1. Dietary Balances; Regulation of Feeding; Obesity and Starvation
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine

2. Energy Intake and Output
used or stored for later use (fat)
appropriate balanced intake (proteins, carbohydrates, fats, minerals, and vitamins)
1 g carbohydrates – 4.1 Cal (98% – 4(17 kJ)
1 g fats – 9.3 Cal (95% – 9 (38 kJ))
1 g proteins – 4.35 kJ (92% – 4 (17 kJ))
45%, 40%, 15% (average Americans)

4. 30-50 g of protein per day (20-30 g are degraded)
partial proteins (inadequate quantities of certain essential amino acids)
protein of corn has almost no tryptophan
protein-deficiency syndrome – kwashiorkor
carbohydrates and fats – protein sparers

7. nitrogen excretion can be used to assess protein metabolism (16% nitrogen)
90% of nitrogen is excreted in the urine (urea, uric acid, creatinine), 10% by feces
rate of protein breakdown (g) =
N2(urine) x 1.1 x 6.25 (100/16)
negative or positive nitrogen balance

8. “respiratory quotient” – ratio of CO2 production to O2 utilization (1h and more)
fat utilization (0.7), carbohydrates (1.0), proteins (0.8)
excess hydrogen atoms
right after meal close to 1.0; 8-10 h after meal about 0.7; in diabetes melitus always about 0.7

9. Regulation of Food Intake and Energy Storage
only 27% of the energy ingested normally reaches the functional systems of the cells
food intake, energy expenditure and fat storage – environmental, cultural and genetic factors + physiological control
“epidemics” of obesity (64% & 33%)
2000 Cal daily expenditure of energy ( Cal)

10. Neural Centers Regulate Food Intake
sensation of hunger (rhythmical contractions of stomach and restlessness)
appetite –desire for particular type of food
feeling of satiety

12. lateral nuclei of the hypothalamus – feeding center (hyperphagia, inanition)
operates by exciting the motor drives to search for food
ventromedial nuclei of the hypothalamus – satiety center (aphagia, hyperphagia)
other centers also play a major role (arcuate!), hormonal secretion (thyroid and adrenal glands, pancreatic islet cells)

13. integration of neural signals from the gastrointestinal tract (stomach filling), chemical signals from nutrients in the blood, signals from gastrointestinal hormones, hormones released by adipose tissue and signals from the cerebral cortex (sight, smell, and taste)
feeding behavior
orexigenic and anorexigenic substances and receptors – therapeutic sites

16. Neurons and Neurotransmitters in the Hypothalamus
pro-opiomelanocortin (POMC) neurons
α-MSH (α-melanocyte-stimulating hormone)
CART (cocaine and amphetamine related transcript)
neurons that produce orexigenic substances
NPY (neuropeptide Y)
AGRP (agouti-related protein)

17. activation of POMC neurons  decreases food intake and increases energy expenditure
activation of NPY-AGRP neurons  increases food intake and reduces energy expenditure
major targets for: leptin, insulin, cholecystokinin (CCK), and ghrelin

18. POMC neurons release α-MSH (acts on melanocortin receptors found especially in neurons of the paraventricular nuclei)
at least five subtypes of melanocortin receptors
MCR-3 and MCR-4 are especially important in regulating food intake and energy balance
activation of these receptors reduces food intake while increasing energy expenditure
inhibition has an opposite effect

19. MCR activation is mediated by activation of nucleus tractus solitarius (sympathetics)
defective signaling of the melanocortin pathway is associated with extreme obesity
mutations of MCR-4 – most common known monogenic (single-gene) cause of human obesity (5-6% of early-onset severe obesity in children)

20. AGRP is a natural antagonist of MCR-3 and MCR-4 receptors
role of AGRP in normal physiologic control of food intake is unclear
excessive formation of AGRP in mice and humans, due to gene mutations, is associated with increased food intake and obesity

21. NPY (arcuate nuclei) – when energy stores of the body are low – stimulates appetite + firing of the POMC neurons is reduced = decreased activity of the melanocortin pathway and further stimulated appetite

23. Factors That Regulate Quantity of Food Intake
short-term regulation – preventing overeating at each meal
long-term regulation – maintenance of normal quantities of energy stores in the body

24. Short-Term Regulation
What turns off the eating?
distending of gastrointestinal tract (stomach and the duodenum – vagus nerve)
humoral and hormonal factors
cholecystokinin (CCK) – fat
peptide YY from the ileum and colon – fat, ??
glucagon-like peptide (GLP) from intestines – enhances glucose-dependent insulin production and secretion from the pancreas – suppress appetite

25. ghrelin – oxyntic cells of the stomach and intestine, concentrations rise during fasting, fall rapidly after a meal; administration of ghrelin increases food intake in experimental animals; ?
oral receptors (experiment with esophageal fistula; chewing, salivation, swallowing, and tasting – shorter duration (20-40 min))

26. Intermediate and Long-Term Regulation
depends on nutritional status of the body
glucostatic, aminostatic and lipostatic theories of regulation
glucoreceptor ( GUK increases the rate of firing) and glucosensitive ( GUK decreases the firing) neurons in the hypothalamus

27. Temperature Regulation and Food Intake
exposition to cold – increased feeding
interaction within the hypothalamus:
increases metabolic rate
provides increased fat for insulation

28. Feedback from Adipose Tissue
hypothalamus senses energy storage through the actions of leptin, a peptide hormone released from adipocytes
POMC neurons of the arcuate nuclei and neurons of the paraventricular nuclei:
 appetite stimulators (NPY i AGRP)
activation of POMC neurons (α-MSH)
 substances that decrease apetite (CRH)
increased sympathetic nerve activity
 insulin secretion by the pancreatic β cells

30. in mice or humans with mutations that render their fat cells unable to produce leptin or mutations that cause defective leptin receptors in the hypothalamus – marked hyperphagia and morbid obesity
in most obese humans – no deficiency of leptin production
many other mechanisms, questionable summary

31. Obesity – excess of body fat
BMI = mass (kg) / hight2 (m2)
25-30 – overweight, 30 – obese
measurment of total body fat (skin-fold thickness, bioelectrical impedance, or underwater weighing; 25% & 35%)
obesity results from greater energy intake than energy expenditure

32. for each 9.3 Cal (38,9 kJ ) of excess energy – 1 gram of fat is stored
1/3 energy used each day by the average person goes into muscular activity (2/3)
increase in physical activity!

33. Psychological factors
three meals a day and that each meal must be filling
during or after stressful situations (death of a parent, a severe illness, or even mental depression)
eating can be a means of releasing tension

34. Childhood Overnutrition
rate of formation of new fat cells
number of fat cells in obese children is often as three times that in normal children
hyperplastic and hypertrophic obesity
new adipocytes can differentiate from fibroblast-like preadipocytes at any period of life

35. Neurogenic Abnormalities
lesions in the ventromedial nuclei of the hypothalamus – tumors
functional organization of the hypothalamic or other neurogenic feeding centers in obese individuals may be different
abnormalities of neurotransmitters or receptor mechanisms

36. Genetic Factors obesity definitely runs in families
identical twins mass is usually within 1.5, or 2.5 kg
20-25% of cases of obesity may be caused by genetic factors
mutations of MCR-4
congenital leptin deficiency
mutations of the leptin receptor

37. Treatment of Obesity
reducing energy intake or/and increasing energy expenditure
large quantities of "bulk“ (non-nutritive cellulose substances, distention)
prevent vitamin deficiencies
amphetamines, sibutramine – dangerous, overexcite sympathetic nervous system and raise pressure, addiction

39. altering lipid metabolism
orilistat (a lipase inhibitor) – reduces the intestinal digestion of fat
loss of fat-soluble vitamins in the feces
increase in physical activity
various surgical procedures (gastric bypass surgery and gastric banding surgery)

41. Inanition lack of food, or psychological and hypothalamic disorders
anorexia nervosa – reduction in food intake caused primarily by diminished appetite, nauseated by food
cachexia – weight loss greater than that caused by reduced food intake alone (tumors, AIDS)

42. Starvation tissues preferentially use carbohydrate for energy
protein depletion: rapid depletion at first, then greatly slowed depletion, and, finally, rapid depletion again shortly before death
gluconeogenesis decreases to 1/5
state of ketosis (β- hydroxybutyrate – brain)

44. Body Temperature Regulation and Fever

45. Normal Body Temperatures
“core” temperature = ± 0,6 ºC (± 1 ºF) (nude person exposed to air temperatures ºC, beautifully designed control system)
skin temperature rises and falls with the temperature of the surroundings (ability to lose heat to the surroundings)

46. Normal Core Temperature
range of normal temperatures (36-37,5 ºC)
average normal core temperature 36,5-37 ºC (measured orally; rectally 0,5 ºC higher)
regulatory mechanisms are not perfect: temperature increases during exercise and varies with temperature extremes of the surroundings
balance between heat production and heat loss

48. Heat Production heat – principal by-product of metabolism
metabolic rate of the body:
basal rate of metabolism
muscle activity
effect of thyroxine, (hGH, testosterone)
effect of sympathetic stimulation
increased chemical activity in the cells
thermogenic effect of food

49. Heat Loss
heat is generated in deep organs: liver, brain, and heart, and in the skeletal muscles
heat is lost to the air via skin
rate at which heat is lost:
how rapidly heat can be conducted from where it is produced to the skin
how rapidly heat can then be transferred from the skin to the surroundings

50. Insulator System of the Body
skin, subcutaneous tissues (fat) – insulator
conduction of heat through fat = 1/3 conduction through other tissues
insulator properties of female body are better than male body

51. Blood Flow to the Skin from the Body Core
enables heat to be conducted from the core of the body to the skin
especially important is a continuous venous plexus
rate of blood flow into the skin venous plexus can vary tremendously (0-30% CO)

54. skin is an effective controlled "heat radiator" system
flow of blood to the skin is a most effective mechanism for heat transfer from the body core to the skin
vasoconstriction of the arterioles and the arteriovenous anastomoses that supply blood to the venous plexus of the skin is controlled almost entirely by the sympathetic nervous system

55. Basic Physics of How Heat Is Lost from the Skin Surface
radiation (about 60%, infrared heat rays, a type of electromagnetic wave (5-20 μm), in all directions)
conduction (about 3% direct conduction from to solid objects, about 15% to air – convection (currents), suspension in water!)
evaporation (evaporation of 1g water – 0.58 Cal (2,5 kJ) heat, insensibly and evaporation of sweat, necessary cooling mechanism at very high air temperatures)

57. Effect of Clothing
increasing the thickness of the so-called private zone of air + decreasing air currents
rate of heat loss from the body by conduction and convection (to 1/2, or 1/6 – arctic-type clothing)
coating the inside of clothing with a thin layer of gold – reflects radiant heat back
extreme caution against allowing the clothing to become wet

58. Sweating
starts by stimulation of the anterior hypothalamus-preoptic area in the brain by electricity or by excess heat
nerve impulses are transmitted in the autonomic pathways to the spinal cord and then through sympathetic outflow to the skin everywhere in the body

59. sweat glands are innervated by cholinergic nerve fibers (but that run in the sympathetic nerves along with the adrenergic fibers)
they can also be stimulated by epinephrine or norepinephrine circulating in the blood

60. Mechanism of Sweat Secretion
deep subdermal coiled portion – secretes the sweat (primary or precursor secretion)
duct portion (modify concentrations of constituents)

62. Primary secretion active secretory product of the epithelial cells
composition is similar to that of plasma (Na+ = 142 mmol/L, a Cl- = 104 mmol/L), does not contain plasma proteins

63. Reabsorption of ions
slight stimulation – most of Na+ and Cl- are reabsorbed (concentration of each falls to as low as 5 mmol/L)
this reduces the osmotic pressure of the sweat fluid to such a low level that most of the water is also reabsorbed, which concentrates most of the other constituents (urea, K+, lactic acid)

64. strong stimulation – Na+ and Cl- are reabsorbed to concentrations of mmol/L, little of the water is reabsorbed – significant loss of NaCl

65. Acclimatization. Role of Aldosterone
normal unacclimatized person ~ 1L/h sweat
after 1-6 weeks ~ 2-3 L/h sweat
removing 10x more heat from the body
change in the internal sweat gland cells to increase their sweating capability
better conservation of body salt – increased secretion of aldosterone (decreases loses from g/day to 3-5 g/day)

66. Loss of Heat by Panting substitute mechanism due to:
surfaces often covered with fur
skin of most lower animals is not supplied with sweat glands
panting center is associated with pneumotaxic respiratory center in the pons
evaporation of saliva from the tongue, without increase in alveolar ventilation

69. Role of the Hypothalamus
experiments with use of a thermode
principal areas in the brain for temperature control are the preoptic and anterior hypothalamic nuclei of the hypothalamus
large numbers of heat-sensitive neurons
about one-third as many cold-sensitive neurons
heating of preoptic area – profuse sweating and vasodilation in the skin

70. Detection of Temperature
temperature receptors in skin and in a few specific deep tissues (spinal cord, abdominal viscera, around the great veins)
in the skin: cold receptors (far more) and warmth receptors
in deep tissues: function differently from the skin receptors because they are exposed to the body core temperature, they detect mainly cold

71. Integration of the Central and Peripheral Temperature Signals
area of the hypothalamus that is located bilaterally in the posterior hypothalamus approximately at the level of the mammillary bodies
combination and integration of signals from the preoptic area and from elsewhere in the body

72. Temperature-Decreasing Mechanisms
vasodilation
in the skin (inhibition of the sympathetic centers in the posterior hypothalamus), 8x  rate of heat transfer to the skin
sweating
rise above 37 ºC (critical level), 1 ºC 10x  removal of heat by evaporation
decrease in heat production
inhibition of shivering and chemical thermogenesis

74. Temperature-Increasing Mechanisms
vasoconstriction
in the skin (stimulation of the posterior hypothalamic sympathetic centers)
piloerection
hairs "standing on end", not important in humans, thick layer of "insulator air"
increase in thermogenesis
promoting shivering, sympathetic excitation of heat production, and thyroxine secretion

75. Hypothalamic Stimulation of Shivering
primary motor center for shivering located in the dorsomedial portion of the posterior hypothalamus near wall of the 3rd ventricle
normally inhibited by signals from the heat center in anterior preoptic area
cold signals from the skin and spinal cord
body heat production can rise 4-5x normal

77. transmits signals to anterior motor neurons
signals are nonrhythmical and do not cause the actual muscle shaking
they increase the tone of the skeletal muscles throughout the body
when the tone rises above a certain critical level, shivering begins

78. results from feedback oscillation of the muscle spindle stretch reflex mechanism

79. Sympathetic "Chemical" Excitation
ability of norepinephrine and epinephrine to uncouple oxidative phosphorylation
foodstuffs are oxidized but do not cause ATP to be formed – release of heat
directly proportional to the amount of brown fat (acclimatization)
adults do not have brown fat ( rate of heat production 10-15%, in infants 100%)

80. Increased Thyroxine Output
cooling preoptic area – increases production of TRH  TSH  tiroksina  activates uncoupling protein
yet another mechanism of chemical thermogenesis
requires several weeks' exposure to cold
humans seldom allow themselves to be exposed to the same degree of cold

81. Concept of a "Set-Point" critical body core temperature 37,1 °C
called the "set-point" of the temperature control mechanism
feedback gain of the temperature control system = (ratio of the change in environmental temperature to the change in body core temperature) - 1

82. changes about 1°C for each 25° to 30°C change in environmental temperature (~ 27)
extremely high gain (baroreceptor feedback gain < 2)

83. Skin Temperature Can Slightly Alter the Set-Point
decrease in skin temperature – increase in set-point for sweating
decrease in skin temperature – increase in set-point for shivering

86. Behavioral Control even more potent
person makes appropriate environmental adjustments to re-establish comfort
there are local skin temperature reflexes
after cutting the spinal cord in the neck above the sympathetic outflow from the cord regulation becomes extremely poor

87. Fever body temperature above the usual range of normal
abnormalities in the brain itself
toxic substances that affect the temperature-regulating centers

89. Resetting the Hypothalamic Temperature-Regulating Center
many proteins, breakdown products of proteins, lipopolysaccharide toxins released from bacterial cell membranes – pyrogens
some pyrogens act directly and immediately
other pyrogens function indirectly and may require several hours of latency (endotoxins from gram-negative bacteria)

90. phagocytizion of bacteria – release of interleukin-1 (IL1, leukocyte or endogenous pyrogen)
IL1 in 8-10 min significantly increases temperature (in nanograms)
IL1 inducing formation of prostaglandin E2
drugs that impedes the formation of prostaglandins from arachidonic acid – antipyretics (aspirin)

92. Fever Caused by Brain Lesions
almost always after surgery in the region of the hypothalamus
compression of the hypothalamus by a brain tumor

93. Characteristics of Febrile Conditions
chills – extremely cold feeling, vasoconstriction in the skin, shivers
crisis or “flush” – after factor is removed, intense sweating and the hot skin
heatstroke body temperature rises beyond a critical temperature – °C (105° to 108°F, dizziness, abdominal distress, vomiting, delirium, loss of consciousness)

94. local hemorrhages and parenchymatous degeneration of cells
especially in the brain, but also liver and kidneys
acclimatization

95. Exposure of the Body to Extreme Cold
person exposed to ice water for 20 to 30 minutes ordinarily dies because of heart standstill or heart fibrillation
once the body temperature has fallen below about 85°F (30 °C), the ability of the hypothalamus to regulate temperature is lost

96. sleepiness, coma – depresses the activity of the central nervous system
frostbites (lobes of the ears and in the digits of the hands and feet) – formation of ice crystals – permanent damage – gangrene
artificial hypothermia (heart surgery)