LICEO DE CAGAYAN UNIVERSITY

COLLEGE OF MEDICINE
BIOCHEMISTRY 4TH BIMONTHLY

Fatima Zahara M. Galawan April 4, 2020

METABOLIC RESPONSE TO STRESS

Learning Objectives

1. Define the following:

1.1 STRESS
 A state produced within an organism subject to a stimulus perceived as a stressor (Hans Selye,
1947) - Any condition that induces a detrimental change in an organism (Hans Selye, 1976)
 A stimulus, a life event, or a set of circumstances causing a disrupted response that increases an
individual’s vulnerability to illness. (Lyon and Werner, 1987)
 A state of threatened homeostasis counteracted by a complex repertoire of physiologic and
behavioral responses that reestablish homeostasis. (Tsigos, Kyrou, and Chrousos, 2004)
 The confusion created when one’s mind overrides the body’s basic desire to choke the living
daylights out of somebody who desperately needs it.
 Defined as any influence, arising either internally or externally to the body that threatens to
disrupt normal structure, function or behavior.

1.2 CYTOKINES

 Cytokines are small proteins such as interferons, interleukins (IL) and tumor necrosis factors that
facilitate cell-to-cell communication between the components of the immune system. They can be
both autocrine and paracrine in nature.
 Cytokines refers to a diverse set of small, generally less than 25 kDa in mass, secreted proteins
that include the interleukins, interferons and chemokines.
 It is released into the ECF and can function as autocrine, paracrine or endocrine hormones and
they trigger the acute phase response.

1.3 IMMUNOMODULATION

 A modulation (regulatory adjustment) of the immune system

 Change in the body's immune system, caused by agents that activate or suppress its function

1.4 ACUTE PHASE PROTEINS

 It is believed to play a role in the body’s response to inflammation.

 A class of proteins whose plasma concentrations increase (positive acute-phase proteins) or
decrease (negative acute-phase proteins) in response to inflammation

1.5 COAGULATION FACTORS

 It may be enhanced during the stress response to infection with the inflammatory and clotting
cascades being closely linked.
 During stress, there are increases concentration of circulating procoagulants such as fibrinogen
and cytokine IL6, which stimulate the expression of tissue factor.
 FACTOR COMMON NAME
I Fibrinogen
II Prothrombin
III Tissue factor
IV Ca2+
V Proaccelerin, labile factor, accelerator (Ac-) globulin
VII Proconvertin, serum prothrombin conversion accelerator (SPCA),
cothromboplastin
VIII Antihemophilic factor A, antihemophilic globulin (AHG)
IX Antihemophilic factor B, Christmas factor, plasma thromboplastin
component (PTC)
X Stuart-Power factor
XI Plasma thromboplastin antecedent (PTA)
XII Hageman factor
XIII Fibrin stabilizing factor (FSF), fibrinoligase
*There is no factor VI.
Note: The numbers indicate the order in which the factors have been discovered and bear no
relationship to the order in which they act.

1.6 INFLAMMATION

 Part of the complex biological response of body tissues to harmful stimuli, such as pathogens,
damaged cells, or irritants, and is a protective response involving immune cells, blood vessels,
and molecular mediators
 This process includes increased blood flow with an influx of white blood cells and other chemical
substances that facilitate healing.

1.7 STRESSOR

 A chemical or biological agent, environmental condition, external stimulus or an event seen as

causing stress to an organism
 Occurs when an individual is unable to cope with the demands of their environment
 Stressors can cause physical, chemical and mental responses internally.
o Physical stressors produce mechanical stresses on skin, bones, ligaments, tendons,
muscles and nerves that cause tissue deformation and (in extreme cases) tissue failure.
o Chemical stresses also produce biomechanical responses associated
with metabolism and tissue repair.
o Mental Stresses affect mental function and performance

STRESSORS
Sensory Pain, bright light
Life events Birth and death, Marriage and divorce
Responsibilities Lack of money, unemployment
Work or Study Exams, project deadlines, group research
Personal Relationships Conflict, deception
Lifestyle Heavy drinking, insufficient sleep
Environmental Lack of control over circumstances: food,
housing, health, freedom or mobility
Social Social defeat
 1.8 HYPOTHALAMO-PITUITARY-ADRENAL AXIS

 An interactive neuroendocrine unit comprising of the hypothalamus, the pituitary gland, and the
adrenal glands
 Plays key roles in basal homeostasis and in the body’s response to stress. The major pathway
of the axis results in the production and secretion of cortisol. The hypothalamus responds to
basal neural input which follows a circadian rhythm and input as a result of stress by increasing
the secretion of corticotrophin-releasing hormone (CRH) from the hypothalamus. 
 Circadian release of CRH/AVP/ACTH/Cortisol is disrupted when a stressor is present.

1.9 C-REACTIVE PROTEIN

 An annular (ring-shaped), pentameric protein found in blood plasma, whose circulating

concentrations rise in response to inflammation
 It reacts with the C-polysaccharide of pneumococci
 Classified as an acute-phase protein
 Can stimulate the classic component pathway

2. Identify and give examples of the four categories of stressors.

.3 IMM
STRESSOR EXAMPLES
Physical Stress trauma, intense physical labor/over-exertion,
environmental pollution (pesticides, herbicides,
toxins, heavy metals, inadequate light, radiation,
noise, electromagnetic fields), illness, fatigue,
inadequate oxygen supply, hypoglycemia,
hormonal and/or biochemical imbalances, dietary
stress, dehydration, substance abuse, dental
challenges, and musculoskeletal
misalignments/imbalances.
Psychological Stress emotional stress, cognitive stress and perceptual
stress (beliefs, roles, stories, attitudes, world view)
Psychosocial Stress relationship/marriage difficulties, lack of social
support, lack of resources for adequate survival,
loss of loved ones, and bankruptcy
Psycho-spiritual Stress A crisis of values, meaning, and purpose; joyless
striving and a misalignment within one’s core
spiritual beliefs.

3. Describe the systemic response to stress

 The stress response is the name given to the hormonal and metabolic changes which follow
injury or trauma. This is part of the systemic reaction to injury which encompasses a wide range
of endocrinological, immunological and haematological effects.
 The hypothalamus senses stress, and then releases a hormone like corticotropin-releasing factor
(CRF) and from the hypothalamic region to pituitary region, which is another area for stress
processing inside the brain. Adrenocorticotropic hormones then are ultimately released from the
pituitary into blood flow. Finally, the kidney tissues then sense the ACTH which stimulates the
generation of glucocorticoids in the cortex of the adrenal gland, which are then released into the
blood. Stress also activates the autonomic sympathetic nerves in the medulla of the adrenal
gland to elicit the production of catecholamines: norepinephrine and epinephrine, which are then
released in the blood. These hormones help in mediating physiologic stress responses.
 SYSTEMIC RESPONSES
Sympathetic Nervous System activation
Endocrine ‘stress response’
Pituitary Hormone secretion
Insulin resistance
Immunological and haematological changes
Cytokine production
Acute Phase Reaction
Neutrophil leukocytosis
Lymphocyte proliferation

4. Describe the response of hypothalamo-pituitary-adrenal axis to stress.

 Hypophysiotropic neurons localized in the paraventricular nucleus (PVN) of the hypothalamus

synthesize corticotropin-releasing factor (CRF) and vasopressin (AVP). In response to stress,
CRF is released into hypophysial portal vessels that access the anterior pituitary gland. Binding of
CRF to the CRF type 1 receptor (CRFR1) on pituitary corticotropes activates cyclic adenosine
monophosphate (cAMP) pathway events that induce the release of adrenocorticotropic hormone
(ACTH) into the systemic circulation. In the presence of CRF, AVP elicits synergistic effects on
ACTH release that are mediated through the vasopressin V 1b receptor. Circulating ACTH binds to
the melanocortin type 2 receptor (MC2-R) in the adrenal cortex where it stimulates glucocorticoid
synthesis and secretion into the systemic circulation. Glucocorticoids regulate physiological
events and inhibit further HPA axis activation (red lines) through intracellular receptors that are
widely distributed throughout the brain and peripheral tissues. Legend: IP3, inositol triphosphate;
DAG, diacylglycerol
 Activation of the HPA axis is a tightly controlled process that involves a wide array of neuronal
and endocrine systems. Glucocorticoids play a prominent role in regulating the magnitude and
duration of HPA axis activation. Following exposure to stress, elevated levels of circulating
glucocorticoids inhibit HPA activity at the level of the hypothalamus and pituitary. The HPA axis is
also subject to glucocorticoid independent regulation. The neuroendocrine effects of CRF are
also modulated by CRF binding proteins that are found at high levels in the systemic circulation
and in the pituitary gland.

 CORTISOL
o DNA independent and involve direct interactions with transcription factors such
as nuclear factor-Кβ (NK-Кβ)
o NF-KB – important in the modulation of stress response
o NF-KB – activates the expression of IL-1, IL-6 and TNF α (key components of the
inflammatory response and interaction with HPAA)
o Exerts negative feedback effect on CRH and ACTH release, affects
carbohydrate, protein and fat metabolism and modulates the immune response.
o Limits glucose utilization in cellular respiration (reducing the oxidation of NADH to
NAD in TCA)
o High concentration levels of cortisol reduce sensitivity of peripheral tissue to
insulin ( anti-insulin effect marked in skeletal muscle and adipose tissue-
reducing glucose uptake and metabolism)
o In hepatic tissue, there is increase protein catabolism and decreased protein
synthesis through reduced RNA formation and amino acid uptake.
o Within the liver, this metabolic picture is reversed, with increase amino acid
uptake and the synthesis of acute phase proteins.
o It enhances the mobilization of fatty acids from adipose tissue, shifting oxidative
metabolism to favor enrgy generation from glucose to fatty acids.
 THYROID HORMONE
o Major disturbances of thyroid hormone metabolism and plasma concentration
occur during the metabolic response to stress
o Fall in the concentrations of T3 and often of thyroxine (T4) and sometimes, in the
critically ill, a fall in concentration of TSH

 SEX HORMONES
o Effects of trauma and sepsis are complex and dependent on the type of injury
o Plasma concentrations of free testosterone may fall without any consistent
change in the concentration of LH, suggesting a change in the sensitivity of
Leydig cells to LH or a disturbance of normal feedback regulation.
o The effects tend to be more marked in women, with reduced activity of the entire
Hypothalamo-pituitary gonadal Axis(HPGA)
o CRH have inhibitory effect including antagonizing the effect of LH on Leydig
cells.
o Chronic activation of HPGA, demonstrated in long distance runners and ballet
dancers causes suppression of gonadal function in males and females

 GROWTH HORMONE
o Stimulated by GHRH produced by the ventral medial nucleus of hypothalamus
o Small protein active in most cells of the body
o It enhances amino acid uptake and protein synthesis
o Under the influence GH, free fatty acids are used as an energy source in
preference to carbohydrates and proteins.
o Reduces glucose uptake by skeletal muscle and fat cells
o Promote gluconeogenesis by the liver
o Increase insulin secretion by pancreas.

5. Describe the response of adrenal medulla to stress.

 Modified neuronal cells in the adrenal medulla secrete noradrenaline and adrenaline into the
circulation.
 Involves in the catecholamine synthesis
o Tryosine convert to L-DOPA to DOPAMINE which is transported into the
secretory vesicles where hydroxylation reaction converts it into
NORADRENALINE (NE). The majority of NE is then metabolized to adrenaline
(E).
o The sympathetic nerve impulse to the adrenal medulla results in the influx of
intracellular calcium and the discharge of catecholamine secretory vesicles
(E:NE ratio =80:20)directly into the circulation.

6. Describe the response of kidneys to stress.

 Fluid conservation occurs as part of the stress response often resulting to low urine output
despite euvolemia.
 Increase sympathetic nervous system activity and raised concentration of circulating
catecholamines – reduces renal blood flow.
 Initiates the metabolism of prorenin to renin in the juxtaglomerular cells of the kidney.
 RENIN is released into the blood where it acts on angiotensinogen to form angiotensin I. With
ACE( angotensin converting enzyme-prediminatly found in lungs), Angeotesin I is converted to
Angiotensin II (potent vasoconstrictor). Angiotensinogen II stimulates AVP release thus having
direct effect tto the kidney by increase salt and water retention.
 Under the influence of Angiotesin II, the mineralocorticoid ALDOSTERONE is synthesized in the
zona glomerulosa of the adrenal cortex by metabolism of corticosterone by enzyme aldosterone
synthase.
 ACTH has a permissive role in aldosterone synthesis, it does not control the rate of release.
 Aldosterone acts on the cortical collecting tubules where it stimulates a Na-K-Atpase, leading to
retention of sodium and water.

7. Identify the cytokines involved in stress response.

 GROUP 1 (IL2, IL3,IL4,IL7,IL!),IL11,IL12 and granulocyte macrophage colony stimulating factor)

o Acts on a variety of cells types as positive or negative growth factors
 GROUP 2
o Are responsible for the induction of fever, muscle catabolism, activation of WBC
precursors and growth of inflammatory fibroblasts and macrophages
 GROUP 3
o Anti-inflamatory activity (IL1 receptor antagonist, soluble IL1 receptors, TNFα
binding protein and IL1 binding protein)

8. Describe the response of inflammation to stress.

 Cortisol and adrenaline act synergistically to induce rapid changes I leukocyte distribution and to
enhance cell mediated and contact hypersensitivity immunity.
 Stressed induced changes include a reduction in the number of lymphocytes and monocytes but
an increase in the number of neutrophils. These changes are rapidly reversed upon cessation of
the stress.
 Acute physiological stress is known to increase circulating TNF alpha, IL1B and IL10 with
glucocorticoids also enhancing the biological activity of IL2, Interferon γ(IFNγ) and granulocyte
colony stimulating factor (G-CSF)
 Chronic stress has been shown to dysregulate immune responses by altering the cytokine
balance from type 1 to type 2.
o Immunosenescence is accelerated and immunity decreased owing to a reduced
number of circulating protective cells and increased populations of suppressor T
cells
 Cortisol exerts its anti-inflammatory effects through a number of mechanisms.
o By stabilizing lysosomal membranes
o Cortisol reduce the release of proinflammatory proteolytic enzymes and reduces
damage to the vascular endothelium therby decreasing the leak.
o Have an antiinflammatory action through the non-genomic binding of GR-cortisol
complex to transcriptase NK-KB, reducing the formation of prostaglandins and
cytokines that would act as positive chemotactic agents for phagocytic WBC.
o Inhibits the production of IL2, which stimulates the proliferation of t CELLS.
 Induces the synthesis of lipocortin (an inhibitor of phospholipase A2-requires for the synthesis of
prostaglandins and leukotreines)
 Promote increased transcription of anti-inflammatory genes.
 Mitogen activated protein kinases (MAPKs) form intracellular signalling pathways that result in the
production and post-transcriptional modification of pro-inflammatory mediators.
o MAPK phosphatases desphospphorelate MAPKs rendering them inactive
o Glucocorticoid increase the expression of MAPK phosphatase thus can down
regulate the inflammatory response.
 Cells that surround the inflammed tissues express specific tissue protective receptors (TPRs) that
bind the type 1 cytokine erythropoietin.
o Binding of this ligand inhibits proinflammatory cytokine production, inhibits
macrophage activity and delimits the volume of injury by countering apoptosis.
 o Activation of TPRs also acts to recruit vascular and tissue specific stem cells and
enhances tissue repair.

9. Identify and describe the hormones involved in stress response.

 Adrenaline
What It Is: Commonly known as the fight or flight hormone, it is produced by the adrenal glands
after receiving a message from the brain that a stressful situation has presented itself.
o Adrenaline, along with norepinephrine (more on that below), is largely
responsible for the immediate reactions we feel when stressed. Imagine you're
trying to change lanes in your car, says Amit Sood, M.D., director of research at
the Complementary and Integrative Medicine and chair of Mayo Mind Body
Initiative at Mayo Clinic. Suddenly, from your blind spot, comes a car racing at
100 miles per hour. You return to your original lane and your heart is pounding.
Your muscles are tense, you're breathing faster, you may start sweating. That's
adrenaline.
o Along with the increase in heart rate, adrenaline also gives you a surge of
energy -- which you might need to run away from a dangerous situation -- and
also focuses your attention.

 Norepinephrine
What It Is: A hormone similar to adrenaline, released from the adrenal glands and also from the
brain, says Sood.
o The primary role of norepinephrine, like adrenaline, is arousal. When you are
stressed, you become more aware, awake, focused. You are just generally more
responsive.
o It also helps to shift blood flow away from areas where it might not be so crucial,
like the skin, and toward more essential areas at the time, like the muscles, so
you can flee the stressful scene.
o Depending on the long-term impact of whatever's stressing you out -- and how
you personally handle stress -- it could take anywhere from half an hour to a
couple of days to return to your normal resting state

 Cortisol
What It Is: A steroid hormone, commonly known as the stress hormone, produced by the adrenal
glands.
o It takes a little more time -- minutes, rather than seconds -- for you to feel the
effects of cortisol in the face of stress because the release of this hormone takes
a multi-step process involving two additional minor hormones.
o First, the part of the brain called the amygdala has to recognize a threat. It then
sends a message to the part of the brain called the hypothalamus, which
releases corticotropin-releasing hormone (CRH). CRH then tells the pituitary
gland to release adrenocorticotropic hormone (ACTH), which tells the adrenal
glands to produce cortisol.
o In survival mode, the optimal amounts of cortisol can be life saving. It helps to
maintain fluid balance and blood pressure, while regulating some body functions
that aren't crucial in the moment, like reproductive drive, immunity, digestion and
growth.
o But when you stew on a problem, the body continuously releases cortisol,
and chronic elevated levels can lead to serious issues. Too much cortisol can
suppress the immune system, increase blood pressure and sugar, decrease
libido, produce acne, contribute to obesity and more.
 10. Describe the response of the coagulation factors to stress.

 It may be enhanced during the stress response to infection with the inflammatory and clotting
cascades being closely linked.
 During stress, there are increases concentration of circulating procoagulants such as fibrinogen
and cytokine IL6, which stimulate the expression of tissue factor.
 There is a down regulation of physiological anti-coagulant mechanisms such as protein C and
protein S (negative acute phase protein) and inhibition of fibrinolysis.
 Consequently, inflammation-induced coagulation is characterized by widesrpead intravacular
fibrin deposition.
 Impairment of thrombolysis occurs because of high circulating concentration of plasminogen
activator inhibitor type 1.
 Blood coagulation/Hemostasis includes three steps that occur in a rapid sequence:
o (1) vascular spasm, or vasoconstriction, a brief and intense contraction of blood vessels;
(2) formation of a platelet plug; and
o (3) blood clotting or coagulation, which reinforces the platelet plug with fibrin mesh that
acts as a glue to hold the clot together. Once blood flow has ceased, tissue repair can
begin.

11. Describe the response of acute phase proteins to stress.

 The acute phase response (APR) is a prominent systemic reaction of the organism to local or
systemic disturbances in its homeostasis caused by infection, tissue injury, trauma or surgery,
neoplastic growth or immunological disorders (Gordon and Koy, 1985; Gruys et al., 1999). At the
site of invasion by a micro-organism and the place of tissue injury, a number of responses of the
tissue itself are initiated.
 Pro-inflammatory cytokines are released, and the vascular system and inflammatory cells are
activated. These responses in turn are associated with production of more cytokines and other
inflammatory mediators which diffuse to the extracellular fluid compartment and circulate in the
blood.
 The cytokines activate receptors on different target cells leading to a systemic reaction resulting
in activation of the hypothalamic-pituitary-adrenal axis, reduction of growth hormone secretion)
and a number of physical changes clinically characterized by fever, anorexia, negative nitrogen
balance and catabolism of muscle cells
 Furthermore, a series of changes can be measured such as:
o (1) a decrease of blood plasma low and high density lipoprotein-bound cholesterol and
leukocyte numbers in blood,
o (2) increased values of adrenocorticotrophic hormone (ACTH) and glucocorticoids
o (3) activation of the complement system and blood coagulation system
o (4) decreased serum levels of calcium, zinc, iron, vitamin A and of α-tocopherol
o (5) a change in concentration of several plasma proteins, the acute phase proteins
(APPs) largely due to a changed hepatic metabolism. 

REFERENCES:
 Harper’s Illustrated Biochemistry
 Lippincott’s Illustrated Reviews: Biochemistry 5th edition
 ScienceDirect
 Wikipedia
 AMN Healthcare Education Services
 NCBI
 National Cancer Institute
 SpringerLink