PHYSIOLOGICAL BASIS OF CONTROL OF APPET

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PHYSIOLOGICAL BASIS OF CONTROL OF APPETITE AND BODY WEIGHT : 

PHYSIOLOGICAL BASIS OF CONTROL OF APPETITE AND BODY WEIGHT DR MD MIRAJ MONDAL CHAIR PERSON DR S BHATTACHARYA DR A K BANDOPADHYAY DEPARTMENT OF MEDICINE MEDICAL COLLEGE KOLKATA,

Slide 2: 

Regulation of food intake Regulation of energy balance Clinical importance

WHY DO WE EAT : 

WHY DO WE EAT Hunger Physiological (internal) drive to eat The feeling that prompts thought of food and motivates food consumption Influenced by nutrients in the bloodstream, eating patterns, climate, etc Controlled internally

WHY DO WE EAT : 

WHY DO WE EAT Appetite Psychological (external) drive to eat Often in the absence of hunger Often of particular type of food Combination of internal and external signals drive us to eat Appetite is affected by a variety of external forces Not a perfect system; desire to eat can be overwhelming

Slide 5: 

Regardless of hunger, people typically overeat when offered the abundance and variety of an “all you can eat” buffet.

WHY WE EAT : 

WHY WE EAT SATIETY If the quest for food is successful the brain signals the body to stop eating (hunger is suppressed). .

Sustaining Hunger and Satiety : 

Sustaining Hunger and Satiety Protein --- most satiating Complex carbohydrates --- satiating Fat --- stimulate and entice people to eat more

NEURAL CENTRES REGULATES FOOD INTAKE : 

NEURAL CENTRES REGULATES FOOD INTAKE Hypothalamus contains HUNGER and SATIETY centre Paraventricular, Dorsomedial, and Arcuate nuclei of the Hypothalamus also play a major role Chemical cross talk among the neurons of the hypothalamus Hypothalamus receives signals from different site

HUNGER AND SATIETY CENTRE : 

HUNGER AND SATIETY CENTRE FEEDING CENTRE SATIETY CENTRE LATERAL NUCLEI OF HYPOTHALAMUS VENTROMEDIAL NUCLEI OF HYOTHALAMUS INHIBITION FOOD INTAKE

SATIETY REGULATOR : 

SATIETY REGULATOR The hypothalamus When feeding cells are stimulated, they signal us to eat When satiety cells are stimulated, they signal us to stop eating Sympathetic nervous system When activity increases, it signals to stop eating When activity decreases, it signals to eat

HYPOTHALAMUS RECEIVES SIGNALS : 

HYPOTHALAMUS RECEIVES SIGNALS HYPOTHALAMUS CEREBRAL CORTEX GIT GIT HORMONE NUTRIENTS IN BLOOD HYPOTHALAMUS CEREBRAL CORTEX GIT GIT HORMONE ADIPOSE TISSUE NUTRIENTS IN BLOOD

THE FACTORS THAT REGULATE APPETITE THROUGH EFFECTS ON CENTRAL NEURAL CIRCUIT : 

THE FACTORS THAT REGULATE APPETITE THROUGH EFFECTS ON CENTRAL NEURAL CIRCUIT HORMONES Leptin Insulin Cortisol METABOLITES Glucose Ketones GUT PEPTIDE CCK Ghrelin PYY NEURAL AFFERENTS ( Vagal ) PSYCHOLOGICAL Factors CULTURAL Factors

NEUROTRANSMITERS AND HORMONES : 

NEUROTRANSMITERS AND HORMONES ANOREXIGENIC α MSH (Melanocyte-stimulating hormone) Leptin Serotonine Nor-epinephrine Corticotropin- realeasing hormone Insulin CCK ( Cholecystokinin) GLP (glucagon-like peptide) CART (Cocain and amphetamine related transcript) Peptide YY OREXIGENIC Neuropeptide Y (NPY) Agouti-related protein (AgRP) MCH (Melanin-concentrating hormone) Orexins A and B Endorphins Galanin (GAL) Amino acids ( glutamate & GABA) Cortisol Ghrelin Cannabinoids

HORMONAL CONTROL : 

HORMONAL CONTROL MCR3 MCR3 MCR4 Y1R Y1R MCR4 MCR3

NEURON AND NEUROTRANSMITTERS IN THE HYPOTHALAMUS THAT STIMULATE OR INHIBIT FEEDING : 

NEURON AND NEUROTRANSMITTERS IN THE HYPOTHALAMUS THAT STIMULATE OR INHIBIT FEEDING

FACTORS THAT REGULATE QUANTITY OF FOOD INTAKE : 

FACTORS THAT REGULATE QUANTITY OF FOOD INTAKE Short term regulation Concerned primarily with preventing over eating at each meal Long term regulation Concerned primarily with maintenance of normal quantities of energy stores in the body

SHORT TERM REGULATION OF FOOD INTAKE : 

SHORT TERM REGULATION OF FOOD INTAKE Gastrointestinal filling inhibits feeding GI hormones CCK GHRELIN PEPTIDE YY GLP INSULIN 3. Oral receptors meter food intake

FEEDBACK MECHANISMS FOR CONTROL OF FOOD INTAKE : 

FEEDBACK MECHANISMS FOR CONTROL OF FOOD INTAKE

C C K : 

C C K CCK FOOD INTAKE Cholecystokinin released from duodenum in response to fat entry Direct effect on feeding centre to reduce subsequent feeding by activation of the MELANOCORTIN pathway in the hypothalamus + MELANOCRTIN SYSTEM

INSULIN : 

INSULIN INSULIN, GLP FOOD INTAKE - + ENERGY EXPENDITURE

PEPTIDE YY : 

PEPTIDE YY PYY: 1. made in response to food entering the GIT especially from ILEUM and COLON 2. Binds to an inhIbitory receptor on NPY/AgRP   secretion of NPY and AgRP   APPETITE PYY FEEDING

GHRELIN - THE HUNGER HORMONE : 

GHRELIN - THE HUNGER HORMONE Identified in 1999 by Kojima and Kangawa 28 amino-acid, orexigenic peptide hormone Secreted by gastric mucosa (oxyntic cells) on an empty stomach  during fasting, peak level before meal, fall rapidly after meal Two major roles GH regulation Energy balance GHRELIN

GHRELIN TO INCREASE APPETITE : 

GHRELIN TO INCREASE APPETITE GHRELIN FOOD INTAKE

INTERMEDIATE AND LONG TERM REGULATION OF FOOD INTAKE : 

INTERMEDIATE AND LONG TERM REGULATION OF FOOD INTAKE Nutrients in blood Environmental temperature Feed back signals from adipose tissue

EFFECT OF NUTRIENTS IN BLOOD : 

EFFECT OF NUTRIENTS IN BLOOD Theories – Glucostatic Lipostatic Aminostatic

GLUCOSTAT : 

GLUCOSTAT SATIETY CENTRE HUNGER CENTRE HUNGRY SATIATED GLUCOSE INCREASE DECREASE INHIBITION BLOOD

AMINOSTAT, LIPOSTAT : 

AMINOSTAT, LIPOSTAT SATIETY CENTRE HUNGER CENTRE HUNGRY SATIATED Aminoacids lipids INCREASE DECREASE INHIBITION BLOOD

TEMPERATURE REGULATION AND FOOD INTAKE : 

TEMPERATURE REGULATION AND FOOD INTAKE The thermostatic hypothesis Exposure to cold increases feeding Exposure to heat decreases feeding Caused by interaction within the hypothalamus between temperature and food intake – regulating system

FEEDBACK SIGNALS FROM ADIPOSE TISSUE BY LEPTIN : 

FEEDBACK SIGNALS FROM ADIPOSE TISSUE BY LEPTIN Hypothalamus senses energy storage through the actions of LEPTIN LEPTIN a peptide hormone released from adipose tissue ↑ adipose tissue increase ↑ LEPTIN production

LEPTIN : 

LEPTIN Leptin – Greek word “LEPTOS” meaning thin Circulating protein – contains 167 amino acids Coded by ob gene Acts on hypothalamus to decrease food intake and increase energy consumtion

FEED BACK SIGNALS FROM ADIPOSE TISSUE : 

FEED BACK SIGNALS FROM ADIPOSE TISSUE

LEPTIN – ON THE HYPOTHALAMUS : 

LEPTIN – ON THE HYPOTHALAMUS LEPTIN FOOD INTAKE SYMPATHETIC ACTIVITY ENERGY EXPENDITURE AgRP NPY α- MSH

OREXINS : 

OREXINS Orexins were discovered in 1998 as peptides of appetite control De Leceaet al., 1998, Sakurai et al., 1998 they are actually peptides of “vigilance” Orexindeficiency leads to hypersomnolence Lin et al., 1999, Chemelliet al., 1999

OREXINS : 

OREXINS Also called Hypocretins – Neuropeptide hormones that increase food intake Synthesized in neurons located in the lateral Hypothalamus Two types Orexin –A, Orexin - B Functions - 1. Wakefulness 2.Food intake Orexin producing cells are inhibited by leptin and activated by Ghrelin and Hypoglycemia

ENDOCANNABINOID SYSTEM : 

ENDOCANNABINOID SYSTEM Two endocannabinoids 1. Anandamide 2. 2 arachidonyl glycerol Receptors are CB1 (abundant in the brain) CB2 ( present in immune cells) Control food intake Regulate action of other mediators of appetite CB1 receptors play a key role in energy balance, and are directly implicated in lipid and glucose metabolism.

Implications of CB1 receptor activation : 

Implications of CB1 receptor activation Central nervous system Hypothalamus ↑ Appetite Limbic system ↑ Motivation to eat/smoke

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (1) : 

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (1) Appetite control centre in hypothalamus Arcuate nucleus NPY/AgRP POMC/CART Two cell types NPY α -MSH Stimulate appetite ↓ Energy expenditure Decreases appetite ↑ Energy expenditure

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (2) : 

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (2) CCK PEPTIDE YY INSULIN LEPTIN GHRELIN Neuropeptide secretion regulated by

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (3) : 

APPETITE CONTROL AT HYPOTHALAMIC LEVEL: SUMMARY (3) Leptin and insulin: 1. Stimulate- POMC/CART neurons   CART and -MSH levels 2. Inhibit NPY/AgRP neurons   NPY and AgRP Net effect : ↑ Satiety and  Appetite Ghrelin stimulates NPY/AgRP   NPY and AgRP secretion ↑ appetite PYY3-36 is a homolog of NPY Binds to an inhibitory receptor on NPY/AgRP   secretion of NPY and AgRP   Appetite

ENERGY BALANCE AND WEIGHT CONTROL : 

ENERGY BALANCE AND WEIGHT CONTROL

ENERGY BALANCE : 

ENERGY BALANCE “State in which energy intake, in the form of food and /or alcohol, matches the energy expended, primarily through basal metabolism and physical activity” Positive energy balance Energy intake > energy expended Results in weight gain Negative energy balance Energy intake < energy expended Results in weight loss

ENERGY BALANCE : 

ENERGY BALANCE

Slide 48: 

70 % 20 % 10 %

BASAL METABOLISM : 

BASAL METABOLISM The minimum energy expended to keep a resting, awake body alive ~60-70% of the total energy needs Includes energy needed for maintaining body functions( heartbeat, respiration, body temperature) Amount of energy needed varies between individuals

INFLUENCES ON BASAL METABOLISM : 

INFLUENCES ON BASAL METABOLISM Body surface area (weight, height) Gender Body temperature Thyroid hormone Age K-Cal intake Pregnancy Use of caffeine and tobacco

PHYSICAL ACTIVITY : 

PHYSICAL ACTIVITY Most variable and changeable Increases energy expenditure beyond BMR Varies widely among individuals More activity, more energy burned Lack of activity is the major cause of weight gain and obesity

Slide 52: 

A healthy body contains enough lean tissue to support health and the right amount of fat to meet body needs.

THERMIC EFFECT OF FOOD : 

THERMIC EFFECT OF FOOD Energy used to digest, absorb, and metabolize food nutrients “Sales tax” of total energy consumed ~5-10% above the total energy consumed TEF is higher for protein (20-30%) and carbohydrate(5-10%) than fat(0-5%) Less energy is used to transfer dietary fat into adipose stores

NONEXERCISE ACTIVITY THERMOGENESIS : 

NONEXERCISE ACTIVITY THERMOGENESIS Nonvoluntary physical activity triggered by overeating Fidgeting Overeating increases sympathetic nervous system activity Resists weight gain

CLINICAL IMPORTANCE : 

CLINICAL IMPORTANCE

A CENTRAL PATHWAY THROUGH WHICH LEPTIN ACTS TO REGULATE APPETITE AND BODY WEIGHT -- MUTATIONS : 

A CENTRAL PATHWAY THROUGH WHICH LEPTIN ACTS TO REGULATE APPETITE AND BODY WEIGHT -- MUTATIONS 1 2 3 4 5 No. indicating mutation sites

SOME OBESITY GENE IN HUMANS : 

SOME OBESITY GENE IN HUMANS

PRADER-WILLI SYDROME : 

PRADER-WILLI SYDROME In Prader-Willi syndrome over production of GHRELIN (highest level ever measured in human) -- hyperphagia OBESITY Other obesity syndromes Laurence-Moon-Biedl Ahlstrom Cohen Carpenter

HYPERPHAGIA : 

HYPERPHAGIA Diabetes –Polyphagia; though blood glucose is high but cellular utilization is low in the satiety centre because of the insulin deficiency Hyperthyroidism – NPY activated by concurrent hypermetabolism induced starvation GI disorder- malabsorption ( coeliac sprue, short bowel syndrome) adaptive hyperphagia Kluver Bucy syndrome- bilateral medial temporal lobe lesion

HYPERPHAGIA : 

HYPERPHAGIA Tumors – direct invasion of the hypothalamus with axial tumors or extrinsic compression and displacement of hypothalamic structure by suprasellar masses or third ventricular lesion

ANOREXIA IN SEVERE INFECTION AND CANCER : 

ANOREXIA IN SEVERE INFECTION AND CANCER Several inflammatory cytokines TNF-α, IL-6, IL-1β, Prteolysis-inducing factor cause anorexia and cachexia by activation of Melanocortin system in the hypothalamus TNF-α, IL-6 IL-1β POMC DECREASED FOOD INTAKE ↓ WEIGHT LOSS + +

ANOREXIA WEIHGT LOSS : 

ANOREXIA WEIHGT LOSS CRF - Anorexia due to uremic toxins COPD ,CCF– due to increase resting energy expenditure

EATING DISORDERS : 

EATING DISORDERS Anorexia nervosa Refuses to attain or maintain a minimal healthy body weight ( BMI ≤ 17.5 kg/m²) Excessive concern with weight or weight gain Distorted perception of weight or body shape and /or related medical dangers Amenorrhea ANOREXIA NERVOSA

EATING DISORDERS : 

EATING DISORDERS Bulimia nervosa Recurrent binge-eating Recurrent behavior to purge or neutralize excessive intake or to control weight Excessive concern with weight or body shape These are multifactorial, with psychodevelopmental, sociocultural, and genetic contribution to risk BULIMIA NERVOSA

DRUGS in WEIGHT CONTROL : 

DRUGS in WEIGHT CONTROL 1.Sibutramine an appetite suppressant, centrally acting 2. Orlistat a lipase inhibitor, peripherally acting 3. Rimonabant CB1 cannabinoid receptor antagonist, centrally as well as peripherally acting

Diet Drugs : 

Diet Drugs Amphetamine (Phenteramine) Prolongs the activity of epinephrine and norepinephrine in the brain Hunger is suppressed as a result of inhibition of hypothalamic feeding centre Not recommended for clinical use

Diet Drugs : 

Diet Drugs Sibutramine Norepinephrine and serotonin reuptake inhibitor Enhances satiety and decreases caloric intake Stimulate thermogenesis by indirectly activating β-3 system in adipose tissue Not recommended for people with HTN

Slide 68: 

The key to good health is to combine sensible eating with regular exercise.

REDUCE YOUR EXTRA WEIGHT : 

REDUCE YOUR EXTRA WEIGHT THANK YOU

EXTRA SLIDES : 

EXTRA SLIDES

NEURON AND NEUROTRANSMITTERS IN THE HYPOTHALAMUS THAT STIMULATE OR INHIBIT FEEDING : 

NEURON AND NEUROTRANSMITTERS IN THE HYPOTHALAMUS THAT STIMULATE OR INHIBIT FEEDING

HORMONAL CONTROL : 

HORMONAL CONTROL

INCREASE THERMOGENESIS VIA UNCOUPLING OF ELECTRON TRANSPORT : 

INCREASE THERMOGENESIS VIA UNCOUPLING OF ELECTRON TRANSPORT

Slide 77: 

“Apple” and “Pear” Body Shapes Compared

PLASMA GHRELIN LEVEL IN RELATION TO MEAL : 

PLASMA GHRELIN LEVEL IN RELATION TO MEAL

LEPTIN and GHRELIN acts as counter regulatory hormone : 

LEPTIN and GHRELIN acts as counter regulatory hormone LEPTIN GHRELIN

HOW LEPTIN ACTS : 

HOW LEPTIN ACTS In the hypothalamus ↓ expression of appetite stimulator NPY and AgRP ↑ expression of -melanocyte-sitimulating (-MSH) hormone, which triggers the next neuron in the circuit to send the “Stop eating!” signal. ↑ Production of Corticotropin Releasing Hormone - ↓ food intake ↓ Insulin secretion (β ) - ↓ energy storage Stimulates the sympathetic nervous system: Increases BP. Increases heart rate. Increases thermogenesis via uncoupling of electron transport.

Slide 84: 

RIMONABANT

ENERGY BALANCE &PATHOPHYSIOLOGY OF WEIGHT LOSS : 

ENERGY BALANCE &PATHOPHYSIOLOGY OF WEIGHT LOSS

PHYSIOLOGIC EFFECTS OF LEPTIN : 

PHYSIOLOGIC EFFECTS OF LEPTIN Regulation of food intake ,energy expenditure and body weight . Thermogenesis . Reproductive function . Suppressed bone formation . Directly act on the cells of liver and muscles . Related to inflammatory response . Contribute to early hematopoiesis.

SIGNALING PATHWAY OF LEPTIN ACTION : 

SIGNALING PATHWAY OF LEPTIN ACTION

HYPERPHAGIA in raised ICT : 

HYPERPHAGIA in raised ICT

Slide 92: 

LEPTIN IN HIV LIPODYSTROPHY

Slide 93: 

LEPTIN IN HIV RELATED LIPODYSTRPHY

ORAL RECEPTORS METER FOOD INTAKE : 

ORAL RECEPTORS METER FOOD INTAKE It is postulated that various ORAL ˝factors" related to feeding , such as chewing, salivation, swallowing, and tasting, METER the food as it passes through the mouth And after a certain amount has passed the hypothalamic feeding centre becomes inhibited This inhibition is less intense and of shorter duration

ESTIMATION OF HEALTHY WEIGHT : 

ESTIMATION OF HEALTHY WEIGHT MEN Weight = ( height in cm-100 ) kg WOMEN Weight= (height in cm-105 ) kg

ESTIMATION OF HEALTHY WEIGHT : 

ESTIMATION OF HEALTHY WEIGHT For men: 106 pounds for the first 5 feet add 6 pounds per each inch over five feet A man who is 5’10” should weigh 166 lbs. For women: 100 pounds for the first 5 feet add 5 pounds per each inch over five feet A women who is 5’10” should weigh 150 lbs.

WHAT IS A HEALTHY BODY WEIGHT? : 

WHAT IS A HEALTHY BODY WEIGHT? Based on how we feel, weight history, fat distribution, family history of obesity-related disease, current health status, and lifestyle Current height/weight standards only provide guides

THE PHYSIOLOGIC SYSTEM REGULATED BY LEPTIN : 

THE PHYSIOLOGIC SYSTEM REGULATED BY LEPTIN HUNGER /SATIETY LEPTIN LEPTIN BETA CELLS