Metabolism

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Metabolism

• Chapter 19

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Objectives for Chapter 19

• To understand the regulation of body growth and
  metabolism by
• Adipocyte hormones
• Pancreatic hormones
• Suprarenal hormones
• Thyroid hormones

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Nutritional Requirements

• Living tissue maintained by constant
  expenditure of energy (ATP)
• ATP derived from glucose, fatty acids, ketones,
  amino acids, and others
• Energy of food is commonly measured in
  kilocalories (1 kcal 1000 calories)
• Carbohydrates and proteins yield 4kcal/gm
  fats-9kcal/gm

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Metabolic Rate and Caloric Requirements

• Metabolic rate (MR) total rate of body
  metabolism
• amount of O2 consumed by body/min
• Basal metabolic rate (BMR) MR of awake relaxed
  person 1214 hrs after eating
• and at a comfortable temperature
• BMR depends on age, sex, body surface area,
  activity level
• Strongly influenced by thyroid hormone levels
• Hyperthyroidism high BMR
• Hypothyroidism low BMR

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Metabolism

• All chemical reactions occurring in the body
• Includes synthesis and energy storage reactions
  (anabolism)
• and energy liberating reactions (catabolism)
• Anabolic Requirements
• Anabolic reactions synthesize DNA and RNA,
  proteins, fats, and carbohydrates
• Must occur constantly to replace molecules that
  are hydrolyzed in catabolic reactions

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Turnover Rate

• Rate at which a molecule is broken down and
  re-synthesized
• Average turnover
• Carbs 250 g/day
• Some glucose reused so net need 150 g/day
• Protein 150 g/day
• Some reused for protein synthesis so net need 35
  g/day
• 9 essential amino acids must be supplied in diet
  (cannot be synthesized)
• Fats 100 g/day
• Little required in diet can be synthesized from
  Carbs
• 2 essential fatty acids must be supplied in diet

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Vitamins

• Small organic molecules serve as coenzymes
• in metabolism or have highly specific functions
• Must be obtained in diet because
• body does not produce them, or does in
  insufficient amounts
• Placed in 2 classes
• Fat-solubles include A, D, E, and K
• Water-solubles include B1, B2, B3, B6, B12,
  pantothenic acid, biotin, folic acid, and vitamin
  C
• Serve as coenzymes in metabolism

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Minerals (Elements)

• Needed as cofactors for specific enzymes and
  other critical functions
• Daily requirements Sodium, potassium,
  magnesium, calcium, phosphate, and chloride
• Trace elements required in small amounts/day
  Iron, zinc, manganese, fluorine, copper,
  molybdenum, chromium, and selenium

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Free Radicals

• Highly reactive and oxidize or reduce other atoms
• Because of an unpaired electron in their outer
  orbital
• Major free radicals reactive oxygen or reactive
  nitrogen species
• contain oxygen or nitrogen with an unpaired
  electron
• NO radical, superoxide radical, and hydroxyl
  radical
• Serve important physiological functions
• Help to destroy bacteria
• Can produce vasodilation
• Can stimulate cell proliferation

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Free Radicals

• In excess exerts oxidative stress contributes
  to disease states
• Can damage lipids, proteins, and DNA
• Promote apoptosis, aging, inflammatory disease,
  degenerative, and other diseases and malignant
  growth
• Underlying cause widespread production of
  superoxide radicals by mitochondria
• Bodys protection against oxidative stress
• Enzymes that neutralize free radicals
  superoxide dismutase (SOD), catalase, and
  glutathione peroxidase
• Nonenzymes that react with free radicals by
  picking up unpaired electrons glutathione,
  vitamins A, C, E

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Reactive Oxygen Species (ROS) Production and
Defense
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Flow Chart of Energy Pathways in the Body

• In the top and bottom molecules found within
  cells
• Blood contains
• glucose, fatty acids, amino acids, and others
  that can be used for energy
• circulating energy substrates from digestion or
  energy reserves (glycogen, protein, or fat)

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Control of Adipose Tissue Levels

• Adipostat negative feedback loops to defend
  maintenance of a certain amount of adipose tissue
• Adipocytes store and release fat under hormonal
  control
• May release their own hormone(s) influence
  metabolism
• Adipocytes secrete regulatory hormones
  (adipokines)
• when their PPAR? (peroxisome proliferator
  activated receptors) are activated
• Regulate hunger, metabolism, and insulin
  sensitivity
• e.g., cause muscle to become more responsive to
  insulin
• Include adiponectin, leptin, resistin, TNF?, and
  retinol-binding protein 4

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Endocrine Functions of Adipocytes

• TNF?, resistin, retinol BP4, leptin increased
  in obesity and Type II diabetes
• All appear to reduce sensitivity of muscle to
  insulin (insulin resistance)
• Leptin signals the hypothalamus on how much fat
  is stored, thereby regulating hunger and food
  intake
• Adiponectin decreased in obesity and Type II
  diabetes
• has an insulin-sensitizing, anti-diabetic effect

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Low Adiposity Starvation

• Starvation and malnutrition diminish immune
  function
• Low adipose levels cause low leptin levels
• Helper T cells have leptin receptors
• Low leptin can lead to diminished immune function
• Leptin may play role in timing of puberty and in
  the amenorrhea of underweight women

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Obesity

• Obesity diagnosed by body mass index BMI wh2
  
• w weight in kilograms (lbs. 2.2)
• h height in meters (inches 39.4)
• Healthy weight is considered to be a BMI between
  19 25
• Obesity defined as BMI gt 30
• 60 of pop in US is either overweight (BMIgt25) or
  obese (BMIgt30)
• Childhood obesity increase in adipocyte size
  and number
• Weight gain in adulthood is due mainly to
  increase in adipocyte size

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Regulation of Hunger

• Partially controlled by hypothalamus
• Lesions in ventromedial area produce hyperphagia
  and obesity in animals
• Lesions in lateral area produce hypophagia
• Involves a number of NTs
• Endorphins promote overeating
• Norepinephrine promotes overeating
• Serotonin suppresses overeating
• successful diet pills Redux and fen-phen worked
  by elevating brain serotonin (banned because of
  heart valve side effects)

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Regulation of Hunger

• Arcuate nucleus (hypothalamus) neurons send
  axons to paraventricular nucleus and lateral
  hypothalamus
• One neuron type produces MSH which suppresses
  hunger
• By acting on its receptor, melanocortin 4
  receptor
• Obesity associated with mutations in this
  receptor that leads to increased hunger and
  decreased energy expenditure
• Another produces neuropeptide Y and
  agouti-related peptide which increase hunger

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Hormonal Signals Regulate Feeding / Energy
Expenditures

• CNS integrates sensory information with other
  information (smell, taste,
• psychological factors) to help regulate hunger
  and satiety, energy
• expenditures as well as growth and reproduction

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Regulation of Hunger Signals from Stomach and SI

• Involves polypeptide hormones secreted by the
  stomach and SI
• Ghrelin stimulates hunger via effect in arcuate
  nucleus
• Secreted by stomach at high levels when stomach
  is empty
• and low levels when full
• CCK from SI promotes satiety
• Levels rise during and immediately after a meal
• Ghrelin and CCK regulate hunger on short-term,
  meal-to-meal basis
• PYY secreted by SI in proportion to caloric
  content of food
• Decreases hunger by signaling arcuate to decrease
  neuropeptide Y and stimulate MSH
• Seems to serve intermediate level of control
  (injections reduce appetite for 12 hrs)

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Regulation of Hunger

• Influenced by leptin a satiety factor secreted
  by adipocytes and involved in long-term
  regulation
• Secretion increases as stored fat increases
• Signals body's level of adiposity
• Stimulates arcuate to suppress Neuropeptide Y and
  agouti-related peptide and stimulate MSH
• Insulin may play role in satiety
• Suppresses Neuropeptide Y

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The Action of Leptin

• Leptin crosses the BBB
• To affect NTs released by neurons in the arcuate
  nucleus
• Influences other hypothalamic nuclei
• Which in turn reduce appetite and increase
  metabolic rate
• Insulin stimulates adipose cells to secrete
  leptin
• And is able to cross the BBB acts similar to
  leptin

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Calorie Expenditure of Body

• Has 3 components
• Number of calories used at BMR makes up 60 of
  total
• Number used in response to temperature changes
  and during digestion/absorption (adaptive
  thermogenesis) make-up 10 of total
• Starvation can lower MR 40
• Eating raises MR 25-40 (thermic effect of food)
• Number used during physical activity depends on
  type and intensity

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Absorptive and Postabsorptive States

• Absorptive state 4 hour period after eating
• Energy substrates from digestion are used and
  deposited in storage forms (anabolism)
• Postabsorptive or fasting state follows
  absorptive state
• Energy is withdrawn from storage (catabolism)

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Hormonal Regulation of Metabolism

• Balance between anabolism and catabolism
• depends on levels of insulin, glucagon, GH,
  thyroxine, and others

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Hormonal Interactions in Metabolic Regulation

• Different hormones may work together
  synergistically or
• May have antagonistic effects on metabolism

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Pancreatic Islets of Langerhans

• Contain 2 cell types involved in energy
  homeostasis
• a cells secrete glucagon when glucose levels are
  low
• By stimulating glycogenolysis in liver
• ß cells secrete insulin when glucose levels are
  high
• By promoting glucose uptake by tissues
• Normal fasting glucose level 65105 mg/dl
• Insulin and glucagon prevent levels from rising
  above 170mg/dl after meals
• Or falling below 50mg/dl between meals

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Insulin

• Overall effect is to promote anabolism
• Promotes storage of digestion products
• Inhibits breakdown of fat and protein
• Inhibits secretion of glucagon
• Stimulates insertion of GLUT4 transporters in
  cell membrane of skeletal muscle, liver, and fat
• Transports by facilitated diffusion

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Insulin Secretion

• Rise in blood glucose causes more glucose to
  enter ?-cells results in
• Increased ATP production
• Closes K channels, so that K cannot leave the
  cell
• Produces a depolarization which
• Opens VG Ca2 channels, allowing entry of Ca2
• Ca2 stimulates vesicles containing insulin to
  undergo exocytosis

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Insulin Secretion

• Rise in plasma glucose concentration acts on
  ?-cells
• leads to opening of K channels producing
  depolarization
• Depolarization opens voltage-gated Ca2 channels
• promoting exocytosis of vesicles containing
  insulin
• A rise in plasma glucose leads to rise in insulin
  secretion
• At the same time, inhibits glucagon from ?-cells

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Glucagon

• Maintains blood glucose concentration above
  50mg/dl
• Stimulates glycogenolysis in liver
• Stimulates gluconeogenesis, lipolysis, and
  ketogenesis
• Skeletal muscle, heart, liver, kidneys use fatty
  acids for energy

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Catabolism During Fasting

• Increased glucagon secretion and decreased
  insulin secretion during fasting favors
  catabolism. Hormonal changes promote release of
  glucose, fatty acids, ketone bodies, and amino
  acids into blood (liver secretes glucose derived
  both from glycogen breakdown and conversion of
  amino acids in gluconeogenesis

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Effects of ANS on Insulin and Glucagon

• ANS innervates islets
• Parasympathetic division activated during meals
• stimulates both GI function and secretion of
  insulin
• Sympathetic division inhibits insulin secretion
• stimulates glucagon secretion
• Glucagon and epinephrine work together to produce
  a stress hyperglycemia
• when the sympathoadrenal system is activated

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Effects of Intestinal Hormones

• Insulin levels increase more after glucose
  ingestion than after intravenous glucose infusion
• Due to hormones secreted by SI after meals "in
  anticipation" of glucose rise
• GIP and GLP-1 from SI are powerful stimulators of
  insulin secretion

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Effect of Feeding and Fasting on Metabolism

• Metabolic balance
• tilted toward anabolism by feeding (absorption)
• Toward catabolism by fasting
• Inverse relationship between insulin and glucagon
  secretion
• Insulin secretion rises, glucagon falls during
  food absorption
• Opposite occurs during fasting

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Diabetes Mellitus

• Hyperglycemia characterized by chronic high
  blood glucose levels
• Type I (insulin dependent or IDDM) due to
  insufficient insulin secretion
• 5 of diabetics are this type
• Type II (insulin independent or NIDDM) due to
  lack of effect of insulin
• 95 of diabetics are this type

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Type I Diabetes

• Autoimmune disease ß cells progressively
  destroyed by killer T lymphocytes
• Glucose is unable to enter resting muscle or
  adipose cells
• Rate of fat synthesis lags behind rate of
  lipolysis
• Fatty acids are converted to ketone bodies,
  producing ketoacidosis
• Increased glucagon levels stimulate
  glycogenolysis in liver

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Type II Diabetes

• Slow to develop
• Has multigene inheritance pattern
• Genetic tendency is increased by obesity
• Involves insulin resistance
• Usually accompanied by normal-to-high insulin
  levels
• Is not usually accompanied by ketoacidosis
• Treatable by exercise and diet
• Exercise increases insertion of GLUT4s into
  skeletal muscle

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Effects of Uncontrolled IDDM can lead to coma
and death
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Oral Glucose TolerancePrediabetic and Type II

• Glucose concentrations
• Insulin values following ingestion of glucose
  normal, Type II, Prediabetic

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Hypoglycemia

• Reactive hypoglycemia oversecretion of insulin
  due to an exaggerated response of ? cells to a
  rise in glucose
• Occurs in people who are genetically predisposed
  to type II diabetes
• Symptoms include tremors, hunger, weakness,
  blurred vision, and confusion

Idealized oral glucose tolerance test on a person
with reactive hypolgycemia
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Metabolic Regulation

• Anabolic effects of insulin are antagonized by
  hormones of adrenals, thyroid, and anterior
  pituitary on carbohydrate and lipid metabolism,
  however
• Insulin, thyroxine, and GH can act
  synergistically to stimulate protein synthesis

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Metabolic Effects of Catecholamines

• Similar to those of glucagon
• Stimulate glycogenolysis and release of glucose
  from the liver
• Stimulate lipolysis and release of fatty acids
  from adipose tissue
• Actions occur in response to glucagon during
  fasting
• And in response to catecholamines during stress
• Provides energy substrates in anticipation of
  intense physical activity
• Glucagon and epinephrine both mediated by cAMP

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Epinephrine and Glucagon Exert Effects on
Metabolism

• cAMP 2nd messenger in epinephrine and glucagon
  signaling on liver and adipose tissue metabolism

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Metabolic Effects of Cortisol

• Cortisol secreted in response to ACTH
• Often released in response to stress, including
  fasting and exercise
• Where it supports effects of glucagon
• Promotes lipolysis, ketogenesis, and protein
  breakdown
• Protein breakdown increases amino acid levels for
  use in gluconeogenesis in liver
• All of these help to compensate for a state of
  prolonged fasting or exercise

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Metabolic Effects of Glucocortiods

• Catabolic actions of glucocorticoids
• help raise the blood concentration of glucose
• and other energy-carrier moleculses

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Thyroxine (T4)

• Thyroid secretes mostly tetraiodothyronine
  (thyroxine) and a little triiodothyronine (T3) in
  response to TSH
• T3 Active form stimulates the rate of cell
  respiration
• Thyroxine converted to T3 in target cells due to
  lowering ATP concentrations
• Sets BMR by regulating cell respiration
• Necessary for growth and development, especially
  of the CNS
• Increases metabolic heat (calorigenic effect)
• Essential for cold adaptation

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Basal Metabolic Rate (BMR)

• 2 components one independent of and one
  regulated by thyroxine action
• Thyroxine acts to set the BMR
• BMR used as an index of thyroid function
• Hypothyroid basal O2 consumption 30 lower
  than normal
• Hyperthyroid basal O2 up to 50 higher than
  normal
• Normal thyroxine level required for growth and
  proper development of CNS in children
• Required to maintain a balance of anabolism and
  catabolism
• Too low or high protein breakdown and muscle
  wasting