C2006/F2402 '07 OUTLINE OF LECTURE #18
(c) 2007 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 04/11/2007 01:41 PM .
Handouts: Need 17B, 18A (Homeostasis) -- Seesaw view for Glucose and Temperature Regulation; 18 B -- Lactation & Typical Circuit
I. Organization -- How are cells set up to co-operate in a multicellular organism? See last lecture & 17B.
II. How is a component of the internal milieu regulated?
A. Let's look at a specific example, namely blood glucose. The see-saw view. See handout 18A or Purves 50.19 (50.20).
1. Have a regulated variable -- glucose level in blood.
2. Need a sensor (or receptor) -- to measure levels of "regulated variable" (glucose). Here, sensor is in pancreas.
3. Need effector(s) -- to control levels of regulated variable (glucose) -- usually have one or more effectors that respond in opposing ways. In this case, effectors for uptake of glucose are liver, adipose tissue, and skeletal muscle; effector for release of glucose is liver.
Note: Some of the terms discussed here are used differently in molecular biology and in physiology. Fortunately, the meaning is usually obvious from the context. For example, the terms "effector" and "negative feedback" are used differently in the two contexts. In physiology, "effector" usually means "a tissue or organ (like muscle or liver) that carries out an action and thus produces an effect." In this example, the effectors = organs that act to raise or lower the blood glucose. In molecular biology, the term "effector" is usually used to mean "a modulator of protein function." A modulator = a small molecule (like an inducer, enzyme activator etc.) that binds to a protein, alters the shape and/or function of the protein, and thus triggers an effect. See below for comments on 'negative feedback.'
4. Have a set point -- the level the regulated variable (blood glucose) should be. Set point is also sometimes used to mean the level at which corrections (to raise or lower the value) kick in.
In most cases, there is no significant difference between these two definitions of set point. In some cases, the desired value (first definition) and the value at which corrections occur (second definition) may be different. For example, there may be two cut-off points-- upper and lower, that bracket the desired level of a regulated variable. At levels above or below the respective cut-off points, messages are sent to the appropriate effectors to take corrective action. The term "critical values" is sometimes used instead of "set points" to describe the cut-off point(s).
5. Signaling -- need some signal system to connect the sensor(s) and the effector(s). Can be nervous &/or hormonal. In this case, primary (but not only) signal is hormonal & primary hormones (signals) are insulin & glucagon.
6. Negative Feedback -- the system responds to negate deviations from the set point. Important features:
a. Works to stabilize blood glucose levels
b. System is self-correcting -- Deviations in either direction (if blood glucose is either too high or too low) are corrected back to standard.
c. There are two opposing actions by effectors, not just one.
(1). If [G] gets too high, effectors take G up from blood. (top half of seesaw diagram)
(2). If blood [G] gets too low, effector releases G to blood. (bottom half of seesaw diagram)
d. Negative feedback is not always inhibition. In this case, an increase in glucose uptake is used to help lower high blood sugar levels. The deviation from the set point was fixed by accelerating, not inhibiting, a process. In negative feedback, deviations from the set point can be corrected either by speeding up a process (such as glucose uptake) or slowing down a process (such as glycogen breakdown to glucose).
e. How is this different from positive feedback? In positive feedback, the system responds to increase deviations from the set point -- a small deviation triggers a bigger one, which triggers a bigger one and so on. The deviations get bigger and bigger until → boom! (See lactation, below, for an example.)
f. Terminology: In physiology, negative feedback means the system is self correcting as in b & d above. It doesn't matter whether the corrections are achieved by inhibition (turning off the heater) or acceleration (turning on the air conditioner). In biochemistry, negative feedback usually means inhibition of an earlier step.
7. Value of regulated variable does not remain exactly constant, but stays within narrow limits.
See problem 5-1 & 5-2 a & b.
B. Example #2 -- Regulation of body temperature (in humans) -- the see-saw view (handout 18A)
1. Note many features are same as in glucose case.
2. Features not found in glucose case:
a. Multiple sensors in different places (for core and skin temp.)
b. Nature of Signal -- Signals are neuronal, not hormonal
c. Integrative center (IC)
(1). Role of IC: Compares set-point to actual value, sends appropriate message to effectors.
(2). Type of IC
(a). Sensor/IC function may be combined, as in Glucose example.
(b). Separate IC needed if there are multiple sensors, as in this case. IC co-ordinates incoming information from multiple sensors
(3). In this example, IC = hypothalamus (HT)
3. Organs/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.
4. Cooling vs. Heating -- What can effectors do? Effectors can increase or decrease heat loss; can only increase heat generation. (Cannot decrease heat generation.) 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.
C. Body Temperature and the General Case -- The Circuit View -- handout 18B.
1. Circuit = 1 loop of seesaw. Seesaw = double circuit. Often two circuits to make opposite types of corrections.
2. Signals: Signals can be hormonal or neuronal.
2. Afferent vs Efferent Signals. Bottom half of circuit has two arms -- afferent vs efferent→ toward effectors
Afferent information goes from sensors → in to IC
Efferent goes out of IC
3. Regulation vs Control.
a. Regulation/regulated variable: The variable (glucose level) you wish to keep at an approximately constant level is said to be "regulated."
b. Control/controlled process: The processes that alter levels of the regulated variable (glucose uptake, release or shivering, sweating, etc.) are said to be "controlled."
c. What's the difference?
The point of the system is to maintain homeostasis of blood glucose levels, internal temperature, etc. Not to maintain homeostasis of rates of glucose uptake, sweating, etc.
The value of the regulated variable stays about the same; the rates of the controlled processes (glucose uptake, sweating etc. ) can vary as much as necessary to achieve homeostasis of blood glucose levels.
4. May be multiple effectors and/or sensors.
5. IC (when there are multiple inputs) is nervous tissue or brain.
a. Major Role -- Compares current value to set point; sends appropriate message to effectors.
b. Adjustments -- IC can adjust set points and/or critical points. Why bother? Fevers & feedforward:
(1). Fevers -- Raise set point for body temperature and critical points for shivering/sweating
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 start 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.
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.
D. 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 A & B. (BMR = basal metabolic rate).
III. Lactation: Example of Positive Feedback See Handout 18B.
A. Overall Loop: Suckling by baby → milk ejection ("letdown) → more suckling → more milk ejection etc. Loop continues 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 neuron activity stimulates 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.
IV. Matching circuits and signaling -- an example: How the glucose circuit works at molecular/signaling level
A. Re-consider the circuit or see saw diagram for homeostatic control of blood glucose levels -- what happens in the boxes? It may help to refer to the table below.
B. How do Effectors Take Up Glucose?
1. Major Effectors: Liver, skeletal muscle, adipose tissue
2. Overall: In response to insulin, effectors increase uptake & utilization of glucose; Glucose is converted to storage forms (fat, glycogen) AND breakdown of storage fuel molecules (stores) is inhibited.
3. How does Insulin Work?
a. Receptor: Insulin works through a special type of tyrosine kinase linked receptor; See Purves 15.6 (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. How Does Insulin Increase Glucose Uptake?
(1). In resting skeletal muscle & adipose tissue -- mobilizes GLUT 4: In these tissues 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.
(2). In liver: Liver (& brain) can take up glucose without insulin -- they do not use GLUT 4. They use different transporters (GLUT 1, 2 &/or 3) located permanently in the plasma membrane.
(a). In liver: Insulin promotes glucose uptake in liver, but not directly. Insulin promotes uptake by increasing phosphorylation (trapping) and utilization of glucose.
(b). Note: Insulin has no affect on glucose uptake in brain.
(3). Working skeletal muscle: Insulin is not required for uptake of glucose in working skeletal muscle because exercise mobilizes GLUT4 in skeletal muscle. (Another good reason to exercise.)
c. Other Effects: In many tissues, insulin promotes utilization of glucose
(1). Activates appropriate enzymes for synthesis of storage forms of metabolites -- synthesis of glycogen, fat, and/or protein.
(2). Inhibits enzymes for breakdown of stores.
(3). Can promote utilization (breakdown) of glucose for energy.
d. Significance: Some effects of insulin are mimicked by other hormones, but mobilization of GLUT4 cannot be triggered by any other hormone. Therefore loss of insulin, or lack of response to insulin, is very serious, and causes diabetes type I or II, respectively. (See absorptive state, below.)
B. How do Effectors Release Glucose?
1. Primary Effector for Release = Liver
a. Only organ that can release significant amounts of glucose into blood -- why? Liver has phosphatase for G-6-P. Muscle and adipose tissue don't.
b. Other tissues can breakdown stores (fat, glycogen) to release fatty acids or lactate into blood, but cannot release glucose.
2. Overall: In absence of insulin, stores are broken down to generate small molecules; liver releases glucose into blood.
3. Role of Glucagon
a. Receptor: Glucagon works through a G protein linked receptor that triggers the cAMP pathway (as for epinephrine). Therefore it activates PKA; see handout 12 B for effect on glycogen metabolism.
b. Effects: Primary physiological effect is on liver; generally promotes production/release of glucose, not uptake or utilization. (Glucose is produced both by breakdown of glycogen, and build up from lactate = gluconeogenesis. See texts if you are interested in details of gluconeogenesis.)
c. Receptor triggers same pathway as epinephrine. Note that the same signaling pathway can be used for two different hormones (epinephrine & glucagon).
(1). Epi.(epinephrine) & glucagon bind to different receptors, but both receptors activate the same G protein and trigger the same series of events → cAMP → etc. so can get same response to both hormones in same tissue.
(2). Two hormones control same process (glycogen metabolism) for different purposes -- Epi to respond to stress; glucagon to respond to low blood sugar (maintain homeostasis).
(3). Different tissues can respond differently to these hormones. How? Both hormones trigger production of cAMP and activation of PKA. But there may be differences in receptors and/or targets of PKA:
(a). Receptors: 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.
(b). Targets: Even if receptors are same, different enzymes and/or processes are available to be affected by same kinase. For example, glycogen metabolism in liver vs. skeletal muscle. Both break down glycogen in response to glucagon or epi, but result is different.
In muscle, breakdown to lactate, and release lactate to blood.
In liver, breakdown to glucose - phosphate, and release glucose into blood.
d. Significance: Actions of glucagon can be mimicked by other hormones; there is no known medical condition caused by lack of glucagon. (See post absorptive state below.)
C. Overall Function of Effectors -- Summary:
1. Liver -- both releases glucose to blood and stores excess (as glycogen).
a. Carries out both storage and release of glucose so acts as buffer.
b. Only organ that can release significant glucose into blood (kidney may do some).
c. Takes up glucose without insulin -- uses GLUT 2 (always in plasma membrane), not GLUT 4. Insulin stimulates phosphorylation & utilization, not uptake.
2. Muscle -- stores or releases energy and protein. (Takes up glucose; stores excess as glycogen. When glycogen is broken down, releases lactate, not glucose, into blood.)
3. Adipose Tissue -- stores or releases fat/ fatty acids. (Uses up glucose & fatty acids; stores excess as fat. When fat is broken down, releases fatty acids into the blood.)
4. All three organs co-operate -- for example lactate generated in muscle is not broken down further in muscle -- it is shipped to liver and metabolized further in the liver. (For details see Purves 50-20 (15-21))
D. Absorptive vs Postabsorptive State -- A more complex view of the circuit (See Purves fig. 50.20 (50.21))
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.
→ 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. Absorptive state is completely dependent on insulin. Insulin affects all three effector organs.
2. There are two main states of food (not just glucose) supply:
a. Absorptive -- anabolic
b. Postabsorptive -- catabolic→ breakdown of macromolecules to release glucose*; 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. Postabsorptive state is largely caused by lack of insulin; also utilizes glucagon, but stress hormones (cortisol and epinephrine) can fill in for glucagon. Glucagon mainly affects liver.
*(Gluconeogenesis also occurs in liver = resynthesis of glucose from smaller molecules; see texts if you are interested.)
For questions on this topic
see problem set 7,
questions 7-22 to 7-25, and 4-14.
To review and to be sure you have this topic straight, fill in the following tables:
|Responds to Insulin?||Responds to Glucagon?||Can Release Glucose to Blood?||Uses GLUT 4||Can take up Glucose w/o Insulin?|
|Skeletal Muscle||+||-||-||+||only when working; not at rest|
* Adipose tissue has glucagon receptors, but there is no known response to physiological levels of glucagon.
|Type of Receptor/signaling pathway|
|Effect on blood glucose -- release or uptake?|
|Effect on glycogen -- synthesis or breakdown?|
|Result of intracellular glucose metabolism -- use it up or generate it?|
|Effect on intracellular glucose production -- inhibit or stimulate?|
V. Stress response -- How do hormones (cortisol & epinephrine) and nerves act together to respond to stress? We'll do this after nerves.
Next Week: The Kidney, and then How do nerves carry signals? (Dr. Stuart Firestein)