Dietary Balances; Regulation of Feeding; Obesity and Starvation

Prof. dr. Zoran ValićDepartment of PhysiologyUniversity of Split School of Medicine

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)

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

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

“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

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

(6000-7000 Cal)

Neural Centers Regulate Food Intake

sensation of hunger (rhythmical contractions of stomach and restlessness)

appetite –desire for particular type of food feeling of satiety

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)

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

Neurons and Neurotransmitters in the Hypothalamus

1) pro-opiomelanocortin (POMC) neurons1) α-MSH (α-melanocyte-stimulating hormone)2) CART (cocaine and amphetamine related transcript)

2) neurons that produce orexigenic substances1) NPY (neuropeptide Y)2) AGRP (agouti-related protein)

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

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

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)

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

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

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

Short-Term Regulation

What turns off the eating? 1) distending of gastrointestinal tract (stomach

and the duodenum – vagus nerve)2) humoral and hormonal factors

1) cholecystokinin (CCK) – fat2) peptide YY from the ileum and colon – fat, ??3) glucagon-like peptide (GLP) from intestines – enhances

glucose-dependent insulin production and secretion from the pancreas – suppress appetite

3) 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; ?

4) oral receptors (experiment with esophageal fistula; chewing, salivation, swallowing, and tasting – shorter duration (20-40 min))

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

Temperature Regulation and Food Intake

exposition to cold – increased feeding interaction within the hypothalamus:1) increases metabolic rate2) provides increased fat for insulation

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:

1) appetite stimulators (NPY i AGRP)2) activation of POMC neurons (α-MSH)3) substances that decrease apetite (CRH)4) increased sympathetic nerve activity 5) insulin secretion by the pancreatic β cells

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

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

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!

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

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

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

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 factors1) mutations of MCR-42) congenital leptin deficiency3) mutations of the leptin receptor

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

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)

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)

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)

Body Temperature Regulation and Fever

Normal Body Temperatures

“core” temperature = ± 0,6 ºC (± 1 ºF) (nude person exposed to air temperatures 10-55 ºC, beautifully designed control system)

skin temperature rises and falls with the temperature of the surroundings (ability to lose heat to the surroundings)

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

Heat Production

heat – principal by-product of metabolism metabolic rate of the body:

1) basal rate of metabolism2) muscle activity3) effect of thyroxine, (hGH, testosterone)4) effect of sympathetic stimulation5) increased chemical activity in the cells6) thermogenic effect of food

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:

1) how rapidly heat can be conducted from where it is produced to the skin

2) how rapidly heat can then be transferred from the skin to the surroundings

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

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)

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

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)

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

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

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

Mechanism of Sweat Secretion

1) deep subdermal coiled portion – secretes the sweat (primary or precursor secretion)

2) duct portion (modify concentrations of constituents)

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

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)

strong stimulation – Na+ and Cl- are reabsorbed to concentrations of 50-60 mmol/L, little of the water is reabsorbed – significant loss of NaCl

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 15-30 g/day to 3-5 g/day)

Loss of Heat by Panting

substitute mechanism due to:1) surfaces often covered with fur2) 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

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

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

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

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

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

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

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

results from feedback oscillation of the muscle spindle stretch reflex mechanism

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%)

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

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

changes about 1°C for each 25° to 30°C change in environmental temperature (~ 27)

extremely high gain (baroreceptor feedback gain < 2)

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

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

Fever

body temperature above the usual range of normal

1) abnormalities in the brain itself2) toxic substances that affect the

temperature-regulating centers

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)

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)

Fever Caused by Brain Lesions

almost always after surgery in the region of the hypothalamus

compression of the hypothalamus by a brain tumor

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 – 40-42 °C (105° to 108°F, dizziness, abdominal distress, vomiting, delirium, loss of consciousness)

local hemorrhages and parenchymatous degeneration of cells

especially in the brain, but also liver and kidneys

acclimatization

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

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)