The hormones that control metabolism week 4 Flashcards by Paris A

Which of the following hormones are catabolic? Which are anabolic?

glucagon

thyroid hormone

insulin

catecholamines

glucocorticoids

testosterone

Catabolic hormones: glucocorticoids, catecholamines, glucagon

Anabolic hormones: insulin, testosterone, thyroid hormones

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List the 3 parts of the pituitary that the hypothalamus innervates.

posterior pituitary

median eminence

anterior pituitary

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T or F: Endocrine glands fxn as more or less independent entities but are organized in a system that integrates their activity and interfaces them to the CNS.

True.

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The ____ and the ____, acting together, control the fxn of a number of endocrine glands that contribute to the regulation of metabolism.

hypothalamus and pituitary

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Explain the functions of each of the parts of the pituitary.

Posterior pituitary (neuro-hypophyse)
- axonal transport of neurohormones
- storage in secretory vesicles
- release into bloodstream
- peripheral target cells
Median eminence (neurovascular region)
- hormones are release into bloodstream
- neurohormones reach anterior pituitary through local circulation
Anterior pituitary (adeno-hypophyse)
- endocrine cells synthesize, store, and
secrete peptides and hormones
- release into bloodstream
- paracrine & endocrine function

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What hormones are contained within each of the 3 parts of the pituitary?

in the Posterior pituitary (neuro-hypophyse)

ADH: Antidiuretic hormone (vasopressin)
OCT: Oxytocin

in the Median eminence (neurovascular region)

TRH: Thyrotropin releasing hormone
CRH: Corticotropin releasing hormone
GHRH: Growth hormone releasing &,inhibiting hormone (somatostatin).
GnRH: Gonadotropin releasing h.
PRF: Prolactin releasing & inhibiting factor

From the anterior pituitary hypothalamic hormones release :

ACTH: Adrenocorticotropic hormone
TSH: Thyroid-stimulating hormone
LH: Luteinizing hormone
FSH: Follicle-stimulating hormone
PRL: Prolactin
GH: Growth hormone (somatotropin)
MSH: Melanocyte-stimulating h.

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Explain the ultrashort, short, and long feedback loops of the hypothalamic pituitary-target
organ axis.

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What are the physiological fxns of the adrenal glands?

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What embryonic layer is the adrenal cortex derived from? What are the 3 parts of the adrenal cortex? What is synthesized in each of the layers of the adrenal cortex?

What is the embryonic origin of the adrenal medulla? What is synthesized in the adrenal medulla?

• Cortex (mesoderm)
– corticosteroids
a. Zona glomerulosa: Mineralocorticoid (Aldosterone)
b. Zona fasiculata: Glucocorticoid (Cortisol)
c. Zona reticularis: Sex steroid precursor (andosterones)
• Medulla (neural crest)
– catecholamines
a. Epinephrine
b. Norepinephrine

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Where do hormones synthesized in the cortex have to go to reach the body?

Cortex hormones diffuse through medulla to reach the central vein.

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How is cholesterol stored in the adrenal cortex?

What is the cellular localization of steroid hormone syntheis?

What enzyme catalyzes steroid hormone synthesis? What is required for its rxn?

When are steroid hormones produced?

Cholesterol is taken up into cells. It is esterified and stored into vesicles. Steroid hormones are synthesized in the ER and mitochondria by CYP11A1 (desmoslase) using NADPH and O2.

Corticosteroids are not stored. Synthesis requires stimulation of the gland. When stimulated, cholesterol is transported to the proper organelles for hormone synthesis.

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The formation of what molecule is rate limiting in steroid hormone synthesis in the mitochondria?

What modification occurs to progesterone? In what organelle is this performed?

What is the immediate precursor to cortisol? To what cellular oganelle is it transported to form cortisol? What modification is made?

Cortisol synthesis: Zona Fasciculata
Pregnenolone formation is rate limiting in mitochondria
Progesterone hydroxylation in the ER
11-deoxycortisol transferred to mitochondria. critical C11 hydroxylation to form cortisol

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What is the precursor to aldosterone? What must be done to its precursor to form aldosterone? What is the cellular localization of this rxn?

Corticosterone is hydroxylated to form the immediate precursor to aldosterone in the mitochondria.

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How is cortisol transported in the blood? What form (bound or unbound) is active?

How does cortisol enter cells? Once there, what does it do?

What are the effects of cortisol on metabolism? (what is its fxn?)

During what times is cortisol important?

What hormone does cortisol oppose?

The major role of Cortisol is the regulation of metabolism and the organism’s response to stress. The latter makes it essential for life. In the plasma, transcortin transports cortisol but only free cortisol is active. Cortisol can be derived from Cortisone and both are entirely metabolized in the liver.
Cortisol enters the cell via facilitated diffusion. Its binding to a cytoplasmic cortisol receptor promotes receptor phosphorylation and its nuclear translocation. Histone acetylation in the nucleus leads to changes in transcription.
Cortisol on metabolism: Cortisol stimulates the conversion of protein to glucose (proteolysis) and storage as glycogen (glycogenesis). The mobilized protein derives mostly from muscle stores leading to decrease in muscle, connective tissue, skin mass. Cortisol promotes fat lipolysis, stimulates appetite and lipogenesis.
increases blood glucose for vital organs
increases glomerular filtration, increased urine production (blocks ADH), increases blood pressure (increases sensitivity of cells to B-adrenergic signaling), suppresses immune response
Glucocorticoid function is important during fasting and hypoglycemia.
Cortisol opposes insulin action by inhibiting insulin dependent glucose uptake and suppression of glucose release from the liver.

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Explain how cortisol is released from the adrenal cortex.

How is cortisol release regulated? (what feedback loops are involved?)

Corticotropin Releasing Hormone (CRH) stimulates
Adrenocorticotropic hormone (ACTH)
- produced by corticotroph cells
-co-secreted with melanocyte stimulating hormone
- stimulates Cortisol release (adrenal androgens, aldosterone)
Short loop : ACTH
- inhibits CRH release
Long loop : Cortisol
- blocks ACTH and CRH release (min)
- attenuates ACTH synthesis (hrs). this effect is observed with prolonged cortisol exposure.

Antidiuretic hormone (ADH)

released from posterior pituitary
potent stimulator of ACTH
cortisol negatively regulates ADH release

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What effect do synthetic glucocorticoids have on CRH and ACTH release? On the adrenal cortex?

Synthetic Glucocorticoids (dexamethasone, prednisone, fludrocortisone, hydrocortisone)

all have negative feedback on CRH and ACTH secretion
ACTH dependent adrenal cortex atrophies (dc cortisol production results)

What effects does ACTH have on the adrenal gland?

ACTH stimulates:
- cAMP production
- stimulates PKA, PKC
Synthesis:
- steroidogenesis – hydrolysis of Cholesterol ester
- transport of cholesterol to mitos
Transcription:
- activation of gene transcription
- increase enzymes for Cortisol synthesis
Growth:
- increase in cell size & number
- hyperplasia

Trophic effects of ACTH on the adrenal cortex

a. ACTH stimulates cell growth and proliferation.
b. A deficiency of ACTH greatly reduces hormone production by the adrenal cortex.
c. An excess of ACTH leads to hyperplasia of the adrenal cortex.

What other type of receptor can cortisol bind to when present in high concentrations?

mineralocorticoid receptors

At what time are ACTH and cortisol levels the highest? What is the timing of the release of CRH, ACTH, and cortisol?

What effect does stress have on cortisol release?

stress overrides the diurnal pattern
stress can attenuate the negative feedback
while exercise is a stressor, training reduces cortisol release in response to exercise
low exercise responders are also low stress responders

What is Cushing’s disease? What is it caused by? What are the sx of Cushing’s disease?

• enhanced Cortisol levels
– ACTH secretion from pituitary adenoma (70%) C. Disease
– ectopic ACTH from non-pituitary tissue (15%)
– adrenal adenoma, hyperplasia (15%) (normal [ACTH])
• Hypertension (β-adrenergic)-cortisol increases sensitization to B-adrenergic stimulation
• weight gain (upper body) fat redistribution-due to water retention
• Hyperglycemia, polyuria-mobilization of proteins and lipids
• muscle weakness, skin thinning
• immune suppression!

What is Addison’s disease? What is it caused by? What are the sx?

Addison’s Disease: adrenal atrophy leading to aldosterone AND cortisol deficiency
• hypoglycemia, weight loss
• hypotension (hyponatremic)
• Hyperkalemia
• skin hyperpigmentation (ACTH is co-secreted with MSH)

What cells of the adrenal medulla synthesize norepinephrine and epinephrine? Which is secreted in higher proportions?

What is the precursor to E and NE synthesis?

How are E and NE stimulated for release?

What is packed in granules with E and NE?

What is the half life for E and NE? Where are they metabolized? How are they excreted?

The chromaffin cells of the adrenal medulla synthesize and secrete the catecholamine hormones; they are innervated by pre-ganglionic neurons (ACh is released from the preganglionic neuron onto nicotinic receptors present on chromaffin cells) that are a part of the sympathetic nervous system.

The adrenal medulla produces catecholamine hormones, norepinephrine and epinephrine. The precursor for their synthesis is tyrosine.

Chromaffin granules contain catecholamines, ATP, chromogranin and other neuropeptides.

The adrenal medulla secretes 85% E and 15% NE. Most of the circulating NE is from sympathetic nerve terminals.

Both NE and E:
short half life of 2 minutes
metabolized in liver & kideney
secreted in the urine

What are the effects of E and NE release? (fight or flight response)

The sympathetic nervous system is stimulated by hypoxia, hypovolemia, and hypoglycemia

Stress stimulates adrenergic neurons, CRH, and ACTH release. Explain the effects of this on the body.

• Stress activates – adrenergic neurons – CRH neurons - ACTH – ADH neurons • mutual reinforcement • enhanced nutrient supply • enhanced centralized blood supply • restrained inflammatory response • arousal, attentiveness • suppression of growth, sexual activity etc.

What are the effects of hypersecretion of NE/E? Hyposecretion?

What is the embyronic origin of the thyroid gland? What cells produce thyroid hormone (TH)? What is the classification of these cells? What is the storage form of TH called? What is the fxn of parafollicular cells? Where are they found within the thyroid gland?

1. endoderm 2. Thyroid hormone is produced by the _follicular cells_. These cells are arranged in a simple cuboidal epithelium that form a more or less spherical structure filled with _colloid_ (storage form of TH) which is called a follicle. 3. A second cell population, the parafollicular cells are located between the follicles. These cells secrete the hormone, calcitonin, which is involved in the regulation of blood calcium levels.

What are the 3 forms of TH? What is required for TH synthesis? Is TH polar or apolar? How is TH transported in blood? What form is active? (bound or unbound)

Tetra-Iodo-thyronine (Thyroxine, T4)-prohormone Tri-Iodo-thyronine (T3)-active Tri-Iodo-thyronine (rT3)-inactive TH is an iodinated derivative of tyrosine-tyrosine and iodine are required for TH synthesis. T3/T4 are amine hormones that are not water soluble (apolar) TH is transported in blood bound to plasma proteins: thyroid binding globulin (TBG)- 70%, 30% to transthyretin. Small amounts exist free in solution. REMEMBER that only the free hormone can reach and bind to receptors. TBG binding of T3/T4 leads to buffering and creates a reservoir of active hormones. Small disturbances in production can be compensated by binding or unbinding of T4 from TBG.

Explain how iodine is transported from the cytosol and into the follicular lumen. What disease can issues with the transport of iodine into cells or lack of iodine in the diet lead to?

1. Sodium Iodide Symporter (NIS) - 2 Na+ and 1 I- - depends only indirectly on ATP-secondary active transport 2. I- crosses apical membrane into follicular lumen 3. _Pendrin_ allows transport along concentration gradient (into the follicular lumen) - lack of iodide leads to hypothyroidism and goiter - mutations in NIS lead to goiter

Explain TH formation and the enzyme involved.

_Thyroglobulin_ is a dimeric glycoprotein, assembled in the Golgi apparatus and exocytosed into the follicular lumen. It binds tyrosine and in the inner lumen of the follicle and allows for its iodination at the 3’ and 5 position. MIT and DIT stands for Mono- and Di-iodothyrosine. Covalent binding between 2 tyrosines (MITs and DITs) occurs through _Thyroid peroxidase_ (which also oxidzes iodide for tyrosine binding). Binding of MIT + DIT results in T3, binding of DIT + DIT produces T4.

Explain how TH is released into the cytoplasm. Which hormone (T3 or T4) is synthesized and released at higher concentrations?

Step 3: Release of Thyroid Hormones - Recovery of thyroglobulin through endocytosis - movement of colloid droplet through cytoplasm - proteolytic release of T3 and T4 from thyroglobulin - MITs and DITs are recycled after deiodination - T4: T3 are released at a 10:1 ratio

What stimulates TRH release from the hypothalamus? What effect does TRH have on TSH? (other than stimulating its release) How is TRH and TSH release regulated?

Thyrotropin releasing hormone (TRH) – TRH is released in response to low body temperature and changes in energy need – stimulates release of thyrotropin / thyroid-stimulating hormone (TSH) – prolonged stimulation increases TSH expression and bioactivity – prolonged TRH exposure negatively regulates its own activity by receptor down-regulation

What effects does TSH have on the thyroid gland? What effect can high levels of TSH have on the thyroid gland?

• Thyroid Stimulating Hormone – increases all aspects of T3/T4 synthesis and release • translation, transcription • cell division and hypertrophy • iodide uptake • secretion increased TSH can lead to thyroid hypertrophy (goiter) due to trophic effects of TSH on the thyroid gland

How to T3 and T4 get into cells? Where is their receptor located? Which form has a higher affinity for the TH receptor? How is T4 converted to T3? What effects do T3 and T4 have on cells?

• Thyroid hormones cross the cell membrane • bind to TH receptor at _nuclear_ membrane – T3 has higher affinity (bioactive form) – TR is a transcription factor itself • _Deiodinase_ (D2) for T4 --\> T3 • T3 increases: – brain maturation - bone growth – increased basal metabolic rate-requires greater oxygen need -increases ventilation to supply more O2 to tissues – βreceptors in the heart-increases CO to increase O2 delivery to tissues

What specific protein does TH induce the expression of?

• Thyroid hormone – stimulates O2 use and metabolism – increased expression of uncoupling protein-1 (UCP-1) – UCP-1 allows proton leak without ATP generation • as a consequence energy is released as heat

What hormone levels are increased in hyperthyroidism? Which hormones are decreased? What are the sx of hyperthyroidism? What is hyperthyroidsim also known as? How can some of the sx of hyperthyroidism be attenuated?

Reflected in decreased TSH, increased T4 & T3 • Heat intolerance (increaed body temp) • Weight loss (increased proteolysis, lipolysis) • CNS hyperexcitability • Diarrhea • Muscle weakness • increased β-adrenergic receptors (chest pain, arrhythmia) Graves disease: autoimmune disease Some can be attenuated by β-adrenergic antagonists

What hormone levels are increased in hypothyroidism? Which hormones are decreased? What are the sx of hypothyroidism? What is cretinism? What are the sx?

Reflected in increased TSH, decreased T3 &T4 • Cold intolerance • Weight gain • Fatigue and extreme sleepiness • Slow muscle responses • Mental sluggishness • Skin and hair changes • Bradycardia, decreased cardiac output Cretinism: endemic due to lack of dietary iodide (goiter formation, growth retardation, immaturity)

What drug may be used in the treatment of hypothyroidism? What additional drug/supplement may need to be given to increase this drug's effectiveness?

• Levothyroxine to replace T4 – relieves symptoms only in 85% of cases – effectiveness increased when Levothyroxine is supplemented with T3 – while T4 is restored, decreased deiodinase activity prevents T3 formation