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Regulation of Organic Metabolism, Growth, and Energy Balance By: Hsiao-Fung Pu

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Metabolism • Anabolism synthesis of the molecules required for cell structure and function • Catabolism breakdown storage molecules and provision of energy for cell functions, and disposing of the waste products of these reaction 2


Compositions of Foods • Carbohydrate → monosaccharides • Protein → amino acids (GI tract → hepatic portal vein →Liver → venous system)

• Lipid → triglycerides (GI tract → chylomicrons → Lymph → venous system)

• Minerals • Vitamins • Water 3


Caloric Stores in Human

(Bern RM & Levy MN., Physiology, 5th Edition, 2004, Fig. 40-3)

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Overview of Energy Balance

(Bern RM & Levy MN., Physiology, 5th Edition, 2004, Fig. 40-1)

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Absorptive State • Ingested nutrients are entering the blood from the gastrointestinal tract • Energy: (1) metabolic heat (2) work (3) storage (an average meal requires approximately 4 h for complete absorption) 6


Postabsorptive State • Gastrointestinal tract is empty of nutrients and energy must be supplied by the body’s own stores (maintain blood glucose, because the brain normally utilize glucose for energy only)

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Major Metabolic Pathways of the Absorptive State

8 (Widmaier EP et al., Vander’s Human Physiology, 11st Edition, 2008, Fig. 16-1)


Lipoprotein Lipase • Located on the blood-facing surface of the capillary endothelium • Hydrolyze the very-low density lipoprotein (VLDL) to monoglycerides and fatty acids

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Major Metabolic Pathways of the Postabsorptive State

10 (Widmaier EP et al., Vander’s Human Physiology, 11st Edition, 2008, Fig. 16-2)


“Feasting” (insulin present)

Synthesis Fuel is glucose Storage molecules

“Fasting” (insulin absent)

Catabolism Diverse fuels Gluconeogenesis

11 (Widmaier EP et al., Vander’s Human Physiology, 11st Edition, 2008, Fig. 16-3)


• Normal total energy expenditure for an average adult equals 1500 to 3000 kcal/day. • The 180 g of glucose per day produced by gluconeogenesis in the liver and kidneys during fasting supplies 720 kcal: 180 g/day × 4 kcal/g = 720 kcal/day

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Glucose Sparing (Fat Utilization) • Most organs & tissues markedly reduced their glucose catabolism increase their fat utilization. This metabolic adjustment, termed glucose sparing, “spare” the glucose produced by the liver for use by the nervous system. • Many areas of the brain are capable of utilizing ketones for energy, and so as these substances being to build up in the blood after the first few days of a fast, the brain beings to utilize them, as well as glucose, for its energy source. 13


Sources of Blood Glucose During the Postabsorptive Period

(Bern RM & Levy MN., Physiology, 5th Edition, 2004, Fig. 40-5)

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Endocrine and Neural Control of the Absorptive and Postabsorptive States • • • •

Insulin Glucagon (effect on Liver) Epinephrine (from the adrenal medulla) Other hormones (cortisol, GH, thyroid hormone, sex steroids, etc.) • Sympathetic nerves to liver and adipose tissues 15


Effects of Insulin on Various Tissues

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(Widmaier EP. et al., Vander’s Human Physiology, 11st Edition, 2008, Fig. 16-6)


Summary of Glucose-Counterregulatory Controls

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(Widmaier EP. et al., Vander’s Human Physiology, 11st Edition, 2008, Table 16-4)


Diabetogenic Effect of Thyroid Hormones • Increase absorption of glucose from the intestine • Cause some degree of hepatic glycogen depletion • Glycogen-depleted liver cells are damaged • Liver take up less of the absorbed glucose • Accelerate the degradation of insulin 18


Effect of Starvation on Plasma Levels of Thyroid Hormones

(Ganong WF. Review of Medical Physiology, 20th Edition, Fig. 18-10)

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Effects of Cortisol on Organic Metabolism

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(Widmaier EP. et al., Vander’s Human Physiology, 11st Edition, 2008, Table 16-3)


Fuel Homeostasis in Prolonged Moderate Exercise Duration time: > 90 min SNS activity↑ EP secretion ↑ Insulin secretion↓ Glucagon secretion↑ Liver: ↑glycogenolysis & gluconeogenesis Adipose tissues: ↑lipolysis GH secretion ↑ Cortisol secretion↑ Muscle: ↑glucose uptake 21

(Widmaier EP et al., Vander’s Human Physiology, 11st Edition, 2008, Fig. 16-11)


Oral Glucose Tolerance Test (OGTT) • Fasting > 12 h Plasma Glucose: 70-105 mg/dl Oral 75 glucose/300 ml H2O Within 2 h: < 140 mg/dl • DM: Plasma Glucose: > 140 mg/dl (twice) Glucose in Urine (> 180 mg/dl in plasma) Plasma Glycohemoglobin: >7% (Ganong WF. Review of Medical Physiology, 22nd Edition, 2005, Fig. 19-8)

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OGTT

(Fox SI., Human Physiology, 5th Edition, 1996, Fig. 19-11)

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Effects of Chronic, Intense Exercise on the Human Body • Non-essential function (reproduction) shut down, so that nutrients can be directed primarily to muscle • Delay puberty • Exercise-induced amenorrhea

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Cholesterol • Precursor of plasma membranes, bile salts, steroid hormones • High plasma concentrations → atherosclerosis

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Plasma Cholesterol (Women vs. Men)

26 (Widmaier EP et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 5th Edition, 1990, Fig. 17-13)


Cholesterol • Normal range: 20 – 200 mg/dl • Borderline high: 200 – 239 mg/dl • High: above 240 mg/dl • Ingesting saturated FA (animal fat – red meats, most cheeses, and whole milk) →↑plasma cholesterol • Ingesting polyunsaturated FA (plant), or monounsaturated FA (olive or peanut oil) →↓plasma cholesterol 27


Low Density Lipoprotein (LDL) • • • • •

Main cholesterol carriers Deliver cholesterol to cells ↑deposition of cholesterol in arterial walls LDL-cholesterol complex: “BAD” cholesterol Estrogen: ↓plasma LDL (by increasing the LDL receptors in the liver) • Normal: < 150 mg/dl

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Cellular Uptake & Metabolism of Cholesterol

(â&#x2020;&#x201C;Cholesterol Synthesis) (acetyl-CoA:cholesterol acyltransferase)

29 (Ganong WF. Review of Medical Physiology, 22nd Edition, 2005, Fig. 17-29)


High Density Lipoproteins (HDL) • Acceptors of cholesterol from various tissues • Removal of cholesterol from cells and its secretion into the bile by the liver • HDL-Cholesterol complex: “GOOD” cholesterol • Smoking: ↓plasma HDL • Weight reduction & exercise: ↑plasma HDL • Estrogen: ↑plasma HDL • EPA (eicosapentaenoic acid): ↑plasma HDL • Norml: > 35 mg/dl 30


Growth (Involves Cell Division and Net Protein Synthesis) • Genetics • Endocrine function growth hormone, IGF-I, IGF-II, thyroid hormone, sex hormone, insulin, cortisol, etc. • Growth factors (mitogen → cell division) and growth inhibiting factors • Environmental factors nutrients (AA, FA, Vit., minerals) and Infection maternal malnutrition: growth retardation in the fetus, low birth weight, ↑infant mortality, stunting brain development, mental retardation 31


Growth of Different Tissues at Various Ages

(Ganong WF, Review of Medical Physiology, 22nd Edition, 2005, Fig. 22-12) 32


Intrauterine Growth (from Conception to Delivery) â&#x20AC;˘ Fetal mass increases 44 x 107 times After birth: 20-fold â&#x20AC;˘ Body length increases 3850 times After birth: 3-4 fold

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IGFs • Growth during early gestation: IGF-II • Growth during later gestation: IGF-I

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Growth Hormone Secretion throughout the Day

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Effect of GH and Insulin on Growth

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Growth hormone & IGF-I interact on the Epiphyseal Plates of Bone are as follows: (1) GH stimulates the chondrocyte precursor cells (prechondrocytes) and/or young differentiating chondrocytes) in the epiphyseal plates to differentiate into chondrocytes (2) the cells begin both to secrete IGF-I and to become responsive to IGF-I (3) IGF-I then acts as an autocrine or paracrine agent to stimulate the differentiating chondrocytes to undergo cell division 37


Fetal â&#x20AC;˘ Little or no effect â&#x20AC;˘ IGF-II, the secretion is independent of GH, is also a crucial mitogen during the prenatal period (for total body growth, for maturation of nervous system)

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During childhood • Excess: gigantism • Deficiency: dwarfism • Normal or elevated Laron Dwarfism (GH insensitivity syndrome) --- gene deletion or point mutation --- GH-R fail to respond to GH --- plasma IGF-I is markedly reduced

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Gigantism

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(Widmaier EP et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Fig. 11-29a)


Adult (after epiphyseal closure) • Excess: acromegaly (almost pituitary tumor) Deficiency: fat distribution randomly IGF-I and GH ↑amino acid uptake ↑synthesis of RNA and ribosomes ↑protein synthesis

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Acromegaly (I)

(Widmaier EP et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Fig. 11-29b, 42 c)


Acromegaly (II)

(Fox SR, Human Physiology, 5th Edition, 1996, Fig. 19.17)

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Epidermal Growth Factor • • • •

Lung maturation Birth weight is not affected ↑Adrenal and gut weight Stimulates gut muscle, enzyme maturation, gut size and content, improving the ability of the infant to absorb nutrients • Maturation of the fetal adrenal cortex, ↑expression of 3-hydroxysteroid dehydrogenase • Somker (mother) →↓EGFRs and affinity for EGF 44


Genetic, Maternal & Uterine Factors • The height of the mother correlates better with fetal size than the height of the father. • First-born infants are on the average 100 g heavier than subsequent infants • Maternal alcohol ingestion: fetal length and mental development • Fetal alcohol syndrome: microcephaly, mental retardation, midfacial hypoplasia, short palpebral fissures, wide-bridge nose, long philtrum (人中), and narrow vermilion border of the lips • Smoking causes not only retarded intrauterine growth but also decreased postnatal growth for as long as 5 years after parturition. • Maternal infection: toxoplasmosis, rubella, cytomegalovirus infection, herpes 45


(Grossman A, Clinical Endocrinology, 1st Edition, 1992, Fig. 59.2)

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Relative Importance of Hormones in Human Growth at Various Ages

(Ganong WF, Review of Medical Physiology, 22nd Edition, 2005, Fig. 22-13) 47


Effect of Thyroid Hormone on Metabolism of Thyroidectomized Rats

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(Ganong WF, Review of Medical Physiology, 22nd Edition, 2005, Fig. 18-10)


Normal and Abnormal Growth

(Ganong WF, Review of Medical Physiology, 22nd Edition, 2005, Fig. 22-14)

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The First Law of Thermodynamics â&#x20AC;˘ Energy can be neither created nor destroyed but can be converted from one form to another

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• ΔE = H + W ΔE: energy liberate H: heat (60%) --- maintain body temperature --- enzyme activity --- membrane permeability W: biological work (40%) --- external work: the movement of external objects by contracting skeletal muscles --- internal work : all other forms of work, including skeletal muscle activity not used in moving external objects 51


Calories • the amount of heat energy necessary to raise the temperature of 1 L water 1 degree: 1 kcal • 1000 cal = 1 kcal = 4184 joules • The heat capacity of human tissue is similar to that of water. If 1 kcal of heat is added to one kg of body tissue, the temperature of that tissue increases nearly 1℃.

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• If the cellular temperature were to drop 10 ℃, however, cellular enzymatic reaction rates would decreased by a factor of approximately 2.5 • Human metabolic activity, therefore, changes about 12% for every degree centigrade of change in body temperature

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Metabolic Rate â&#x20AC;˘ the amount of energy liberated per unit of time

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Basal Metabolic Rate (BMR) • the metabolic rate determined at rest in a room at a comfortable temperature in the thermoneutral zone (25 – 30 ℃) 12 – 14 h after the last meal • Falls about 10% - 15% during sleep • Adult human of average size is about 20 - 25 kcal/Kg BW/day, and requires the use of approximately 200 – 250 ml O2/min • ~40% of BMR is accounted for by the CNS ~20-30% of BMR by the skeletal muscle mass • absolute BMR: large animal > small animal • BMR/BW: large animal < small animal • women is slightly lower than man 55


Correlation Between Body Weight vs. Surface Area (black line) and Heat Production vs. Body Weight (red line)

(Ganong WF. Review of Medical Physiology, 22nd Edition, 2005, Fig 17-2) 56


Surface Area in Human • S = 0.007184 x W 0.425 x H 0.725 • S: surface area in m2 W: body weight in kg H: height in cm

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Caloric Value • In vitro: Carbohydrate: 4.1 kcal/g Fat: 9.3 kcal/g Protein: 5.3 kcal/g • In vivo: Carbohydrate: 4.1 kcal/g Fat: 9.3 kcal/g Protein: 4.1 kcal/g (exclude urea and related nitrogenous compounds) 58


Direct Method for Measuring Metabolic Rate

(Widmaier EP et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 8th Edition, 1990, Fig. 17-17) 59


Indirect Method for Measuring Metabolic Rate (Except O2 Debt is Being Incurred or Repaid)

60 (Widmaier EP. et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 8th Edition, 1990, Fig. 17-18)


61 (Widmaier EP. et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Table 16-5)


Thyroxine â&#x20AC;˘ Increases oxygen consumption and heat production of most body tissues except brain â&#x20AC;˘ Thyroxine increases proteins in inner mitochondrial membrane and reduce the amount of ATP to increase cell respiration and generate heat

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Body Mass Index (BMI) Weight (Kg)/Heigh2 (M2)

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Classification of Overweight and Obesity Based on Body Mass Index (BMI)

• • • •

Underweight Normal Overweight Obesity Class I Class II Class III (extreme)

< 18.5 18.5 – 24.9 25.0 – 29.9 30.0 – 34.9 35.0 – 39.9 > 40.0 64


Health Consequences of Overweight & Obesity • • • • • •

Diabetes Mellitus Type 2 Hypertension Hyperlipidemia and Dyslipidemia Arteriosclerotic heart disease & stroke Gallbladder disease, Osteoarthritis Cancers: uterine endometrium, breast, prostate, and colon • Sleep apnea: BMI > 30 • Menstrual irregularity, infertility, and polycystic ovarian syndrome 65


• Abdominal fat (“apples”, central or visceralabdominal obesity) are at greater risk for developing serious conditions such as diabetes and cardiovascular diseases than people whose fat is mainly in the lower body (“pears”, gluteal-femoral obesity) – on the buttocks and thighs. • High-risk abdominal obesity is defined as a waist measurement of >102 cm (>40 inches) in men and >88 cm (>35 inches) in women. • Adipose tissue cells in the abdomen are much more adept at breaking down fat stores and releasing the products into the blood. 66


Fat cells, synthesize and secrete a protein called leptin, which is a putative hormone that acts on the Central Nervous System to reduce appetite in persons with adequate energy reserves.

â&#x2020;&#x201C;NPY Release

(Widmaier EP. et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Fig. 16-14)67


Long-term Fasting • ↓sex steroids secretion • ↓thyroid hormones secretion • ↑adrenal glucocorticoids secretion

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Overview of a Current Concept of Regulation of Energy Stores

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(Bern RM & Levy MN, Physiology,

4th

Edition, 1998, Fig. 46-13)


Drugs Treatment (BMI > 30) • 食慾抑制劑 (刺激serotonine or adrenaline分泌或抑制 回收) (A) PPA (phenylpropanolamine) 感冒藥中成份,已被禁用,會增加年輕女性中 風機率,約可減6 Kg (B) prozao: 抗憂鬱劑,約可減12 Kg (C) dexfenfluramine: 會造成心瓣膜疾病及肺部 高壓之危險性 (D) fen-fen:會造成心瓣膜疾病,已禁用

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Drugs Treatment (BMI > 30) • 熱量消耗劑 主要成份: ephedrine與caffiene, 約可減 16 Kg • 消化抑制劑 (A) xenical: lipase inhibitor, 約可減4 Kg, 會有 腹瀉產生 (B) 纖維素: 主要用於DM及高血脂病人,約可減 4 Kg

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Eating Disorders (almost in adolescent girls & young women) • Anorexia Nervosa afraid of gaining weight and reduced food intake so severely < 25 years old ↓15% BW ↓heart rate (< 60/min) Loss of menstrual periods ( 3 times) Low blood pressure Low body temperature Altered secretion of many hormones Die of starvation 72


(Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Table 22-4) 73


(Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Table 22-6) 74


Eating Disorders (almost in adolescent girls & young women)

â&#x20AC;˘ Bulimia Nervosa: Recurrent episodes of being eating Self-induced vomiting, laxatives or diuretics Strict dieting, fasting or vigorous exercise in order to prevent weight gain

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(Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Table 22-5)76


(自殘) (自殺)

(Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Table 22-7) 77


Endocrine Changes in Anorexia Nervosa and Bulimia Nervosa

78 (Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Table 22-8)


Gastric Bypass Operation for Morbid Obesity

(Wilson JD, et al., Williams Textbook of Endocrinology, 9th Edition, 1998, Fig. 22-14) 79


From: 聯合報

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Effect of Starvation on the Food Stores of the Body

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• Exercise plus caloric restriction causes lose more fat and less protein than with caloric restriction alone • Fat: 9.3 kcal/g 1000 kcal/day ÷ 9.3 kcal/g = 107.5 g/day 107.5 g/day × 7 day = 752.7 g/week another 75.3 g water lost Total: 828 g/week

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Summary of National Research Council Dietary Recommendations

83 (Widmaier EP. et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Table 16-8)


Mechanisms of Heat Exchange between the Body and the Environment

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-4) 84


Relationship of Skin’s Insulating Capacity to Skin Blood Flow

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(Widmaier EP. et al., Vander’s Human Physiology, 5th Edition, 1990, Fig. 17-24)


Static Discharge Frequency of Cold and Warm Nerve Fibers as a Function of Skin Temperature

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-2)86


Summary of Thermoregulatory Effector Responses to Decreased Core and Skin Temperature

87

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Table 27-1)


Involuntary Muscle Activity • The upper limit of shivering-induced heat production is perhaps only a 3-fold increase above resting levels, and shivering is inefficient for two reasons: 1. shivering → ↑ activated muscle’s blood flow → ↑ local skin surface temperature → ↑ heat loss 2. shaking motions of shivering increase heat loss by convection 88


Summary of Thermoregulatory Effector Responses to Increased Core and Skin Temperature

89 (Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Table 27-2)


Summary of Temperature-regulating Mechanisms

90

(Widmaier EP. et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Fig. 16-18)


Sweating â&#x20AC;˘ 2-3 million sweat glands distributed over most of the body surface â&#x20AC;˘ The rate of sweat evaporation depends upon environmental humidity and the rate of air movement at the skin surface (2L/h).

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-8)

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Thermoneutral Zone : 25 - 30 ℃ (Environmental Temperature) Thermoneutral Zone: 36.8 – 37.2 ℃ (Hypothalamus Temperature) at this range, without either sweating or shivering being initiated 92


Measurement of Core Temperature 窶「 Both the tympanic membrane temperature and the rectal temperature are reasonably accurate estimates of core temperature. 窶「 The oral (sublingual) temperature is also representative, averaging approximately 0.6 邃ネower than rectal or tympanic membrane temperature.

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Survival Range of Body Temperature in Humans

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-9)94


Circadian Rhythm in Core Temperature

(Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-11)95


Menopause — Hot Flashes • Estrogen deficiency narrows the hypothalamic thermoneutral zone from 0.4 to less than o.1℃

96 (Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Fig. 27-12)


Tolerance • Dry air: 130 ℃ for 20 min or longer • Very moist air: 46 ℃ for only few min • Body temperature tolerance range: 21-24 ℃

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Long Term Acclimatization • Heat: ↑mineralocorticoid hormone secretion (aldosterone) ↓sodium concentration in sweat • Cold: ↑metabolic rate

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Fever • Fever is an elevation of body temperature due to a “resetting of the thermostat” in the hypothalamus. • The most common cause of fever is infection, but physical trauma and stress can also induce fever.

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Fever Pathway

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(Widmaier EP et al., Vanderâ&#x20AC;&#x2122;s Human Physiology, 11st Edition, 2008, Fig. 16-19)


Hyperthermia â&#x20AC;˘ Hyperthermia is defined as an increase in core temperature that does not represent a new set point for control of hypothalamic temperature. â&#x20AC;˘ Exercise increases energy expenditure and heat production, and despite activation of heat loss mechanisms, core temperature increases. 101


Factors Affecting Heat Production Diet-induced thermogenesis: ↑10-20% Hormones: EP, NE, thyroid hormone Exercise: ↑voluntary skeletal muscle contraction Drug-induced malignant hyperthermia: most common in patients receiving antipsychotic medications (alter brain neurotransmitter levels and can provoke inappropriate catecholamineinduced vasoconstriction and increased heat production) • Malignant hyperthermia (during anesthesia): rare genetic disorder; muscle rigidity and increased energy expenditure develop from interaction of specific anesthetics with skeletal muscle proteins involved with calcium release and storage 102 • • • •


Comparison of Thermoregulatory Responses to Fever and Exercise at Matched Core Temperature

103 (Rhoades R and Pflanzer R, Human Physiology, 4th Edition, 2003, Table 27-5)


Benefit of Fever • Antibody production ↑ • Inhibits microorganisms growth • Slow the growth of some tumors

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Heat Exhaustion Core temperature ↑ → vasodilation and sweating ↑ → CO and peripheral resistance ↓ → blood volume, BP & body temperature↓ Symptoms: dizziness and nausea Therapy: oral fluid replacement 105


Heat stroke • Exposure to hot & humid environment • Conduction and convection of heat from the skin to the environment decrease (Sweating ↓) • Body temperature ↑↑↑ ( 41-42℃) • Symptoms: dizziness, abdominal distress, absence of sweating, delirium, loss of consciousness or death

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Regulation of Organic Metabolism Growth and Energy Balance 0524