Exercise Endocrinology Chapter 5

Exercise Endocrinology

• Reading: Chapter 5

Introduction

• Fuel sources are mobilized and utilized in a coordinated manner.
• Adipose tissue is stimulated to release more FFAs.
• The liver is notified to create/release more glucose into the blood.

Neuroendocrinology

• The neuroendocrine system includes the nervous and endocrine systems.
• The endocrine system releases hormones.
• The nervous system uses neurotransmitters.
• Endocrine glands release hormones (chemical messengers) directly into the bloodstream.
• Hormones alter the activity of tissues that possess receptors to which the hormone can bind.
• It is the binding that initiates the action.

Hormones

• Several classes of hormones are based upon their chemical makeup:
  • Amino acid derivatives
  • Peptides
  • Proteins
  • Steroids
• Chemical structure impacts how hormones are transported and their effects on a tissue.

Blood Hormone Control

• The effect a hormone exerts on a tissue is proportional to its concentration in the blood and the number of active receptors.
• Hormone concentration depends upon:
  • Rate of secretion from the gland
  • Rate of metabolism or excretion
  • Quality of transport proteins (for steroids)
  • Changes in plasma volume

Hormone Secretion

• The rate of hormone secretion depends on the magnitude and nature (stimulatory or inhibitory) of the input.
• Input is always a chemical, such as an ion, neurotransmitter, or another hormone.
• Hormone control of processes is redundant with many inhibitors of secretion.

Factors Influencing Insulin Secretion

• Plasma concentration and sympathetic neurons inhibit insulin secretion.
• Plasma glucose, amino acids, and parasympathetic neurons stimulate insulin secretion.
• Plasma Epinephrine and other hormones affect insulin secretion.

Metabolism of Hormones

• Plasma concentration is influenced by the rate of metabolism.
• Inactivation can occur at or near the receptor or in the liver, which is the major site for hormone metabolism.
• Kidneys also help in hormone secretion.

Transport Protein & Plasma Volume

• Some hormones, particularly steroid hormones, require transport in blood via a binding/transport protein.
• A hormone must exist freely to exert an effect.
• The amount of free hormone depends on the transport protein's quality, capacity, and affinity to bind hormone molecules.
• Changes in plasma volume occur with changes in body position, during exercise, and in response to heat.
• This concentrates the blood, increasing the concentration of a hormone and, therefore, enhancing its effects on a tissue.

Hormone-Receptor Interactions

• Hormones are carried via circulation to all tissues, but effects are exerted only on those with specific receptors.
• Receptors are not static fixtures.
• Downregulation: a decrease in receptor number in response to high hormone concentration, diminishing response for same hormone concentration/sensitivity.
• Upregulation: an increase in receptor number in response to low hormone concentration, enhancing sensitivity.
• Saturation: when all receptors are bound; additional increases in concentration will have no effect.
• Competition: hormones with similar chemical shapes can compete for binding.

Mechanisms of Hormone Action

• Hormones can exert effects in several ways:
  • Altering DNA activity in the nucleus to initiate or suppress the synthesis of a specific protein (steroids)
  • Activating special proteins called "second messengers"
  • Altering membrane transport mechanisms (insulin)

Altering Activity of DNA in the Nucleus

• Steroid hormones easily diffuse into cells.
• Once inside, a steroid hormone binds to a receptor protein in the cytoplasm or nucleus.
• If bound, the complex enters the nucleus.
• In the nucleus, the complex binds to hormone-responsive elements on DNA.
• This activates (or could suppress) genes that lead to mRNA synthesis.

Cyclic AMP “Second Messenger” Mechanism

• A hormone binds to a receptor on the cell surface.
• This activates a G protein located within the cell membrane.
  • Link between inside of cell and hormone-receptor complex on surface
• G protein activates adenylate cyclase, causing the formation of cyclic AMP.
• Increased cyclic AMP concentration activates protein kinase A.
• PKA activates response proteins to alter cellular activity.

Ion Channel "Second Messenger” Mechanism

• A hormone binds to a receptor on the cell surface.
• This activates a G protein located within the cell membrane.
  • Link between inside of cell and hormone-receptor complex on surface
• G protein activates phospholipase C.
• Phospholipid on the membrane (PIP2) is hydrolyzed into IP3 (causing Ca++ release) and DAG
• Ca++ binds to and activates calmodulin.
• DAG activates protein kinase C, which activates proteins in the cell.
• Works in concert with calmodulin effects

Membrane Transport

• Hormones bind to receptors, activating carrier molecules to facilitate substrate/ion movement into the cell.

Hormones: Regulation and Action

• Hormones are secreted from endocrine glands.
• These glands include:
  • Hypothalamus and pituitary glands
  • Thyroid and parathyroid glands
  • Adrenal gland
  • Pancreas
  • Testes and ovaries

Hypothalamus and Pituitary Gland

• The hypothalamus controls secretions from the pituitary gland and is located at the base of the brain, attached to the pituitary.
• Hormone release from the anterior pituitary gland is controlled via chemicals originating in neurons in the hypothalamus.
• The hypothalamus-derived chemicals stimulate or inhibit the anterior pituitary release of specific hormones.
• Hormone delivery to the posterior pituitary gland is also controlled by the hypothalamus.
• Hormones move down the axon to blood vessels and discharge into the general circulation.

Hypothalamus and Pituitary Gland

• The anterior pituitary gland hormones include:
  • Adrenocorticotropic hormone (ACTH)
  • Follicle-stimulating hormone (FSH)
  • Luteinizing hormone (LH)
  • Melanocyte-stimulating hormone (MSH)
  • Thyroid-stimulating hormone (TSH)
  • Growth hormone (GH)
  • Prolactin
• The posterior pituitary gland hormones include:
  • Oxytocin
  • Antidiuretic hormone (ADH)

Growth Hormone

• GH secretion is stimulated by most potent stimuli like exercise, also sleep, stress, and low plasma glucose
• Stimulates growth of all tissues through the action of insulin-like growth factors (IGFs)
• Induces uptake of amino acids, synthesis of new proteins, and long-bone growth while sparing glucose.
• GH release is controlled via negative feedback, where GH and IGF concentration inhibit further GH release.

Role of GH and Maintenance of Plasma Glucose

• Growth hormone increases gluconeogenesis in the liver, adipose tissue triglycerides, and FFA oxidation while blocking glucose entry.

GH and Exercise

• GH is very responsive to exercise, increasing by about 2,000% at max.
• The GH response is greater in trained versus untrained individuals.
• Exact reasons are unclear.

GH and Performance

• GH increases protein synthesis and long-bone growth.
• It treats childhood dwarfism and is used by the elderly and athletes.
• Athletes, despite a potential history of use and more adverse than beneficial effects, may benefit from micro-dosing.
• There is minimal empirical evidence of performance improvement.
• Possible effect for recovery; faster or more complete recovery may lead to more intense training > bigger gains.

Posterior Pituitary Gland

• Antidiuretic Hormone (ADH) reduces water loss (via urine output) to maintain plasma volume.
• This results in increased water reabsorption from the renal tubules to capillaries.
• Release is stimulated by high plasma osmolality and low plasma volume.
• Sweat loss without water replacement causes osmoreceptors in the hypothalamus sense water (osmolality) concentration changes in interstitial fluid.
• When osmolality is high, osmoreceptors shrink and a neural reflex results in the release of ADH.
• When osmolality is normal but plasma volume is low, stretch receptors in the left atrium initiate a reflex resulting in ADH release

Thyroid Gland

• The thyroid gland, stimulated by TSH, synthesizes two iodine-containing hormones:
  • Triiodothyronin (T3)
  • Thyroxine (T4)
• T4 is released in greater amounts than T3, but most T4 is converted to T3, which is more potent.

Thyroid Hormones

• They are central to establishing overall metabolic rate, and therefore, weight control.
• Long latent period between T3 and T4 release and observed effects:
  • T3: 6-12 hours
  • T4: 2-3 days
• These releases have long-lasting effects and are controlled via negative feedback.
• During exercise, "free" hormone concentration increases due to changes in transport protein binding characteristics, which accelerates uptake by tissues.
• Calcitonin (released from the thyroid gland) plays a minor Ca++ regulation role.

Parathyroid Gland/Hormone

• The parathyroid hormone is the primary hormone involved in calcium regulation.
• It is released in response to low plasma Ca++.
• Stimulates bone to release Ca++ into the plasma and increases renal absorption of Ca++.

Adrenal Gland

• The adrenal medulla secretes catecholamines (Epinephrine (EPI) and norepinephrine (NE)).
• The adrenal cortex secretes mineralocorticoids (aldosterone), glucocorticoids (cortisol), and sex steroids (androgens and estrogens).

Adrenal Medulla

• Adrenal Medulla is part of the SNS.
• It secretes catecholamines (80% EPI, 20% NE), which are fast-acting hormones and part of the "fight or flight" response.
• Catecholamines are wide acting, affecting many different tissues and organs by binding to adrenergic receptors like alpha (a) and beta (β) on target tissues.
• Effects depend upon the hormone and receptor type.

EPI and NE

• These are fast-acting hormones that appear and disappear quickly and maintain blood glucose during exercise.
• Plasma EPI and NE increase during exercise.
• Decreased plasma EPI and NE occur following training.

Effect of EPI and NE

• EPI and NE have different receptor types with varying membrane-bound enzymes and effects on various tissues.

Adrenal Cortex

• It secretes a variety of steroid hormones.
• Mineralocorticoids regulate aldosterone, involved in the maintenance of plasma Na+ and K+ concentration
• Glucocorticoids (cortisol) are involved in plasma glucose regulation
• Sex steroids (androgens and estrogens) support prepubescent growth and androgens associated with post-pubescent sex drive in women

Aldosterone

• Aldosterone is an regulator of Na+ and K+, thus plays an important role in blood volume control and, therefore, blood pressure regulation.
• Release is controlled by:
  • K+ concentration
  • RAA system: ↓ blood volume -> ↓ blood pressure sensed by kidney -> increased secretion of renin which converts angiotensinogen to angiotensin I -> lungs convert this to angiotensin II -> stimulates aldosterone production/ release.

Cortisol

• Controls blood glucose during long-term fasting and exercise
• Promotes breakdown of tissue protein to form amino acids and undergo gluconeogenesis via Cori Cycle in the liver.
• Stimulates mobilization of FFA from adipose tissue
• Stimulates liver enzymes involved in metabolic pathways leading to glucose synthesis.
• Blocks glucose entry into tissues, forcing tissues to use more FFA as fuel

Pancreas

• Hormones released from pancreas play a role in blood glucose control.
• Insulin – secreted from β cells and the most important hormone during the absorptive state
  • Facilitates the movement of glucose from circulation to the inside of cells
    • Stimulated by: plasma amino acid and glucose concentration, parasympathetic tone
    • Inhibited by: sympathetic outflow, EPI, low plasma glucose
• Glucagon - secreted from α cells
  • mobilizes glucose from hepatic glycogen stores and FFA from adipose tissue, also stimulates gluconeogenesis similar to cortisol
    • Stimulated by: low plasma glucose, EPI

Hormonal Control of Substrate Mobilization During Exercise

• The type of substrate and rate of utilization depends on the intensity and duration of exercise.
  • Intense = more carbohydrates
  • Prolonged = more fats

Control of Muscle Glycogen Utilization

• Exercise intensity is inversely related to duration.
• Higher intensity = shorter duration.
• There is a rate of glycogen breakdown for various exercise intensities (% VO2 max).
• Higher the intensity = quicker the depletion.

Control of Muscle Glycogen Utilization

• Plasma EPI stimulates glycogen breakdown.
• Figures show EPI concentration and glycogen depletion for a variety of intensities (%VO2 max) and durations.

Control of Muscle Glycogen Utilization

• Selective β-adrenergic receptor blockade does not change glycogen depletion.
• Intracellular Ca+ plays a prominent role in glycogen usage/depletion, along with other players in the second messenger system .

Blood Glucose Homeostasis During Exercise

• Exercise provides a significant challenge to blood glucose control mechanisms.
• Plasma glucose is maintained through 4 processes:
  • Mobilize glucose from hepatic glycogen stores
  • Mobilize FFA from adipose tissue to spare plasma glucose
  • Synthesize new glucose via hepatic gluconeogenesis from amino acids, lactate, and glycerol
  • Block glucose entry into cells to force the use of FFA as fuel
• The overall goal is to maintain plasma glucose AND sustain work.

Blood Glucose Homeostasis During Exercise

• Hormones:
  • Permissive and/or Slow Acting:
    • Thyroxine
    • Cortisol
    • GH
  • Fast Acting:
    • EPI and NE
    • Insulin and Glucagon

Permissive and Slow Acting Hormones

• Thyroid hormones
  • T3 and T4 are responsible for establishing basal metabolic rate and allow other hormones to have their full(permissive) effect from them by impacting number of receptors at the cell surface or altering the affinity of the receptor for a hormone.
  • EPI has minimal effect on FFA mobilization from adipose tissue in the absence of T3

Permissive and Slow Acting Hormones

• Cortisol:
  • Stimulates FFA mobilization from adipose tissue.
  • Mobilizes tissue protein to yield amino acids for hepatic gluconeogenesis.
  • Decreases the rate of glucose utilization by cells
• The story is complicated, but cortisol plays a "slow" and "permissive" role in blood glucose control during exercise

Permissive and Slow Acting Hormones

• Growth Hormone
  • Decreases glucose uptake by tissues
  • Increases FFA mobilization
  • Enhances hepatic gluconeogenesis
• Increases during exercise and to a greater extent in trained vs. untrained.
• Has a direct, but slow effect on blood glucose control during exercise.

Fast Acting Hormones

• EPI and NE:
  • Mobilization of glucose from the liver (glycogenolysis)
  • Mobilization of FFA from adipose tissue
  • Interference with the uptake of glucose by tissues
• NE usually taken to reflect SNS activity
• EPI viewed as primary catecholamine in the mobilization of glucose

Fast Acting Hormones

• EPI and NE are responsive to endurance training.
• Plasma glucose is maintained because less is needed at a given workload.
• EPI/NE at maximal exercise is higher following training.

Fast Acting Hormones

• Insulin and Glucagon:
  • Sensed variables are the same but have opposite effects.
  • Insulin - increases glucose storage and lowers blood glucose concentration.
  • Glucagon - increases glycogen breakdown and increases blood glucose concentration.

Fast Acting Hormones

• Insulin
  • Involved in glucose uptake in ALL tissue
  • Decreases the uptake during graded exercise
• Glucagon
  • Increases during exercise and favors FFA mobilization and hepatic glycogen breakdown
• If blood glucose levels stay relatively constant during exercise, then what causes insulin to decrease and glucagon to increase?

Fast Acting Hormones

• Multiple levels of hormonal control of blood glucose
• SNS modifies the secretion of insulin and glucagon
• Confirmed using alpha- and beta- receptor blockade

Fast Acting Hormones

• Insulin binding to its receptor stimulates the translocation of GLUT proteins inside the cell, which moves the cell's glucose from the circulation to the inside of the cell.
• If insulin decreases during exercise, muscles still get glucose because exercise also facilitates GLUT transporter translocation via complicated mechanisms involving Ca++.
• These effects are additive. High insulin + exercise = more glucose uptake and possibly hypoglycemia.