C2006/F2402 '09 OUTLINE OF LECTURE #20
(c) 2009 Dr. Deborah Mowshowitz, Columbia University, New York, NY. Last update 04/12/2009 02:12 PM .
Handouts: Need 20A (Homeostasis) -- Seesaw view for Glucose and Temperature Regulation; 20 B -- Lining of the GI Tract & Typical Circuit
I. Wrap up of Heart Structure/Function -- See notes of previous lecture and handouts 19C & 19D.
A. Pacemaker cells -- Properties and location
B. Overview of heart structure & circulation
II. Introduction to Physiology & Multicellular organisms
A. Single cell Life Style vs. Multicellular
1. Single celled organisms
a. Surrounded by external environment -- Can't change or regulate it
b. Have one basic function -- grow and multiply
c. Respond to external conditions (since can't change them) to maintain optimal intracellular state
(1). Pick up and/or dump what is necessary for metabolism
(2). Keep intracellular conditions (pH, level of amino acids, oxygen, etc.) as constant as possible and expend minimal energy by adjusting rates of transcription, enzyme activity, etc.
d. Note no specialization: each cell does all possible functions
2. Multicellular organisms & Homeostasis
a. Each cell in organism surrounded by internal environment. Extracellular fluid (ECF) that makes up internal environment is composed of:
plasma = liquid part of blood = fluid between blood cells
interstitial fluid (IF) = fluid between all other cells
b. Organism as whole can regulate composition of internal environment (milieu); therefore can maintain relatively constant external environment for each cell. Process of maintaining a relatively constant internal environment (of whole organism) = homeostasis.
c. Each cell has two basic functions
(1). Grow or maintain itself as above
(2). Specialized role in maintaining homeostasis of whole organism
d. Cells are Specialized. Maintenance of homeostasis requires co-operation of many different cell types, not just circuits within a single cell.
Summary of Above:
|Unicellular Organisms||Multicellular Organisms|
|What surrounds cell?||External environment||Internal environment of organism|
|Can organism regulate what surrounds each cell?||No||Yes|
|How many functions of each cell?||1||2 or more|
|Is cell specialized?||No||Yes|
B. Organization -- How are cells set up to co-operate in a multicellular organism? See 20B.
1. Cells, Tissues & the 4 major tissue types (5, if you count the blood separately) -- see lecture #4, & Sadava 40.7 (41.2)
a. Made of (different kinds of) tissues.
b. Example: lining of GI tract. Has layers of different tissues -- epithelial, connective, muscle, and nervous; these serve primarily for absorption (of material from lumen), support, contraction, and regulation respectively. (See handout 20B or Sadava fig. 40.7 (41.2)) The blood (a type of connective) doesn't really fit in this classification -- serves for transport of materials in and out.
3. Systems -- Group of Organs → body or organ system. Work together to maintain homeostasis for some component. See Sadava 40.1 (41.1). Number of systems depends on who's counting. Usual # is 8-12; see Sadava Table 41.1 (in 7th ed only) for a list.
III. How is a component of the internal milieu regulated?
A. General Principle -- Homeostasis is maintained by Negative Feedback
1. What is negative feedback? The system is self correcting -- it responds so as to decrease deviations from the set point. Deviations in either direction (too high or too low) are corrected back to standard (the set point).
2. How is negative feedback different from positive feedback? In positive feedback, the system responds so as 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.)
3. Results of negative FB: Value of regulated variable (blood glucose, or temperature) does not remain exactly constant, but stays within narrow limits.
4. Note on Terminology 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, negative and positive feedback are defined as above. For negative fb, it doesn't matter whether the corrections are achieved by inhibition (turning off the heater; stopping glucose production) or acceleration (turning on the air conditioner, increasing glucose uptake from blood).
In biochemistry, negative feedback usually means inhibition of an earlier step (& positive fb usually means activation).
'Effector' is also used differently in physio and biochem; see below.
B. Example #1 -- Regulation of blood glucose levels. The see-saw view. See handout 20A or Sadava fig. 50.19.
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 on terminology: 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.
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. Operation of Negative Feedback -- the system responds to negate deviations from the set point. Important features:
a. Works to stabilize levels of blood glucose (the regulated variable)
b. System is self-correcting -- Deviations in either direction (if blood glucose is either too high or too low) are corrected.
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).
See problem 5-1 & 5-2 a & b.
C. Example #2 -- Regulation of body temperature (in humans) -- the see-saw view (handout 20A)
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.
5. Does drinking make you warmer in winter? See this 'Really?' column from the NYTimes.
Try Problem 5-2, c. & 5-5.
C. Body Temperature and the General Case -- The Circuit View -- handout 20B.
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.
3. 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
4. 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, heat loss, heat generation, etc. ) can vary as much as necessary to achieve homeostasis of blood glucose levels or temperature.
5. May be multiple effectors and/or sensors.
6. 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, & 5-10.
IV. Lactation: Example of Positive Feedback
A. Overall Loop: Suckling by baby → milk ejection ("letdown") & milk production → more suckling → more milk ejection & production etc. Loop continues until baby stops nursing.
B. Signaling Pathway: Involves both nerves and 2 dif. hormones (oxytocin and prolactin). We'll postpone specifics until after hormones.
General idea: Suckling by
baby stimulates nerve endings in nipple →
afferent nerve signal to part of pituitary gland/brain
efferent hormonal signals from pituitary (2 dif. hormones from dif.
parts of pit.) → breast; hormone 1 (PL) promotes milk production,
secretion of milk into lumen of gland; hormone 2 (oxytocin) promotes ejection of
milk (letdown) from mammary gland.
V. 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 cell surface receptor, a tyrosine kinase linked receptor; See Sadava 15.6. Insulin has many affects on cells and the mechanism of signal transduction is complex (activating multiple pathways). In many ways, insulin acts more like a typical growth factor than like a typical endocrine. (Insulin has GF-like effects on other cells; is in same family as ILGFs = insulin like growth factors). More on GFs and TK receptors later.
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: 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 text or handout on glycogen metabolism for details.
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 are differences in which receptors are present and/or which targets of PKA:
(a). Receptors: Receptors present on cell surface determine which tissues will respond to each hormone.
Muscle has Epi receptors (but no glucagon receptors); therefore responds to Epi but not glucagon
Liver has receptors for both epi and glucagon 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 tissues break down glycogen in response to epi, but result is different.
In muscle, breakdown to lactate, and release lactate to blood.
In liver, breakdown to glucose - P, 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. (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 many more details than you need see Sadava 50-20 (7th ed only))
D. Absorptive vs Postabsorptive State -- A more complex view of the circuit
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 detailed diagram of fuel traffic in both states (that goes way beyond what you need) is in Sadava fig. 50.20 (7th ed only) and in all physiology books.
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 7-23 to 7-26, and 4R-3.
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?|
Next Time: Wrap up of homeostasis, as needed. Than: What are the other major hormones (other than insulin and glucagon)? How do they control the internal milieu? What else do they do?