approved drugs act by suppressing appetite, increasing metabolism, or interfering with the absorption of nutrients - Modest weight loss (5-10 lbs in one year) - Benefits must be weighed against side effects Surgical interventions: stomach stapling and gastric bypass procedures - Significant weight loss (average loss of 90 pounds within three months of gastric bypass) - represent major surgery, often result in complications, and should be considered carefully

NPY & feeding

When Food deprived... - ___ builds up within the arcuate nucleus When ____ is applied directly to hypothalamus... - Immediate feeding behavior If ____ receptors in hypothalamus are blocked - animals will fail to eat following either food deprivation or NPY infusions

High, higher

When body-fat levels are ____, ____ concentrations of leptin are found in the blood.

Feeding inhibitory circuit

When leptin and insulin levels are high, some ARC cells release alpha melanocyte stimulating hormone (aMSH) and cocaine and amphetamine-related transcript (CART)

brain, periphery-neural, periphery-hormonal

Where are fuel detectors located? (3 types) How can the brain detect available fuel in the body?

release of NPY and AgRP in the lateral hypothalamus and PVN

activates the parasympathetic nervous system (PNS) and stimulates eating behavior suppresses the release of two pituitary hormones (TSH and ACTH)

Without normal insulin function...

glucose from food circulates through the bloodstream without being absorbed or stored by the body's tissues The cells are literally starving while high levels of glucose are excreted in the urine

Insulin

helps store glucose as glycogen (in liver) and assists in moving glucose from the blood supply into body tissue cells (Reduces blood glucose level, allows cells to utilize glucose) Levels: - Increase after meal (helping some glucose circulating in the blood supply to move into cells and the rest to be stored as glycogen) - Lowest during fasting

"lipostatic theory"

hunger results from low fat supplies also likely that we have mechanisms for assessing levels of circulating amino acids assessing these mechanisms experimentally would be difficult to do

Type 1 diabetes mellitus

insufficient production of insulin that occurs when insulin-producing pancreatic cells are attacked and destroyed by the body's immune system Juvenile diabetes = Often diagnosed in childhood or young adulthood Symptoms = increase in thirst, frequent urination, fatigue, blurred vision Treatment = find ways to monitor blood sugar levels and keep it steady; insulin therapy

Digestive phase of insulin release

insulin is released when food enters the digestive tract

Cephalic phase of insulin release

mediated by brain in response to seeing, smelling or tasting food

Future treatments for obesity

might involve methods that influence the relative frequency of various types of gut bacteria

Type 2 diabetes mellitus

resistance to insulin that occurs when individuals produce insulin but either don't make enough or don't use it efficiently Adult onset diabetes = often result of other health issues, diagnosed in middle aged adults Symptoms = increase in thirst, frequent urination, fatigue, blurred vision Treatment = changes to diet and exercise routine, medications Can develop into more serious conditions through life (heart and blood vessel issues, eye/nerve damage, slowly healing / not healing wounds)

Suppression of TSH & ACTH

slows the body's use of energy, allowing some of the nutrients taken in during feeding to be used to replenish the fat stores (TSH and ACTH both increase metabolic rate)

Glucoreceptors

specialized liver cells sensitive to the presence of glucose (assesses nutrient levels and communicates with areas of the brain that initiate feeding behavior) Located in the hindbrain, particularly in the medulla In the liver: influence the release of insulin from the pancreas _____ signal the pancreas to release even more insulin during Absorptive phase of insulin release

Absorptive phase of insulin release

specialized liver cells - glucoreceptors - signal the pancreas to release even more insulin

Fasting / dieting

stores of glycogen are depleted - all body structures except the brain begin to use fatty acids from adipose tissue for energy causes muscle tissue to break down, and the liver converts the resulting amino acids into glucose Even with the loss of two to three pounds per week on a sensible, balanced diet, approximately 25 percent of the weight lost will be from bone and muscle