Nutrition, Metabolism, Energy: Part 2 (copy)

Pancreas

• Triangular gland located partially behind stomach

• Has both exocrine and endocrine cells

  • Acinar cells

  • Pancreatic islets

Acinar cells

exocrine cells that produce enzyme-rich juice for digestion

What cells does pancreatic islets contain?

• Pancreatic islets (islets of Langerhans) contain endocrine cells for control of blood glucose

• Alpha cells produce glucagon

• Beta cells produce insulin

• Delta (D) cells secrete somatostatin

• F cells produce pancreatic polypeptide

Insulin and Glucagon from the pancreas regulate blood glucose levels

Insulin mechanism of Action

• Via facilitated diffusion

Diabetes Mellitus

• is a group of metabolic diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both.

• complex disorders of CHO, fat and protein metabolism

• Blurry vision= humor in the eye becomes sugary

Type 1 Diabetes

• Autoimmune destruction of beta cells

• Absolute insulin deficiency-WHY? because there isn’t any other organ or gland that can produce insulin leads to hyperglycemia

• require daily insulin injections multiple times a day

Type 2 Diabetes Mellitus

• Insulin resistance = relative insulin deficiency

  • e.g. interference with insulin binding to target tissue

  • Net results in inefficient transport of blood glucose into the cells also leads to hyperglycemia

• Require oral hypoglycemics

Consequence of insulin deficit (diabetes mellitus)

• Polyphagia occurs because body think body is going into starvation mode

Metabolic consequences of Type 1 DM

• When sugars cannot be used as fuel, as in DM, fats are used, causing lipidemia (high levels of fatty acids in blood)

• Fatty acid metabolism (lipolysis) results in formation of ketones (ketone bodies)

• Ketones are acidic, and their build-up in blood can cause ketoacidosis

  • Also causes ketonuria

  • acute consequences of type 1 DM

  • rarely in type 2 because of small insulin production

• Untreated ketoacidosis causes hyperpnea, disrupted heart activity and O2 transport, and severe depression of nervous system that can possibly lead to coma and death

Hyperinsulinism (hyperinsulinemia)

• Excessive insulin secretion(sometimes from injections)

  • Causes hypoglycemia: low blood glucose levels

• Symptoms: anxiety, nervousness, disorientation, unconsciousness, even death

• Treatment: sugar ingestion

Type 2 Diabetes Mellitus risk factors

age, obesity, hypertension, physical inactivity, and family history.

Consequences of obesity

• adipose tissue secrete hormone that decrease insulin sensitivity

• increased FFAs/ TGs and cholesterol:

  • interfere with intracellular insulin signalling

  • decrease tissue responses to insulin

  • alter incretin actions (from GIP or GLP)

  • promote inflammation

  • increase inflammatory cytokines that cause insulin resistance and are toxic to beta cells

Metabolic role of liver (5)

Hepatocytes carry out ~500 metabolic functions

• Process nearly every class of nutrient

• Play major role in regulating plasma cholesterol levels

• responsible for producing clotting factors

• Store vitamins and minerals

• Metabolize alcohol, drugs, hormones, and bilirubin

Summary of metabolic functions of liver

• Biotransformation: ability to take a compound and convert it to something else

  • EX: bilirubin broken down from RBCs is conjugated by liver into something that can be excreted

Cholesterol metabolism and regulation of blood cholesterol levels(6)

• Not used as an energy source

• Structural basis of bile salts, steroid hormones, and vitamin D

• Major component of plasma membranes

• 15% is ingested, the rest made in body, primarily by liver

• Lost from body when catabolized or secreted in bile salts that are lost in feces

• is hydrophobic and must be transported via lipoproteins

4 types and Composition of lipoprotein

Includes

• VLDLs: when they dump triglycerides, they become LDLs

• LDLs: Along with VLDLs start to deposit cholesterol into peripheral structures like artery walls causing health problems

• HDLs: can be reused and is there to prevent accumulation of cholesterol in and around tissues

• Chylomicrons: is the least dense of all

The more protein, the more density it has. The more triglycerides, the less dense

VLDLs

• transport triglycerides from liver to peripheral tissues (mostly adipose

LDLs

• transport cholesterol to peripheral tissues for membranes, storage, or hormone synthesis

HDLs

• transport excess cholesterol from peripheral tissues to liver to be broken down and secreted into bile

• Also provide cholesterol to steroid-producing organs

Blood levels of total cholesterol, LDL, and HDL

• Generally, Blood tests measure total cholesterol < 200 mg/dL (< 5.2 mmol/L) of blood is desirable for adults

  • More important to look at ratio of lipoproteins transporting cholesterol in blood esp. for ppl with high cardiovascular risk

    • High levels of LDL are generally considered bad (associated with atherosclerosis)

    • High levels of HDL were considered good because it transported cholesterol destined for degradation

Why does restricting dietary cholesterol not markedly reduce cholesterol levels?

• Because the liver produces cholesterol at a basal level regardless of dietary cholesterol intake so reducing dietary cholesterol intake doesn’t make a huge difference

what is the MOST important effect on regulating blood cholesterol levels?

• The relative amounts of saturated and usaturated fatty acids

  • Saturated fatty acids: stimulate liver synthesis of cholesterol & inhibit its excretion from body

  • Unsaturated fatty acids: enhance excretion of cholesterol into bile salts. Should be in diets

  • Trans fats: increases LDL & reduce HDL

Unsaturated omega-3 fatty acids effect on regulating cholesterol levels

• Very good for body

• Unsaturated omega-3 fatty acids (found in cold-water fish) have lower proportions of saturated fats and cholesterol

  • Helps cardiovascular system: Make platelets less sticky and help prevent spontaneous clotting

    • reduces risk of thrombus and embolism

  • Appear to lower blood pressure

Other factors that regulate blood cholesterol levels

• Cigarette smoking and stress lower HDL levels

• Regular aerobic exercise and estrogens lower LDL and increase HDL levels.

  • Menopausal women are at risk since they have lower estrogen

• Body Shape

How does body shape contribute to regulating blood cholesterol levels

• Apples” (people with upper body and abdominal fat, seen more often in males) tend to have higher levels of cholesterol and LDLs

  • higher risk of type 2, metabolic syndrome, etc.

• “Pears” (whose fat is localized in the hips and thighs, more common in females) tend to have lower levels

  • because fat is away from key organs

Location and structure of thyroid gland

• Butterfly-shaped gland in anterior neck on the trachea, just inferior to larynx, that consists of:

• Isthmus: median mass connecting two lateral lobes

• closed follicles: hollow sphere of epithelial follicular cells that produce glycoprotein thyroglobulin

  • Colloid: fluid of follicle lumen containing thyroglobulin & iodine (precursor to thyroid hormone)

  • Parafollicular cells: produce hormone calcitonin

    • calcitonin lowers blood calcium levels

Role of thyroid hormone

• the body’s major metabolic hormone

• Is lipid soluble so transported as lipoprotein

  • functions like a STEROID hormone

• affects virtually every cell in the body

• Just like steroid hormones, it enters target cell and binds to intracellular receptors within nucleus

  • triggers transcription of various metabolic gene

  • takes longer

2 forms of thyroid hormone

• Both are iodine-containing amine hormones and both work together

  • T4 (thyroxine): major form that consists of two tyrosine molecules with four bound iodine atoms. 94% of TH is T4

    • Most converted to T3 at tissue level

  • T3 (triiodothyronine): form that has two tyrosine molecules with three bound iodine atoms. The most potent/active form

    • T3 has higher affinity for receptors than T4

3 major Effects of thyroid hormone

• Increases basal metabolic rate and heat production

  • Referred to as calorigenic effect

• Regulates tissue growth and development

  • Critical for normal skeletal and nervous system development and reproductive capabilities

• Maintains blood pressure

  • Increases adrenergic receptors in blood vessels

  • can increase cardiac rate and cardiac output

    • hypothyroidism does opposite of that

Major effects of thyroid hormone in the body

Synthesis of thyroid hormone

• T3 and T4 are stored in the follicles lumen until triggered for release by TSH

• amounts sufficient for 2-3 months

• DIT has 2 iodines attached (FYI)

Role of iodine in TH synthesis

• Iodine - ingested in the form of iodides is necessary for the formation of T3/T4

• Iodide from the GI→ the blood and is trapped in the thyroid follicles that actively pump iodide from the blood into the interior of the cells

• The rate of iodide trapping is influenced by Thyroid Stimulating Hormone(TSH)

Transport and regulation of thyroid hormone

• T4 & T3 transported by thyroxine-binding globulins (TBGs)

  • Both bind to target receptors, but T3 is 10 times more active than T4

  • Peripheral tissues have enzyme that to convert T4 to T3 (-1 iodine)

Negative feedback regulation of TH release

• Falling TH levels stimulate release of thyroid-stimulating hormone (TSH)

• Rising TH levels provide negative feedback inhibition on TSH

• TSH can also be inhibited by GHIH, dopamine, and increased levels of cortisol and iodide

Hypersecretion of TH

most common type is Graves’ disease

Grave’s disease

• Autoimmune disease: body makes abnormal antibodies(they mimic TSH) directed against thyroid follicular cells

• Antibodies mimic TSH, stimulating TH release

6 Symptoms of Grave’s disease

• Symptoms include elevated metabolic rate, sweating, rapid and irregular heartbeats, nervousness, and weight loss despite adequate food

  • Exophthalmos may result in eyes protruding as fatty tissue behind eyes becomes edematous and fibrous

Treatments for Grave’s disease

• Treatments include

  • surgical removal of thyroid gland

  • radioactive iodine to destroy active thyroid cells(less common)

TH hyposecretion

in adults can lead to myxedema/goiter.

in infants can lead to cretinism

8 Symptoms of myxedema

• low metabolic rate

• thick and/or dry skin

• puffy eyes

• feeling chilled

• constipation

• edema

• mental sluggishness

• lethargy

Hyposecretion due to lack of iodine

• If due to lack of iodine, a goiter may develop

  • not enough thyroid hormone so thyroid glands ramps up amount of thyroglobulin but there is not iodine to collect precursor, thus enlargement of thyroid gland

• ↑ synthesize of unusable thyroglobulin causes thyroid to enlarge

Cretinism

• Congenital hypothyroidism leads to cretinism

• Symptoms include intellectual disabilities, short and disproportionately sized body, thick tongue and neck

Energy balance

energy released from food (intake) must equal total energy output

Energy intake

energy derived from absorbable foods = energy liberated during food oxidation

Energy output

• immediately lost as heat (~60%)

• used to do work (driven by ATP)

• stored as fat or glycogen

Uses of energy in the body

• Nearly all energy from food is eventually converted to heat, which cannot be used to do work, but it

  • warms tissues and blood

  • helps maintain homeostatic body temperature

  • allows metabolic reactions to occur efficiently

• Positive energy balance = weight, energy intake exceeds energy output. Vice versa for negative energy balance

Body mass Index (BMI)

• is a formula used to determine obesity based on a person’s weight relative to height

How is BMI maintained

• Body mass (BM) is maintained when energy intake = energy expenditure

• Clinically, overweight is defined by a BMI of 25–30 (carries some health risk)

• Obesity is a BMI > 30 (with markedly increased health risk)

health risks associated with BMI doesn’t account for age, sex, ethnicity, muscle mass, etc…

5 major Risks of obesity

• highest risk factor of type 2 diabetes mellitus

• hypertension

• heart disease / atherosclerosis

• cancer

• osteoarthritis

Canadian statistics of obesity

• Nearly 68 % of adults are overweight or obese combined

  • Around 33 % of Canadian adults (ages 18– 79) are classified as obese based on BMI

• 30 %+ of children and youth aged 5–17 fall into overweight or obesity combined

  • around 8.6 % of Canadian children and youth aged 6 to 17 years are classified as obese

About 3.9 million Canadians (≈9.7 % of the population aged 1+ years) live with diagnosed diabetes (both type 1 and type 2), according to 2023–2024 surveillance

Metabolic syndrome

• cluster of five risk factors

• High blood pressure comes from storing fat into adipose tissues, which are vascularized. This means more work for heart to pump blood to those sites

5 factors seen in metabolic syndrome

• ↑ Waist circumference

• ↑ Blood pressure

• ↑ Blood glucose

• ↑ Blood triglycerides

• ↓ Blood HDL cholesterol

• Presence of these factors can:

  • Double chance of heart disease

  • Increase risk of diabetes five times

  • Increased risk of stroke

Regulation of food intake

• Current theories focus mainly on neural signals from GI tract, hormones, and blood nutrient levels

  • To lesser extent, body temperature and psychological factors also play role

• Areas of hypothalamus release peptides that influence feeding behavior

  • Arcuate nucleus (ARC): controls hunger, fullness, and regulating body weight

  • stimulates/inhibits:

    • Ventromedial Nucleus (VMN)

    • Lateral Hypothalamic Area (LHA)

Hunger-promoting neurons

• Some ARC neurons release neuropeptide Y (NPY) and agouti-related peptides(AgRP) that enhance appetite.

• These increase appetite by stimulating release of orexins from Lateral hypothalamic area (LHA) neurons

• orexins increase in food-seeking behavior AND trying to reduce energy expenditure

• too much NPY can trigger obesity

• With type 1 diabetes, lack of insulin will not prevent food-seeking behavior

• Type 2 diabetes, downstream of insulin isn’t functioning also leading to food seeking behavior

Satiety-promoting neurons

• Other ARC neurons release pro- opiomelanocortin (POMC) and cocaine-/amphetamine-regulated transcript (CART), which suppress appetite

• These act on the ventromedial nucleus (VMN), causing it to release CRH (important appetite suppressor) when energy supply is sufficient

• if VMN is damaged, continuous feeding will occur

What is feeding behavior and hunger regulated by?

• Neural signals from digestive tract via vagus nerve

• Bloodborne signals related to body energy stores (glucose, amino acids, fatty acids)

• Hormones(grehlin, etc..)

• To lesser extent, body temperature and psychological factors

All operate through brain thermoreceptors, chemoreceptors, and others

Food intake is subject to both short- and long-term controls

What contributes to short-term regulation of food intake

• Neural signals from digestive tract

• Nutrient signals related to energy stores

• Hormones

How do neural signals from digestive tract play a role in short-term regulation of food intake

• High protein content of meal increases and prolongs afferent vagal signals

• Distension sends signals to mechanoreceptors along vagus nerve that suppress hunger center

How do nutrient signals related to energy stores play a role in short-term regulation of food intake

• Increased nutrient levels in blood depress eating

  • Rising blood glucose levels

  • Elevated blood amino acid levels

  • Blood levels of fatty acids

How do hormones play a role in short-term regulation of food intake

• Gut hormones (e.g., insulin and CCK are activated in presence of nutrients. CCK is present during entire digestive process) signal satiety and depress hunger

• Glucagon and epinephrine released during fasting and stimulate hunger

• Ghrelin (Ghr) from stomach is a powerful appetite stimulant. Body’s main hunger hormone

  • Levels peak prior to mealtime and drop after a meal

How does Leptin play a role in LONG-term regulation of food intake

• Hormone secreted by fat cells in response to increased body fat mass

  • If fat mass increases, leptin levels rise; more leptin binds to receptors in

• ARC that:

  • Stimulate expression of CART

  • Suppress release of NPY (most potent appetite stimulant known)

    • Decreasing release of appetite-enhancing orexins from LHA

      • Decreasing appetite/food intake, eventually promoting weight loss

• If fat stores decrease, leptin levels fall, producing opposite effect

  • Increasing appetite/food intake, eventually promoting weight gain

• Rising leptin level causes some weight loss but is no “magic bullet” for obese patients

  • Obese people have high leptin levels but seem to be resistant to its action (unknown reason)

• Consensus: leptin’s main role is to protect against weight loss in times of nutritional deprivation

6 additional factors play a role in regulation of food intake

• Temperature: cold activates hunger

• Stress: depends on individual

• Psychological factors

• Adenovirus infections

• Sleep deprivation

• Composition of gut bacteria

Metabolic rate

• total heat produced by chemical reactions and mechanical work of body

How is metabolic rate measured

• Directly: calorimeter measures heat liberated into water chamber

• Indirectly: respirometer measures oxygen consumption (directly proportional to heat production)

Basal metabolic rate

• MINIMUM amount of energy body needs to perform its most essential activities

• Measured in fasting state (12-hour fast)

  • reclining position

  • relaxed mentally & physically

  • at a certain room temperature 20–25°C

Not lowest metabolic state, that’s during sleep (skeletal muscles fully relaxed)

• Recorded as kilocalories per square meter of body surface per hour (kcal/m2/h)

• Example: 70 kg adult BMR = 66 kcal/h

BMR is not the lowest metabolic rate (that occurs when sleeping)

5 major influences on BMR

• Age and gender: BMR decreases with age

  • Males have disproportionately higher BMR due to higher muscle mass

  • higher in children

  • lower in females, EXCEPT during pregnancy

• Body temperature: BMR increases with temperature

• Stress: BMR increases with stress

• Thyroxine: increases oxygen consumption, cellular respiration, and BMR

Hyperthyroidism

• level of thyroid hormone is higher in the body

• causes many problems resulting from the high BMR it produces

  • Body catabolizes stored fats and tissue proteins

  • Person often loses weight despite increased hunger and food intake

  • Bones weaken, and muscles, including heart, begin to atrophy

• Hypothyroidism results in slowed metabolism, obesity, and diminished thought processes due to decrease of thyroid hormone

Total metabolic rate(TMR)

• sum of all calories burned in a 24hr period

• Rate of energy consumption to fuel all ongoing activities

  • e.g. female whose energy needs are ~ 2000 kcal/day may spend about 1400 kcal supporting vital body activities

• Increases with skeletal muscle activity

  • Even slight increases in muscular work significantly increase TMR and heat production

• TMR also increases with food ingestion (food-induced thermogenesis)

  • Greatest with protein ingestion

  • Fasting or very low caloric intake depresses TMR

• Total metabolic rate (TMR) = Total daily energy expenditure (TDEE)

  • Components are

    • Basal metabolic rate (BMR)

    • The thermic effect of food (TEF)

    • Energy expended on physical activity (thermic effect of activity = TEA)

Regulation of body temperature

• Only ~ 40% of energy released by catabolism can be captured by ATP; the rest is lost as heat

  • Cannot be used to do work

  • Warms the tissues and blood

  • Helps maintain the homeostatic body temperature

• Body temperature reflects the balance between heat production and heat loss

  • At rest, the liver, heart, brain, kidneys & endocrine organs generate most heat

    • Inactive skeletal muscles account for only ~ 20 – 30%

• During exercise, heat production from skeletal muscles increases dramatically

  • Active muscle can produce 30-40X more heat than the rest of the body

What is normal body temperature

• Normal body temperature = 37°C

  • Optimal enzyme activity at this temperature

  • Increased temperature denatures proteins and depresses neurons

  • Rate of chemical reactions increases ~10% for each 1°C rise in temperature

• Body can handle the cold better than heat

• In children under 5, temperature of 41°C (106°F) can lead to convulsions

  • ~43°C (109°F) is the limit for life

• Tissues can tolerate low body temperatures better

Core and shell temperature

• Core (organs within skull and thoracic and abdominal cavities) has highest temperature

  • Rectal temperature is best clinical indicator

• Shell (skin) has lowest temperature

  • Fluctuates between 20°C and 40°C

• Core temperature is regulated and is fairly constant.

  • Blood is major agent of heat exchange between core and shell

4 mechanisms of heat transfer

• Radiation

• Conduction

• Convection

• Evaporation

Radiation as a mechanism of heat transfer

• loss of heat by infrared rays ; objects are not in contact (receiving heat from the sun)

• Explains why cold room warms up after it fills with people

• Normally accounts for about 50% of body’s heat loss

Conduction

• heat transfer between molecules of objects in direct contact

• E.g., transfer of heat from hot tub water to skin

Convection

• heat transfer to surrounding air or water

• warm air expands and rises (away from skin) and denser cool air falls (replacing warm air)

• Conduction and Convection account for 15– 20% of body’s heat loss

• Ex: cooling down from a fan

Evaporation

• heat loss due to evaporation of water from body surfaces; heat absorbed by water during evaporation is known as heat of vaporization

• a mechanism of cooling the body down

Insensible heat loss

• accompanies insensible water loss from lungs, oral mucosa, and skin

• unnoticeable

• Loss ~ 10% of basal heat production

Sensible heat loss

• when body temperature rises and sweating increases water vaporization

Factors contributing to heat balance

Thermoregulatory centers

• preoptic region of hypothalamus is main integrating center for thermoregulation

2 thermoregulatory centers of hypothalamus

• Heat-loss center: as core warms up, dissipates heat

• Heat-promoting center: as body feels cold, body will generate heat

Where does hypothalamus receive afferent input from

• Peripheral thermoreceptors in shell (skin)

• Central thermoreceptors in core (some in hypothalamus

Initiates appropriate heat-loss and heat-promoting activities

Central thermoreceptors have more influence, but varying inputs from peripheral probably alert hypothalamus to the need to prevent temperature changes in the core

Heat promoting mechanisms

• prevents hypothermia

• When external temperature is low (or blood temperature falls), heat-promoting center is activated, triggering one or more of the following mechanisms:

  • Constriction

  • shivering

  • increases in metabolic rate

  • enhanced release of thyroxine

Constriction of cutaneous blood vessels as a heat-promoting mechanism

Regulated by sympathetic nervous system

shivering as a heat-promoting mechanism

• Heat from skeletal muscle activity and activation increases heat

increases in metabolic rate as a heat-promoting mechanism

• Chemical (non-shivering) thermogenesis: via epinephrine and norepinephrine stimulated by cold temperatures

  • Mechanism seen primarily in infants (in brown adipose tissue: has increased capacity to generate heat, cells don’t capture that and instead is converted to heat)

• Enhanced release of thyroxine

  • Seen only in infants when environmental temperature decreases gradually (e.g., transition from summer to winter

Behavioral modifications (voluntary) to temp changes (cold temp)

• Putting on more clothing

• Drinking hot fluids

• Changing posture (clasping arms across chest)

• Increasing physical activity (jumping up and down)

Heat-loss mechanisms

• When core body temperature rises above normal, the heat-loss center is activated, triggering one or both:

• Inhibition of heat-promoting center

• Dilation of cutaneous blood vessels: increasing heat loss by radiation, conduction, and convection

• Enhanced sweating: works well in dry air but is less effective when humidity is high

Voluntary measures of heat-loss mechanisms include…

• Wearing light-colored, loose-fitting clothing

• take off a sweater, turn on a fan, get a cold drink

• Reducing activity and seeking a cooler environment

Mechanisms of body temperature regulation

Hyperthermia (high body temperature)

• Elevated body temp overwhelms the heat loss processes

• At ~ 41°C hypothalamus is depressed (heat loss ceases) leading to positive- feedback cycle

• heat stroke results is not corrected

• Can be fatal if not corrected

Heat exhaustion (exertion-induced heat exhaustion)

• Heat-associated extreme sweating and collapse during or following vigorous physical exertion due to dehydration and low blood pressure

  • Causes elevated body temperature and mental confusion and/or fainting

• As heat-loss mechanisms struggle to function, may progress to heat stroke

Hypothermia (low body temp)

• Caused by prolonged cold exposure

• Vital signs (respiratory and heart rate, blood pressure) decrease as cellular (enzymatic) activities slow

  • Person begins to feel drowsy, even (oddly) comfortable (no longer feels cold)

  • Shivering stops at core temperature of 30-32°C

• Can progress to coma and finally death (by cardiac arrest) at ~21°C

Fever

• Controlled hyperthermia

  • Cause: mostly due to infection, but also cancer, allergies, or CNS injuries

  • Function: rising temp enhances immune response, speeds healing, and inhibits bacterial growth

• Macrophages release cytokines called pyrogens that cause release of prostaglandins, resetting hypothalamic thermostat higher than normal temperature.

  • Triggers heat-producing mechanisms, and temperature rises

• The set-point temperature of the body will remain elevated until

  • prostaglandins (PGE) are no longer present

  • Natural body defenses or antibiotics reverse disease process

• Thermostat returns to normal after infection (or disease process) is controlled

  • Heat-loss mechanisms active again; sweating begins, skin becomes flushed and warm (signs that fever has broken