BIOL 1080 Lecture Notes - Lecture 4: Chronobiology, Dual-Energy X-Ray Absorptiometry, Hydroxylapatite
2 May 2018
School
Department
Course
Professor
Chronobiology -the study of timescales and cycles in biology
Appetite (e.g. gherlin; meals)
○
Cortisol (pulsatile)
○
Ultraradian (<24 hrs)
•
Cortisol: nadir, midnight (sleep initiation), peak, 8 am
○
Circadian (24 hrs)
•
Menstrual cycle
○
Infraradian (>24 hrs)
•
Biological Rhythms:
Criteria: loss of >2cm in one year
○
Height is charted over years by physicians to alert them to
possible osteoporosis development and increased risk of
bone fracture
•
Due to compression/expansion of intervertebral disks
of the spinal cord (33 vertebrae, 16 disks)
○
But, there is approximately a 1.5cm diurnal variation in
height
•
Varies during the day, timing of measurements need to
be standardized
○
Needs to be measured over time in each individuals
○
Doesn’t change much during disease process (low
sensitivity)
○
Doesn’t directly precede (or predict) the disease state
○
Considerations for changes in height to be used as a
biomarker for osteoporosis:
•
Ex. Average Height (in men)
More definitive approach
•
Ca2+ deposited as calcium phosphate hydroxide
(hydroxyapatite) absorbs x-rays
•
Quick and non-invasive -usually done on lower spine/hip
•
0 = normal
○
-1 to -2.5 = osteopenia
○
< -2.5 = osteoporosis
○
Given a T-score due to incremental changes in BMD:
•
Neck of femur and intravertebral disks are main site of
fracture
○
Note: changes occur in both trabecular and cortical
bone
○
*see normal vs. osteoporotic bone
•
Time of day -not an issue
○
Low sensitivity -not an issue
○
Not prective -not an issue
○
*it is a sensitive biomarker
○
BMD via DEXA as a biomarker:
•
Dual energy X-ray absorptiometry (DEXA) to determine BMD:
*see figure on slide
•
Men and women have different bone densities, and different
patterns of bone loss as they age
•
Therefore, an effective way to help avoid low bone
density as you age is to attain a peak bone density
between these ages
○
Age peak of bone mass is between 20-30 years
•
*see gradient risk of osteoporosis fracture
•
Consume sufficient calcium1.
Get adequate vitamin D2.
Participate weight bearing physical activity most days
of the week
3.
To maximize bone density from 20-30 years of age:
•
Note: 90+ % of max bone density is achieved by age 20 in
the average individual
Smoking, alcohol, caffeine
○
High phosphate
○
Drugs (e.g.corticosteroids)
○
Factors that hinder maximal bone density:
•
Age Related Loss of Bone Density in Males and Females:
Acts as a 'buffer' for plasma calcium levels
○
Bone serves as a functional calcium store in the body
•
Via normal cell signalling and generation of action
potentials
○
Plasma calcium must be maintained over a very narrow
range
•
Parathyroid hormone: prevents decrease in plasma Ca2
+
○
Calcitonin: prevents an increase in plasma Ca2+
○
*see figure on slide
•
Bone and Plasma Ca2+ Homeostasis:
Involved in many physiological processes
•
Controls gene expression of enzymes/proteins that
affect many metabolic processes
○
Controlled by peripheral "clocks" governed by a "master
clock"
•
Coordinate sleep, nutrient supply and activity patterns with
the metabolic patterns required at different stages in the day
•
Elevated inflammatory cytokines (TNF, IL-6, C-
reactive protein)
○
Gastrointestinal function (ulcer, irritable bowel)
○
Obesity
○
Metabolic function
○
Their disruption in experimental animals causes a wide
spectrum of health problems and premature aging:
•
Nearly every cell in the body has a subsidiary
(peripheral) clock which coordinates its metabolism
with the rest of the body
○
*see slide
○
Peripheral clocks are guided by the SCN, but
also receives cues from inputs such as food
intake
!
SCN is the master clock and takes cues from light
○
The central "clock" is a brain region called the
"suprachiasmatic nucleus", which keeps time based on the
light signals from the retina
•
*see actual molecular circadian clock mechanism
•
Transcription factors BMAL1 and CLOCK bind as
heterodimers to promoters of Per and Cry genes
○
Per and Cry transcription is induced
○
Per and Cry feed back negatively to repress BMAL-
CLOCK and stop the cycle
○
Per/Cry inhibit REV-ERB which allows the
loop to begin again
!
For this to happen, inhibition of REV-ERB
happens after Per/Cry repress BMAL-CLOCK
!
However, BMAL is also controlled by a family of
repressors including REV-ERB
○
Molecular clock feedback loop:
•
Circadium Rhythms:
*see slide
•
Relative expression of BMAL1 is lower initially than the
control (diabetic plus insulin is even lower) but do not
change as drastically as the control
•
Relative expression of Per2 fluctuates less with diabetes
(little more with insulin)
•
Diurnal Rhythm of Clock Genes in the Liver are Alterated in Type
1 Diabetic Rats:
Insulin stimulated glucose uptake is impaired in muscle
which does not express BMAL1
•
Muscle specific knockout of BMAL1 and induced muscle
specific knockout of BMAL1 are both decreased
•
Insulin Sensitivity of Skeletal Muscle is Controlled by the
Molecular Clock
Still intact in most blind individuals (retina can still
detect light)
○
Entrained by light/dark cycles
•
Probably involves melatonin (pineal gland)
○
Blue spectrum light (screens and monitors) inhibit
melatonin release
○
Chemical signals involved not clear
•
Controlling the Molecular Clock (not very well understood)
Heart attacks
○
Obesity, diabetes, cardiovascular complications
○
Cancer
○
Alzheimer's
○
Shift workers tend to experience a greater incidence of:
•
Late chronotypes (night owls) are more likely to suffer from
mental stress and to smoke
•
Disruption of Circadian Rhythms -Health Implications
Greater insulin release, better sensitivity
○
No such rhythm in overweight people
○
Eat biggest meal in morning?
!
A factor when testing diabetes?
!
Practical implications:
○
Glucose tolerance are greater in the morning in normal
weight individuals
•
No clear answer
○
May be due to protein Klf15 (affects K+ efflux in
heart)
○
Combination of: caffeine, stress, non-healthy breakfast
foods
○
Risk of sudden heart attack is greatest mid-morning
•
Examples of Circadium Rhythm Relevant to Human Health:
Ghrelin release is entrained by mealtime patterns
(anticipation)
○
Some evidence that a high protein breakfast can
keep ghrelin reduced during the day
!
The decline of ghrelin post-meal is blunted in obese
individuals (not fasting levels?)
○
Ghrelin increases with weight loss (making it harder to
keep off weight?)
○
Appetite is stimulated by ghrelin, which is produced in the
stomach
•
Example of Ultradium Rhythm Relevant to Human Health:
*see article on slide: Why eating at the wrong time is tied to such
profound and negative effects on our bodies
Note: rodents are nocturnal but most research occurs during the
day…how does this affect our research findings?
Chronobiology
Saturday,*October* 7,*2017
3:35*PM
Chronobiology -the study of timescales and cycles in biology
Appetite (e.g. gherlin; meals)
○
Cortisol (pulsatile)
○
Ultraradian (<24 hrs)
•
Cortisol: nadir, midnight (sleep initiation), peak, 8 am
○
Circadian (24 hrs)
•
Menstrual cycle
○
Infraradian (>24 hrs)
•
Biological Rhythms:
Criteria: loss of >2cm in one year
○
Height is charted over years by physicians to alert them to
possible osteoporosis development and increased risk of
bone fracture
•
Due to compression/expansion of intervertebral disks
of the spinal cord (33 vertebrae, 16 disks)
○
But, there is approximately a 1.5cm diurnal variation in
height
•
Varies during the day, timing of measurements need to
be standardized
○
Needs to be measured over time in each individuals
○
Doesn’t change much during disease process (low
sensitivity)
○
Doesn’t directly precede (or predict) the disease state
○
Considerations for changes in height to be used as a
biomarker for osteoporosis:
•
Ex. Average Height (in men)
More definitive approach
•
Ca2+ deposited as calcium phosphate hydroxide
(hydroxyapatite) absorbs x-rays
•
Quick and non-invasive -usually done on lower spine/hip
•
0 = normal
○
-1 to -2.5 = osteopenia
○
< -2.5 = osteoporosis
○
Given a T-score due to incremental changes in BMD:
•
Neck of femur and intravertebral disks are main site of
fracture
○
Note: changes occur in both trabecular and cortical
bone
○
*see normal vs. osteoporotic bone
•
Time of day -not an issue
○
Low sensitivity -not an issue
○
Not prective -not an issue
○
*it is a sensitive biomarker
○
BMD via DEXA as a biomarker:
•
Dual energy X-ray absorptiometry (DEXA) to determine BMD:
*see figure on slide
•
Men and women have different bone densities, and different
patterns of bone loss as they age
•
Therefore, an effective way to help avoid low bone
density as you age is to attain a peak bone density
between these ages
○
Age peak of bone mass is between 20-30 years
•
*see gradient risk of osteoporosis fracture
•
Consume sufficient calcium
1.
Get adequate vitamin D
2.
Participate weight bearing physical activity most days
of the week
3.
To maximize bone density from 20-30 years of age:
•
Note: 90+ % of max bone density is achieved by age 20 in
the average individual
Smoking, alcohol, caffeine
○
High phosphate
○
Drugs (e.g.corticosteroids)
○
Factors that hinder maximal bone density:
•
Age Related Loss of Bone Density in Males and Females:
Acts as a 'buffer' for plasma calcium levels
○
Bone serves as a functional calcium store in the body
•
Via normal cell signalling and generation of action
potentials
○
Plasma calcium must be maintained over a very narrow
range
•
Parathyroid hormone: prevents decrease in plasma Ca2
+
○
Calcitonin: prevents an increase in plasma Ca2+
○
*see figure on slide
•
Bone and Plasma Ca2+ Homeostasis:
Involved in many physiological processes
•
Controls gene expression of enzymes/proteins that
affect many metabolic processes
○
Controlled by peripheral "clocks" governed by a "master
clock"
•
Coordinate sleep, nutrient supply and activity patterns with
the metabolic patterns required at different stages in the day
•
Elevated inflammatory cytokines (TNF, IL-6, C-
reactive protein)
○
Gastrointestinal function (ulcer, irritable bowel)
○
Obesity
○
Metabolic function
○
Their disruption in experimental animals causes a wide
spectrum of health problems and premature aging:
•
Nearly every cell in the body has a subsidiary
(peripheral) clock which coordinates its metabolism
with the rest of the body
○
*see slide
○
Peripheral clocks are guided by the SCN, but
also receives cues from inputs such as food
intake
!
SCN is the master clock and takes cues from light
○
The central "clock" is a brain region called the
"suprachiasmatic nucleus", which keeps time based on the
light signals from the retina
•
*see actual molecular circadian clock mechanism
•
Transcription factors BMAL1 and CLOCK bind as
heterodimers to promoters of Per and Cry genes
○
Per and Cry transcription is induced
○
Per and Cry feed back negatively to repress BMAL-
CLOCK and stop the cycle
○
Per/Cry inhibit REV-ERB which allows the
loop to begin again
!
For this to happen, inhibition of REV-ERB
happens after Per/Cry repress BMAL-CLOCK
!
However, BMAL is also controlled by a family of
repressors including REV-ERB
○
Molecular clock feedback loop:
•
Circadium Rhythms:
*see slide
•
Relative expression of BMAL1 is lower initially than the
control (diabetic plus insulin is even lower) but do not
change as drastically as the control
•
Relative expression of Per2 fluctuates less with diabetes
(little more with insulin)
•
Diurnal Rhythm of Clock Genes in the Liver are Alterated in Type
1 Diabetic Rats:
Insulin stimulated glucose uptake is impaired in muscle
which does not express BMAL1
•
Muscle specific knockout of BMAL1 and induced muscle
specific knockout of BMAL1 are both decreased
•
Insulin Sensitivity of Skeletal Muscle is Controlled by the
Molecular Clock
Still intact in most blind individuals (retina can still
detect light)
○
Entrained by light/dark cycles
•
Probably involves melatonin (pineal gland)
○
Blue spectrum light (screens and monitors) inhibit
melatonin release
○
Chemical signals involved not clear
•
Controlling the Molecular Clock (not very well understood)
Heart attacks
○
Obesity, diabetes, cardiovascular complications
○
Cancer
○
Alzheimer's
○
Shift workers tend to experience a greater incidence of:
•
Late chronotypes (night owls) are more likely to suffer from
mental stress and to smoke
•
Disruption of Circadian Rhythms -Health Implications
Greater insulin release, better sensitivity
○
No such rhythm in overweight people
○
Eat biggest meal in morning?
!
A factor when testing diabetes?
!
Practical implications:
○
Glucose tolerance are greater in the morning in normal
weight individuals
•
No clear answer
○
May be due to protein Klf15 (affects K+ efflux in
heart)
○
Combination of: caffeine, stress, non-healthy breakfast
foods
○
Risk of sudden heart attack is greatest mid-morning
•
Examples of Circadium Rhythm Relevant to Human Health:
Ghrelin release is entrained by mealtime patterns
(anticipation)
○
Some evidence that a high protein breakfast can
keep ghrelin reduced during the day
!
The decline of ghrelin post-meal is blunted in obese
individuals (not fasting levels?)
○
Ghrelin increases with weight loss (making it harder to
keep off weight?)
○
Appetite is stimulated by ghrelin, which is produced in the
stomach
•
Example of Ultradium Rhythm Relevant to Human Health:
*see article on slide: Why eating at the wrong time is tied to such
profound and negative effects on our bodies
Note: rodents are nocturnal but most research occurs during the
day…how does this affect our research findings?
Chronobiology
Saturday,*October* 7,*2017 3:35*PM
Document Summary
Chronobiology - the study of timescales and cycles in biology. Cortisol: nadir, midnight (sleep initiation), peak, 8 am. Height is charted over years by physicians to alert them to possible osteoporosis development and increased risk of bone fracture. But, there is approximately a 1. 5cm diurnal variation in height. Due to compression/expansion of intervertebral disks of the spinal cord (33 vertebrae, 16 disks) Considerations for changes in height to be used as a biomarker for osteoporosis: Varies during the day, timing of measurements need to be standardized. Needs to be measured over time in each individuals. Doesn"t change much during disease process (low sensitivity) Doesn"t directly precede (or predict) the disease state. Dual energy x-ray absorptiometry (dexa) to determine bmd: Ca2+ deposited as calcium phosphate hydroxide (hydroxyapatite) absorbs x-rays. Quick and non-invasive - usually done on lower spine/hip. Given a t-score due to incremental changes in bmd: Neck of femur and intravertebral disks are main site of fracture.
