Lecture 1.2 Week 1 part 2 Homeostatic Control Mechanisms: Feedback, Feedforward, and Lipid Regulation

Feedback and Feedforward Control Mechanisms

• Negative Feedback and Stability

  • Negative feedback is the primary mechanism for maintaining homeostasis by promoting stability within the body.

  • The defining characteristic of negative feedback is that it blocks the directionality of a process. If a physiological parameter deviates from the norm, negative feedback mechanisms act to reverse that direction and return the parameter toward the set point.

  • It is a common misconception that negative feedback always results in a "negative" or harmful consequence; in biology, it refers to the inhibitory nature of the response relative to the stimulus.

• Positive Feedback and Instability

  • Positive feedback promotes movement in the same direction as the initial stimulus, effectively accelerating the process.

  • This mechanism is often associated with instability and, in many cases, disease or pathophysiology.

  • Positive feedback continues the directionality rather than blocking it.

• Feedforward Mechanisms and Anticipation

  • Feedforward control is the anticipation of change before it actually occurs.

  • These mechanisms allow the body to prepare for a stimulus in advance, rather than simply reacting to it after the fact.

Physiological Examples of Negative Feedback

• The Endocrine System (Thyroid Regulation)

  • The hypothalamic-pituitary-thyroid axis is a classic example of a negative feedback loop.

  • The process begins when the hypothalamus secretes Thyrotrophic Releasing Hormone ($TRH$).

  • $TRH$ stimulates the anterior pituitary gland to secrete Thyroid Stimulating Hormone ($TSH$).

  • $TSH$ then stimulates the thyroid gland to produce and secrete thyroid hormones: Triiodothyronine ($T_3$) and Thyroxine ($T_4$).

  • These hormones are delivered to peripheral tissues to regulate metabolism.

  • Feedback Loop: When blood levels of $T_3$ and $T_4$ become too high, they exert a negative feedback effect on both the hypothalamus and the anterior pituitary. This inhibits the further secretion of $TRH$ and $TSH$, thereby stopping the production of additional thyroid hormones and maintaining homeostasis.

• Melatonin Regulation

  • The regulation of melatonin involves several organ systems, including the pituitary gland, the liver, and the adrenal glands.

  • This system is central to the regulation of the sleep-wake cycle.

  • Like the thyroid system, it utilizes negative feedback on the hypothalamus and pituitary to ensure that once sufficient levels are reached, production is controlled and decreased.

• Arterial Blood Pressure (The Baroreceptor System)

  • The baroreceptor system is a rapid-response negative feedback mechanism for blood pressure regulation.

  • High Pressure Response: When arterial pressure rises too high, baroreceptors located in the neck and thorax sense the stretch and send nerve impulses to the medulla in the brain. The medulla then sends signals to decrease the pumping action of the heart and dilate blood vessels, lowering the pressure.

  • Low Pressure Response: If arterial pressure falls below normal levels, the vasomotor system is activated to cause vasoconstriction and increase the heart's pumping action.

  • The "Negative on Negative" Concept: In the case of low blood pressure, the system senses a negative deviation (the drop in pressure) and responds by activating the sympathetic nervous system to increase heart rate and cause vasoconstriction. Because this response blocks the reduction in arterial pressure, it is still classified as negative feedback, even though the ultimate result is an increase in blood pressure ($\text{negative response} \times \text{negative stimulus} = \text{positive result}$).

Physiological Examples of Positive Feedback

• Useful Positive Feedback Processes

  • Blood Clotting: When a wound occurs, the induction of clotting factors triggers the activation of more clotting factors in a positive feedback cascade. This is essential for stopping blood loss. However, this must eventually be limited by negative feedback control; otherwise, it could lead to abnormal thrombosis or a pulmonary embolism.

  • Childbirth (Parturition): Repeated contractions of the uterus during labor are governed by positive feedback. One contraction induces the release of hormones (like oxytocin) that cause more powerful and frequent contractions until the baby is born.

  • Lactation: A suckling infant stimulates the production of milk; more suckling induces more lactation. The positive feedback loop is broken only when the infant stops suckling.

  • Action Potentials: In nerve cells, the depolarization of the cell membrane leads to an influx of sodium ions ($Na^+$). This change in membrane potential causes even more sodium channels to open, leading to a massive influx of $Na^+$ and the rapid generation of an action potential to accelerate nervous responses. This cycle involves $Na^+$ moving into the cell while potassium ($K^+$) moves out.

• Pathophysiological Positive Feedback: Hemorrhagic Shock

  • In the event of a severe hemorrhage, there is a reduction in venous return to the heart, which reduces cardiac output.

  • Lower cardiac output leads to reduced blood pressure and reduced coronary blood flow, which in turn weakens the heart (reduced cardiac contractility).

  • The weakened heart further reduces cardiac output, creating a lethal positive feedback loop.

  • Thresholds for Recovery: If a person loses approximately $1\,liter$ of blood, the body's compensatory negative feedback mechanisms can typically return the system to normalcy. However, if blood loss reaches $2\,liters$ or greater, the positive feedback of heart failure becomes too strong to overcome, often leading to death.

Feedforward Mechanism Details

• Anticipatory Responses

  • Cephalic Response: When a person is presented with a delicious meal, the brain sends signals to the salivary glands, causing the person to drool in anticipation of eating.

  • Thermoregulation: A person may begin shivering before they actually step out into the cold, as the body anticipates the drop in temperature.

  • Physical Exertion: The heart rate often increases in advance of physical exercise (e.g., before starting a marathon) or due to stress (e.g., before taking an exam) via the sympathetic nervous system.

• Molecular and Neural Feedforward

  • Transcription factors can induce changes in gene expression in response to an anticipated environmental shift.

  • The brain can trigger muscle contractions through sensory nerve signals prior to the actual need for full movement.

• Regulation of Feedforward Control

  • Feedforward mechanisms can be corrected or overridden by negative control systems if the anticipation is inaccurate. For example, if a person puts on a warm sweater, the feedforward shivering response will be inhibited.

  • Similarly, once a person begins eating, the brain modulates the salivary signals to prevent excessive drooling during the meal.

System Integration and Homeostasis

• Organ systems do not function in isolation; they work together to maintain the internal environment of the extracellular fluid.

• Respiratory and Nervous Systems: These systems collaborate to regulate $CO_2$ levels. High levels of $CO_2$ in the extracellular fluid excite the nervous system, which then induces rapid breathing to expel the excess gas.

• Hemoglobin Function: Hemoglobin in the lungs combines with oxygen and releases it into the bloodstream in varying amounts based on the specific needs and levels present in the tissues.

Cholesterol and Homeostasis

• Bad Cholesterol (LDL): Low-Density Lipoprotein ($LDL$) is known as "bad" cholesterol because it can build up in blood vessels to form plaque. This narrows the arteries and makes them less flexible, leading to atherosclerosis.

• Good Cholesterol (HDL): High-Density Lipoprotein ($HDL$) is "good" because it regulates the storage of $LDL$ and promotes its excretion. It helps prevent $LDL$ from lodging in artery walls and serves as a protective factor against heart attacks.

• Cholesterol Sources: Approximately $75\%$ of blood cholesterol is synthesized in the liver, while the remaining $25\%$ is derived from dietary intake.

• Essential Roles of Cholesterol:

  • Membrane Synthesis: Required for the formation and maintenance of phospholipid cell membranes.

  • Myelin Sheath: Necessary for creating the myelin sheath that surrounds neurons, providing insulation and significantly increasing the rate of neural conduction.

Advanced Pharmacology: PCSK9 and Statins

• The PCSK9 Genetic Discovery

  • In two unrelated cases—a $32$-year-old aerobics instructor in Dallas and a young woman in Zimbabwe—researchers found extremely low cholesterol levels of $14\,mg/dL$ and $15\,mg/dL$ respectively (where normal levels are typically above $100\,mg/dL$).

  • Both women possessed a double mutation in the $PCSK9$ gene.

  • This discovery triggered a pharmaceutical race involving companies like Amgen, Pfizer, and Sanofi to develop drugs that could mimic this effect to treat high cholesterol.

• Mechanism of PCSK9 Inhibitors

  • Normal Function: $PCSK9$ binds to $LDL$ receptors on the surface of hepatocytes (liver cells). This binding leads to the internalization and degradation of the receptors within lysosomes.

  • Effect: Fewer available $LDL$ receptors mean less $LDL$ is removed from the blood, allowing it to build up in the arteries.

  • Inhibition: Drugs like Praluent and Repatha (injectables) block the $PCSK9$ protein. This prevents the degradation of $LDL$ receptors, resulting in an abundance of receptors on the liver cell surface that can then bind to and remove $LDL$ from the bloodstream.

• Statins vs. PCSK9 Inhibitors

  • Statins: These are considered first-line therapy. They work by inhibiting the enzyme $HMG\,CoA\,reductase$, which is a critical step in the hepatic synthesis of cholesterol (blocking $HMG\,CoA$ production).

  • PCSK9 Inhibitors: These are second-line therapies, often reserved for patients with very high cholesterol who do not respond sufficiently to statins, partly because they are more expensive injectables.

  • Both interventions effectively reduce $LDL$ levels to prevent atherosclerosis.