C2006/F2402 '04 OUTLINE OF LECTURE #15
(c) 2004 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 03/11/2004 12:46 PM .
Handouts: Need 14C (Homeostasis), 14D (Temperature Regulation), 15 A -- Glucose Homeostasis; 15 B -- Lactation & Stress Response
I. Homeostasis, cont. How are components of the internal milieu regulated?
A. Regulation of body temperature (in humans) -- the see-saw view (14C)
1. Features not found in glucose case:
a. Multiple sensors in different places (for core and skin temp.)
b. Need separate integrative center (IC).
(1). Role of IC: Compares set-point to actual value, sends appropriate message to effectors.
(2). Sensor/IC function may be combined, as in Glucose example.
(3). Separate IC needed if there are multiple sensors, as in this case.
(4). In this example, IC = hypothalamus (HT)
(5). Role of separate IC: Co-ordinates incoming (afferent) information from sensors; compares set-point to actual value, sends appropriate outgoing (efferent) information to effectors.
2. Different body systems involved as effectors
Action To Raise Temp
Action To Lower Temp
Contraction generates heat (shivering)
Smooth muscle of peripheral blood vessels in skin
Muscles contract; vessels constrict to reduce heat loss
Muscles relax; vessels dilate to increase heat loss
Produce sweat; evaporation increases heat loss
Behavioral (nonphysiological) responses-- put on coat, curl up, etc.
Behavioral (nonphysiological) responses -- take off coat, etc.
3. Cooling vs. Heating -- What can effectors do? Effectors can increase or decrease heat loss; can only increase heat generation. (No air conditioner.) Therefore ability of humans to cope with very cold environments is better than their ability to cope with excessively hot environments.
Try Problem 5-2, c. & 5-5.
4. Metabolic rate and temperature control in homeotherms (organisms with aprox. const. internal temp.) that are endotherms (generate own heat internally) as vs. poikilotherms/ectotherms. (See Purves p. 700 [p. 817] for further discussion of these terms.) See handout 14D, top.
a. Constriction/dilation of blood vessels uses relatively little energy. This allows adjustment of body temperature without changing metabolic rate in range of external temperature called the "neutral zone."
b. Both heating (by shivering) and cooling (by sweating) require lots of energy. Therefore MR (metabolic rate) increases outside neutral zone at both high and low temperatures.
c. Overall how MR (metabolic rate) changes with external temperature (see handout 14D, top or Purves, fig. 40.15 [37-19]). Thermo-neutral zone is bounded by critical temperatures = points at which shivering or sweating occur = set points for shivering or sweating.
B. Body Temperature and the General Case -- The Circuit View -- see handout 14D, bottom.
1. Signals: System involves more than one cell so signals must be sent using nerves and/or hormones from sensor to effectors. (For comparison: only 1 cell involved in 2 cases of f.b. previously discussed: Fe circuit with Ferritin/Transferrin Receptor or interconversion of glycogen and glucose 1P in skeletal muscle)
2. Afferent vs Efferent Signals. Bottom half of circuit has two arms -- Afferent information (from sensors in to IC) vs efferent (out of IC --> effectors)
3. Regulation vs Control. Note the variable (glucose level) you wish to keep at an approximately constant level is said to be "regulated" but the processes that alter levels of the regulated variable (glucose uptake, release, etc.) are said to be "controlled." The point of the system is to maintain homeostasis of glucose levels, not homeostasis of rates of glucose uptake, release, etc. The rates of the controlled processes -- uptake, release etc. -- can vary as much as necessary to achieve homeostasis of glucose levels.
4. May be multiple effectors and/or sensors.
5. IC (when there are multiple inputs) is nervous tissue or brain.
a. Compares current value to set point; sends appropriate message to effectors.
b. Can adjust set points and/or critical points. Fevers & feedforward.:
(1). Fevers -- Raise set point for body temperature and critical points for shivering/sweating
Shift curve of MR vs external temp to right; shivering and sweating both kick in at higher temps. (You don't have to cool off as much to start shivering and you need to heat up more to stop sweating.) Raises set point (desired level) & actual level of internal body temperature.
Why fevers? High temperatures prevent bacteria from obtaining iron from host & improve immune function.
(2). Feedforward or anticipation -- Planning ahead. Altering set points and/or critical points to adjust to anticipated factors. (Or you can think of it as just ignoring the usual critical points.) Examples:
Body temperature: Skin temperature affects critical temperature/set points for generating heat and/or shivering. If body is cold, but it's warm outside, shivering can be postponed, saving energy, and you'll still warm up. This is equivalent to lowering (or ignoring) set point/critical points for shivering, not changing set point of internal body temperature. Changes what effectors and what controlled processes you use to warm up, but not the end result. (See Purves, fig. 40. 19 [37.23]).
Secreting insulin when you start to digest food in the stomach, but before the digestion products (glucose, amino acids etc.) reach the blood. This way tissues will be ready to take up the glucose as soon as it enters the blood.
C. What other components of internal milieu are regulated besides glucose, temperature? Many nutrients like amino acids; concentrations of water, salts and ions (Na+, K+ etc.), gases (CO2, O2), waste products, volume & pressure of blood, and pH.
Try Problems 5-3, 5-4, & 5-9.
II. Matching circuits and signaling -- an example: How the glucose circuit works at molecular/signaling level
A. Re-consider the circuit diagram for homeostatic control of blood glucose levels -- what goes along the arrows, and what happens in the black boxes? (See handouts 14C & 14D or Purves 50.20 [47.19])
B. Mechanism of Action of hormones Involved
a. Receptor: Insulin works through a special type of tyrosine kinase linked receptor; See Purves 15.7. Insulin has many affects on cells and the mechanism of signal transduction is complex (activating multiple pathways). In many ways, insulin acts like a GF (it has GF-like effects on other cells; is in same family as ILGF's).
b. Effect on GLUT 4: In some tissues (muscle, adipose), insulin mobilizes transporter for facilitated diffusion (of glucose) -- GLUT 4 protein -- promotes fusion of vesicles containing the transporters with plasma membrane. No other hormone can cause this effect.
c. Other Effects: In other tissues, insulin promotes utilization of glucose -- activates appropriate enzymes for glycogen, fat storage.
d. Overall: promotes uptake & utilization of glucose.
a. Receptor: Glucagon works through a G protein linked receptor that triggers the cAMP pathway (as for epinephrine).
b. Effects: Effects on tissues vary; generally promotes production/release of glucose, not uptake or utilization.
c. Receptor triggers same pathway as epinephrine. Note that the same signaling pathway can be used for two different hormones (epinephrine & glucagon).
(1). Epi. & glucagon bind to different receptors, but both receptors activate the same G protein and trigger the same series of events --> cAMP --> etc. so get same response to both hormones in same tissue.
(2). Receptors present on cell surface determine which tissues will respond to each hormone. Muscle has Epi receptors and responds to Epi but not glucagon; liver has receptors for both and responds to both.
(3). Two hormones control same process (glycogen metabolism) for different purposes -- Epi to respond to stress; glucagon to respond to low blood sugar (maintain homeostasis).
(4). Same hormones give different response in liver vs adipose tissue. How? Both hormones trigger production of cAMP and activation of PKA. But different enzymes and processes (glycogen metabolism vs. fat metabolism) available to be controlled by same kinase.
C. Absorptive vs Postabsorptive State -- A more complex view of the circuit (See Purves fig. 50.21 [47.20]) & handout 15A.
1. What is really being regulated by insulin & glucagon? Really two different things:
a. Maintenance of glucose homeostasis
b. Managing an episodic event (eating) -- this can be considered just another example of homeostasis -- here the 'episodic' nature of eating generates two basic states that must be controlled differently to maintain homeostasis.
2. There are two main states of food (not just glucose) supply:
a. Absorptive -- anabolic --> synthesis & storage of macromolecules; glucose is primary energy source. In this state, right after you eat, the risk is that blood glucose levels will rise too much.
b. Postabsorptive -- catabolic --> breakdown of macromolecules. and synthesis of glucose from smaller stuff (gluconeogenesis); fatty acids are primary energy source (except in brain). In this state, between meals, the risk is that blood glucose levels will fall too much.
3. Roles of Effectors = target organs (see handout 15A) in raising/lowering glucose levels.
a. Liver -- carries out both storage and release of glucose so acts as buffer; only organ that can release glucose into blood and does gluconeogenesis; takes up glucose without insulin (does not use GLUT 4).
b. Muscle -- stores or releases energy and protein.
c. Adipose -- stores or releases fat/ fatty acids.
d. All three organs co-operate -- have pathway in post-absorptive state that uses all three; involves traffic of components from one tissue to another.
4. Roles of the Hormones
a. Insulin. Absorptive state is absolutely dependent on insulin. What does insulin do?
(1). In liver
(a). Insulin promotes glycogen synthesis (& breakdown of glucose for energy) -- uses glucose up.
(b). Insulin inhibits glycogen breakdown (& gluconeogenesis) -- inhibits production and release of glucose.
(c). Insulin also promotes glucose uptake, but not directly. Insulin promotes uptake by increasing phosphorylation and utilization of glucose.
(2). In other tissues (adipose tissue, resting skeletal muscle)
(a). Insulin promotes synthesis of storage forms of metabolites -- fat (triglycerides), glycogen, &/or protein
(b). Insulin inhibits breakdown of stores of fat, glycogen etc.
(c) Insulin directly stimulates glucose uptake. Insulin mobilizes the glucose transporter (GLUT4) so glucose uptake can occur. Insulin is required for uptake of glucose into these tissues.
(3). Note: Insulin is not required for uptake of glucose in brain, liver or working skeletal muscle. Liver and brain use different transporters (GLUT 1, 2 & 3) located permanently in the plasma membrane, and exercise mobilizes GLUT4 in skeletal muscle.
b. Glucagon. Postabs. state largely caused by lack of insulin; also utilizes glucagon but stress hormones (cortisol and epinephrine) can fill in for glucagon. What steps are affected by Glucagon?
(1). In liver: Promotes catabolism (breakdown) of glycogen, promotes gluconeogenesis and inhibits synthesis of glycogen (all through cAMP).
(2). In adipose: Inhibits synthesis and promotes breakdown of fats (through cAMP).
(3). In muscle: No effects -- muscle lacks glucagon receptors.
For questions on this topic see problem set 7 -- additional problems.
III. Lactation: Example of Positive Feedback & Use of Neuronal signals See 15B.
A. Overall Loop: suckling by baby ---> milk ejection ("letdown) --> more suckling --> more milk ejection etc. until baby stops nursing.
B. Signaling Pathway: Suckling by baby stimulates nerve endings in nipple ---> nerve signal to HT --> release of oxytocin from post. pit. --> contraction of myoepithelial cells (similar to smooth muscle) surrounding alveolus (milk producing section of mammary gland) ---> milk ejection from lumen of alveolus ---> etc.
At same time, HT neurons stimulate ant. pit to release prolactin (PL) ---> stimulates inner layer of cells surrounding lumen of alveolus --> promotes milk production and secretion of milk into lumen of gland.
Question to think about: what's the circuit look like here? What's the IC? The effector? Etc.
Try problems 7-14 & 7-18.
To look at a more complex case using nerves & hormones helps to look at basic organization of nervous system first. This section is FYI -- not covered in class -- will be discussed after nerve cell function.
IV. How is Nervous System organized overall?
A. CNS & PNS.
1. CNS = brain + spinal cord
2. PNS -- Part of nervous system outside of CNS. See Purves 46.2 [43.2] -- Names of Divisons
a. Two divisions of PNS: Afferent (carrying info into the CNS) vs Efferent (carrying info away from the CNS)
b. Two divisions of Efferent: Somatic (controls skeletal muscle = voluntary actions) vs autonomic (controls all unconscious responses = automatic actions)
c. Two divisions of autonomic: Parasympathetic (PS) vs Sympathetic (S)
B. How do PS and S co-operate? (See Purves 46.11 [3.11])
1. What do they innervate (what organs to they connect to)?
a. Many organs innervated by both
b. Some organs innervated by only one
(1). liver, sweat glands -- S only
(2). tears -- PS only
2. What results does stimulation (signal from nerve) produce?
a. Not always S excites; PS inhibits. Ex: salivation -- S inhibits; PS excites
b. Usually S --> response needed in a crisis; PS --> response needed to return to relaxed state.
(1). Effects of S -- heart rate increases; liver releases glucose; bladder relaxes (to hold more).
(2). Effects of PS -- heart rate decreases, digestion & salivation increase.
V. Stress response -- How do hormones and nerves act together to respond to stress? See handout 15B.
A. Phase one -- Sympathetic activity stimulates target organs (that are not glands) --> Direct response of heart, liver, lungs, etc.
B. Phase two -- Sympathetic activity --> activation of glands
1. Stimulate pancreas ---> glucagon increases; insulin decreases --> additional stimulation of some target organs
2. Stimulate adrenal medulla --> release of epinephrine --> stimulation of same targets as sympathetic activity & some additional targets -- hormones can reach where nerves can't go.
C. Phase three
-- stimulate HT/AP axis to produce cortisol
HT in brain ---> releases CRH --> AP ---> releases ACTH --> adrenal cortex ---> produces cortisol --> target organs ---> stimulation of breakdown of fats & protein (instead of glucose); inhibition of immune system.
Note that each additional phase is slower but involves additional degrees of amplification due to second messengers, transcription, etc.