1
Q
AVP fx
A
- water reabsorption ➔ ↑ # of aquaporins & translocation to apical membrane of principal cells of the collecting duct cells of kidney
- osmoreceptors
- dehydration = main signal ➔ ↑ osmolarity & cell shrinks in size ➔ osmoreceptors can sense shrinked MP
- ↑ BP: vasoconstriction
- baroreceptors in aorta arch receptors & carotid sinus
- stimulated by ↓ BP/BV
- ↑ expression of ACTHR (MC2R)
2
Q
AVP action in kidneys
A
V2R = Gs ⍺ subunit GPCR
- AVP binds to V2R ➔ adenylyl cyclase converts ATP ➔ cAMP ➔ activates PKA
- PKA phosphorylates APQ2 vesicles to transport to apical membrane for water reabsorption
- extra water in cell moves through APQ3 & APQ4 channels in basolateral membrane into interstitial space
- APQ2 & APQ3 = targets of AVP
- APQ4 is permanent
3
Q
diabetes insipidus
A
- consequence of AVP deficiency
- indiv cannot concentrate urine ➔ diluted urine, no smell or color
- neurogenic: caused by mutations that inactivate AVP production ➔ issue is in PVN & SON nuclei
- nephrogenic: caused by mutations in the V2R or APQ2 genes in the kidneys
4
Q
CYP11A1 gene encoding P450scc
location:
fx:
goal:
A
located in mitochondria
fx: 10,10-desmolase
goal: CHO side chain cleavage ➔ first step in steroidogenic pathway
5
Q
CYP17A1 gene encoding protein P450c17
location:
fx:
goal:
A
locted in SER
fxs:
- 17⍺-hydroxylase (in zona fasciculata)
- 17,20-lyase (in zona reticulata)**
goals:
- 17⍺-hydroxylase: pregnenolone ➔ 17⍺-hydroxypregnenolone
- 17,20-lyase: 17⍺-hydroxypregnenolone ➔ DHEA**
6
Q
CYP21A2 gene encoding protein P450c21
location:
fx:
goal:
A
located in SER
fx: 21-hydroxylation
- progesterone ➔ 11-deoxycorticosterone
- 17⍺-hydroxyprogesterone ➔ 11-deoxycortisol
- most common mutation for congenital adrenal hyperplasia (CAH)
7
Q
CYP11B2 gene encoding protein P450aldo
location:
fx:
goal:
A
located in mitochondria of zg cells
fx: 18-hydroxylation
goal: biosynthesis of aldosterone
8
Q
CYP11B1 gene encoding protein P450c11β
location:
fx:
goal:
A
located in mitochondria of ZG cells
fx: 11β-hydroxylation
goal: 11-deoxycortisol ➔ cortisol
9
Q
3β-hydroxysteroid dehydrogenase (3β-HSD)
A
- located in SER
- pregnenolone ➔ progesterone
- 17𝛼-pregnenolone ➔ 17𝛼-progesterone
- DHEA ➔ androstenedione
- androstenediol ➔ testosterone
10
Q
17β-hydroxysteroid dehydrogenase (17β-HSD)
A
- located in SER
- androstenedione ➔ testosterone
- DHEA ➔ androstenediol
11
Q
aldosterone pathway in steroidogenesis
A
CHO
↓ CHO desmolase (CPY11A1➞ P450scc)
pregnenolone
↓ 3β-HSD
progesterone
↓ 21-hydroxylase (CYP21A2 ➞ P450c21)
11-deoxycorticosterone
↓ 11β-hydroxylase (CYP11B1 ➞ P450c11)
corticosterone
↓ aldosterone synthase (CYP11B2 ➞ P450aldo)
aldosterone
12
Q
androgen pathway in steroidogenesis
A
CHO
↓ CHO desmolase (CPY11A1 ➞ P450scc)
pregnenolone
↓ 17𝛼-hydroxylase (CYP17A1 ➞ P450c17)
17⍺-hydroxypregnenolone
↓ 17,20-lyase (CYP17A1 ➞ P450c17)
DHEA
↓ 3β-HSD
androstenedione
↓ 17β-HSD
testosterone**
13
Q
cortisol pathway in steroidogenesis
A
CHO
↓ CHO desmolase (CPY11A1 ➞ P450scc)
pregnenolone
↓ 17𝛼-hydroxylase (CYP17A1 ➞ P450c17)
17⍺-hydroxypregnenolone
↓ 3β-HSD
17⍺-hydroxyprogesterone
↓ 21-hydroxylase (CYP21A2 ➞ P45c21)
11-deoxycortisol
↓ 11β-hydroxylase (CYP11B1 ➞ P450c11)
cortisol**
14
Q
zones of the adrenal gland
A
- zona glomerulosa ➔ aldosterone synthesis
- mineralocorticoids ➔ aldosterone
- “minerals” ➔ regulating mineral balance (salt) in kidneys
- virtually no MC2R ➔ non-responsive to ACTH
- mineralocorticoids ➔ aldosterone
- zona fasciculata ➔ glucocorticoids ➔ cortisol synthesis
- cortisol fx: ↑ glucose levels in blood via gluconeogenesis in liver
- majority of cortex
- most responsive to ACTH ➔ slight hypertrophy & hyperplasia
- zona reticularis ➔ androgen synthesis
- dehydroepiandosterone (DHEA)
- important for females
- responsive to ACTH
medulla: non-HPA hormones
- epinephrine
- norepinephrine
- derived from neuroectoderm: ANS/SNS**
15
Q
CHO uptake & initiation of steroidogenic pathway
A
- LDL internalized by cell via LDLR
- LDL is hydrolyzed by CHO esterase to release free CHO
- StAR protein finds free CHO & carries to mitochondria to start steroidogenesis
- steroidogenesis starts in mitochondria ➔ goes to SER ➔ back to mitochondria for adrenal hormone synthesis
16
Q
parvocellular hypothalamaic nuclei
A
PVN
- CRH ➔ corticotroph cells secrete ACTH ➔ act on adrenal gland
- TRH ➔ thyrotroph cells secrete TSH ➔ act on thyroid gland
- AVP produced by magnocellular neurons & secreted by neurohypophysis to regulate water & BP & also produced by parvocellular neurons as a 2º stimulatory signal for ACTH release
ARC
- GnRH ➔ gonadotrophs cells secrete LH & FSH ➔ act on gonads
- GHRH ➔ somatotroph cells secrete GH ➔ act on liver
- SST: somatostatin ➔ inhibitory: ⊖ regulator of GH
- dopamine ➔ inhibitory: ⊖ regulator of PRL
POA
- GnRH
VIP: prolactin-releasing factor ➔ lactotroph cells secrete PRL
17
Q
ACTH action
A
- ↑ glucocorticoids (main response)
- ↑ DHEA
- ↑ adrenal weight via hypertrophy (increased secretory activity ➔ cells swell) & hyperplasia
- ↑ medullary hyperplasia (from cortisol) ➔ ↑ release of EPI & NEPI
- ↑ expression & translocation of LDLR to membrane to facilitate LDL internalization of CHO for steroidogenesis
- intracellular activation by PKA:
- CHO esterase
- Star
- P450scc
- ↑ gene expression of CHO esterase, StAR protein, & P450scc
18
Q
ACTH response to hypoglycemia
A
- stimulates PVN in hypothalamus to release CRH ➔ enters portal system
- stimulates corticotrophs in adenohypophysis to release ACTH into systemic circulation
- stimulates adrenal gland to produce cortisol in the zona fascicularis
- stimulates liver gluconeogenesis
19
Q
congenital adrenal hyperplasia (CAH)
A
- lack of cortisol prod during fetal development ➔ lack of ⊖ feedback for HPA axis
- results from a defficiency in an enzyme in the cortisol pathway (mutations in the CYP21A2 gene that encodes P450c21 that converts progesterone ➔ 11-deoxycorticosterone & 17⍺-hydroxyprogesterone ➔ 11-deoxycortisol)
- excess of ACTH & overstimulation of adrenal gland cause:
- adrenal hyperplasia
- excess prod of adrenal androgens ➔ pathway will be overactivated but the only direction it can go is towards androgens (masculinization = problematic for females)
20
Q
glucocorticoid regulation of BG
A
↑ BG by inhibiting uptake in peripheral tissues & by stimulating gluconeogenesis
- muscle: stimulates myostatin ➔ proteolysis to release AA
- adipose tissue: stimulates hormone-sensitive lipase (HSL) ➔ lipolysis to release FA & glycerides
- liver: stimulates PEPCK & G6P (gluconeogenic enzymes)
21
Q
targets of cortisol in BG in homeostasis
A
- stimulates gluconeogenesis (G6P & PEPCK)
- stimulates glycogen synthase
- inhibits glycogen phosphorylase
- Activates hormone-sensitive lipase (HSL) ➞ lipolysis:
- ↓ protein synthesis
- stimulates myostatin to break down muscle fibers
22
Q
PNMT
A
phentolamine N-methyltransferase
- converts NE ➔ EPI
- only expressed in chromaffin cells in adrenal medula
23
Q
cortisol action on inflammatory pathway
A
cortisol blocks phospholipase A2 ➔ inhibits entire inflammation pathway
24
Q
arachidonic acid
A
precursor of pro-inflammatory eicosanoids
- released from PM by phospholipase A2
25
NSAID action on inflammatory pathway
block cox 2 ezyme ➞ inhibit prostanoids
- EETs & HETEs still synthesized
- minimize inflammatory response
- other inflammation pathways are still active
26
glucocorticoid: innate immunity regulation
**decreased pro-inflammatory mols:** prostaglandins & cytokines
**decreased cell-mediated immune response**: ↓ vascular permeability, mast cell #s, & antigen-presenting cell #s
27
glucocorticoid: acquired immunity regulation
**↓ differentiation of antigen-fighting cells**
1. inhibits T & B lymphocytes in circulation
2. inhibits synthesis of immunoglobulins
**stimulates lymphocyte apoptosis** ➔ removes antigen-fighting cells from circulation
28
epinephrine synthesis
tyrosine ➔ dopamine (dopamine β-hydroxylase - DBH) ➔ NE (PNMT) ➔ EPI
29
epinephrine
* synthesized from NE
* precursor mol: tyrosine
* **produced exclusively by adrenal medulla cells** (main product ~80%)
* NE present in CNS, adrenal medulla, & sympathetic neurons
30
effects of EPI
1. lipolysis
2. stimulates glycogenolysis
3. stimulates gluconeogenesis
4. ↑HR & SV
5. peripheral vasoconstriction ➞ blood redirected where it's needed
6. ↑BP
7. dilation of coronary arteries & muscles (↑ perfusion)
31
epinephrine response to hypoglycemia
1. stimulates HSL enzyme to ↑ lipolysis
2. stimulates glycogen phosphorylase to break down glycogen
3. inhibits glycogen synthesis
* 2 & 3 oppose cortisol: EPI is breaking glycogen that cortisol is making
32
EPI & NE effects
* NE fxs primarily as a neurotransmitter for cardiac effects
* both NE & EPI influence vascular tone
* EPI affects metabolic processes (e.g carbohydrate metabolism)
* ↑ RR
* ↑ bf to skeletal muscles
* intestinal muscles relax
* pupils dilate
* ↑BP
* ↑BG
* ↑HR
33
main receptor type for EPI at low concentrations
β2-adrenergic receptor
34
main receptor for EPI during high concentrations (during fight-or-flight)
⍺2-adrenergic
35
effects of circulating EPI
- ↑ HR & inotropy (β1)
- systemic vasoconstriction (⍺1)
- muscle & liver vasculatures:
- vasodilation at low concentrations (β2)
- vasoconstriction at high concentrations (⍺1)
- @ low-to-moderate circulating [EPI]: ↑ CO w/ only a small change in MAP b/c systemic vascular resistance falls due to β2-adrenoceptor activation
- @ ↑ plasma [EPI]: MAP ↑ b/c of binding to ⍺-adrenoreceptors on bv that offsets β2-adrenoceptor vasodilation
36
pheochromocytomas
* **catecholamine-secreting tumors from chromaffin cells of adrenal medulla**
* relatively rare: ≤0.5% of hypertensive patients
* secrete mainly **NE**
- episodes of ↑ catecholamine secretion cause **hypertension, palpitation, headache, & sweating**
37
aldosterone
* mineralocorticoid
* synthesized in zona glomerulosa
* steroidogenesis pathway: cholesterol (cholesterol desmolase) ➔ pregnenolone (3β-HSD) ➔ progesterone (21⍺-hydroxylase) ➔ 11-deoxycorticosterone (P450c11/11β-hydroxylase) ➔ corticosterone (p450aldo/adosterone synthase) ➔ aldosterone
* NO p450c17 (17⍺hydroxylase or 17,20-lyase)
* NO 17β-HSD
38
majority of Na reabsorption in the kidneys
proximal tutbule & loop of Henle via countercurrent system (~94%)
* not under endocrine control
* remaining Na will be reabsorbed in the principle cells of the collecting duct in response to aldosterone
39
actions of aldosterone
* stimulates Na reabsorption in principal cell of collecting duct
* facilitates **transcription of Na/K ATPase** pumps in basolateral membrane
* stimulates **Sgk1 to inactivate Nedd4-2 channels** → cannot destroy ENaC (Na channels) ∴ Na can re-enter cell via apical membrane
* ↑ BP by ↑ ECF volume
* ↑ urine excretion of K ➞ stimulates **expression of K channels** in apical membrane
40
renin
enzyme produced in juxtaglomerular cells on afferent arteriole that converts angiotensinogen ➔ angiotensin I
- pathway to ↑BP, ↑[Na], ↑ECF V
- control of renin release:
1. baroreceptors in JGC detect renal perfusion pressure
2. macula densa cell chemoreceptors detect levels of Na & Cl in filtrate & communicate with adjacent JGC cells to release renin at low [NaCl]
- factors that stimulate renin release:
1. ↓BP
2. ↓[Na]
41
aldosterone & K
* aldosterone facilitates K removal from ECF
* ↑ K stimulates aldosterone synthesis (hyperkalemia)
* depolarization of zona glomerulosa cell membrane opens Ca v-gated channels ➞ ↑ in intracellular Ca stimulates expression of P450aldo/aldosterone synthase
42
regulation of aldosterone
* stimulated by:
* K
* angiotensin II
* ACTH (minimal)
* inhibited by: atrial natriuretic peptide (ANP) ➔ involved in diuresis
43
renin-angiotensen-aldosterone system (RAAS)
1. macula densa cells in distal tubule detect ↓ [NaCl] & JGC detect ↓BP in afferent arteriole ➔ JGC release renin
2. renin converts angiotensinogen ➔ angiotensin I (precursor)
3. ACE (angiotensin converting enzyme) produced mainly in lungs converts angiotensin I ➔ angiotensin II (potent vasopressor)
4. angiotensin II stimulates:
1. SNS ➔ release catecholamines from adrenal medulla to stimulate vasoconstriction
2. transcription of P450aldo ➔ ↑ aldosterone: reabsorption of Na & Cl in kidney to retain water
3. vasoconstriction ➔ ↑ BP & ↑ renal bf
4. AVP secretion in neurohypophysis ➔ ↑ water reabsorption
5. normal perfusion removes stimulus & acts as ⊖ feedback
44
angiotensin II actions
maintain normal ECF V & BP
1. ↑ transcription of P450aldo ➞ ↑ aldosterone production
2. vasoconstriction ➞ ↑BP ➞ ↑renal bf
3. release of EPI & NE from adrenal medulla
4. promote release of AVP ➞ water reabsorption in kidneys
45
ANP
* atrial natriuretic peptide secreted by atrial myocytes in response to volume expansion
1. vasodilation
2. hyperfiltration: ↑ GFR
3. natriuresis (Na excretion): inhibits Na & water reabsorption in principal cells of collecting duct
4. **inhibits secretion of renin, aldosterone, AVP, & ACTH**
46
hyperaldosteronism (primary aldosteronism)
* primary overproduction of aldosterone with low renin
* Conn's syndrome
* ↑BP from ↑ retention of NaCl & H2O by kidneys + ↓ serum [K] (hypokalemia) from excess K secretion in urine
* causes:
- benign adrenal tumor (adenoma)
- hyperplasia of 1 or both adrenal glands (idiopathic: unknown cause)
47
aldosterone in target cells
1. **↑ K channels in apical membrane** to excrete more K
2. **↑ Na/K ATPase pumps in basolateral membrane** to pump Na out of cell into blood & K into cell (out of blood) where it can move through channels in apical membrane to be excreted in urine
3. **↑ expression of Sgk1** to inactivate destruction complex for Na channels to keep them in membrane
* **ENaC** = epithelial Na channel ➔ brings Na back from lumen into cell
* **ubiquitin** = system cells use to recycle mol ➔ tags cells & targets for destruction
* **Nedd4-2** = ubiquitin protein that targets & destroys Na channels
* **Sgk1** (serum-and-glucocorticoid kinase) phosphorylates Nedd4-2 ➔ inactivates them
* aldosterone stimulates Sgk1 ➔ Nedd4-2 cannot destroy ENaC
48
11β-hydroxysteroid dehydrogenase (11β-HSD)
enzyme that converts cortisol ➔ cortisone (inactive form)
* cortisol has good affinity for mineralocorticoid receptor & because plasma [cortisol] > than [aldosterone] cortisol would occupy all MCR
* aldosterone ≠ substrate for 11β-HSD
49
Tg synthesis
synthesized in ER of thyrocyte & packaged into exocytosis vesicles that fuse w/ apical membrane releasing contents into colloid
* contains tyrosyl residues that can be iodinated
- stimulated by TSH
50
rT3
reverse T3 = inactive form
* control mechanism for TH level regulation
* no 5 iodine
51
thyrotroph cell receptor
* Gq ⍺ subunit GPCR
* Ca & PKC involved in activation of transcription of TSH gene
* TRH also promotes glycosylation of TSH gene making TSH biologically active
52
TSH stimulates:
1. iodine uptake via NIS
2. Tg synthesis
3. Tg iodination
4. deposition of Tg in colloid
5. colloid uptake into follicular cells (thyrocytes)
6. proteolysis of Tg (T3/T4 production)
7. immediate release of T3/T4 from colloid storage
8. follicular cell metabolism & cell growth
53
short-term effecft of TSH
activated PKA stimulates:
1. **hypertrophy of thyroid cells**
2. activation of iodine pumps (**NIS**)
3. Tg exocytosis
4. TPO activity
5. induces pseudopods to ↑ Tg reabsorption at colloid border
6. lysosome-mediated **proteolysis of Tg**
54
long-term effects of TSH
expression of (synthesis via transcription):
* Tg
* thyroid peroxidase (TPO)
55
NIS
Na/I symporter = pump that actively transports I (& Na) into thyrocyte across the thyrocyte **basolateral membrane**
* activated by binding TSH to its receptor
* disorders of NIS associated w/ **hypothyroidism**
* inactivating mutation of the NIS gene: **congenital hypothyroidism**
* autoimmune disease = antibiodies against NIS: **acquired hypothyroidism**
56
congenital hypothyroidism cause
inactivating mutation of the NIS gene
57
acquired hypothyroidism
autoimmune disease where the body produces antibodies against NIS
58
TPO fx
1. oxidation of iodine
2. iodination (organification) of thyroglobulin
3. coupling of MIT & DIT to form T3 & T4
59
synthesis of TH
T3 & T4 made of iodinated Tg
1. iodine is oxidized by TPO activity
2. tyrosine residues on Tg are iodinated (iodination/organification)
3. **iodination** of tyrosines yields MIT & DIT: adding iodines
4. **coupling** = binding of MIT & DITs (catalyzed by TPO) to get T3 & T4
5. **pendrin channels** in apical membrane transport I into colloid (not TSH-dependent − always there on a [gradient])
60
transport & delivery of TH
transported via plasma carriers: **thyroid-binding globulin (TBG)**, **albumin**, **transthyretin**
1. occupy space on TH ∴ only free portion of TH not bound to carrier is available to enter target cell & become metabolically active
2. extend TH half-life by protecting from degradation
3. maintain large circulating pool of TH
61
autoregulation of thyroid gland
* thyroid gland can modify its activity **independent** of TSH to adapt to changes in iodine availability
* in response to **iodine deficiency**:
* ↑ iodine transport efficiency
* T3 preferentially synthesized over T4
* in response to **iodine excess**: inhibit NIS i.e. **Wolff-Chaikoff effect** aka **iodide block**)
62
mechanism of action of TH receptors
1. **monocarboxylate transporter (MCT8)** = highly specific transporter ➞ carries TH across PM
2. **binding of T3 dislocates co-repressors & activates co-activators** (or vica-versa)
- **co-regulator proteins** = co-activators (CoA) & co-repressors (CoR)
- CoR bind to TR inactivating it
- T3-binding exchanges CoR with CoA
- sometimes TR has a CoA bound already & is actively transcribing ➞ T3 binding changes CoA ➔ CoR so binding represses gene transcription
3. modulation of gene expression in target cells
63
gene expression regulation by TH receptors (TR)
* THRs binding to DNA is **independent** of hormone binding
* THRs bind to DNA as:
* **homodimers**: combination of TR isoforms (⍺, β)
* **heterodimers**: associated w/ other nuclear receptors − most commonly retinoid X receptor (RXR)
64
TH control at multiple levels
1. hormone synthesis can autoregulate depending on iodine availability
2. T4 converted to T3 on demand
3. multiple carrier proteins ensure that TH is stable in circulation: **thyroid-binding globulin (TBG), transthyretin, albumin**
4. **deiodinases** are present in a variety of tissues
65
epinephrine & cortisol similarities
synergistic response with cortisol:
* maintaining/↑ levels of glucose
* stopping immune system in response to stressor
66
cushing's syndrome
**hyperadrenocorticism**
- **excess circulating cortisol or glucocorticoids**
- **ACTH-independent**: ↑ cortisol but not from adrenal gland being overstimulated
- most commonly iatrogenic: induced by tx given to animals by humans
- **ACTH-dependent**: pituitary or non-pituitary tumors secreting ACTH or CRH ➔ **Cushing's disease**
-
67
cushing's disease
excess circulating cortisol or glucocorticoids from tumors
**ACTH-dependent hyperadrenocorticism**
- **pituitary-dependent:** pituitary tumor producing ACTH ➔ hyperstimulation of adrenal gland
- ectopic ACTH expression by nonpituitary tumor cells: POMC precursor incorrectly cleaved to release ACTH
- bilateral hyperplasia of zona fasciculata & zona reticularis
**ACTH-independent hyperadrenocorticism** from adrenal tumor secreting excess cortisol/glucocorticoids
68
cushing's syndrome/disease symptoms
- **atrophy of epidermis & connective tissue** ➞ skin thinning & alopecia
- **centripetal obesity**: visceral fat accumulation ➞ pendulous abdomen
- dehydration
- osteoporosis
- muscle weakness
- **polyphagia**: feeling of extreme insatiable hunger
- **exophthalmos**: bulging eyes
- bruising & poor healing
- pruritus: itching
- acne
- hyperpigmentation
69
addison's disease
**hypoadrenocorticism**:
- associated w/ mineralocorticoid deficiency
- primary hypoadrenocorticism = **glucocorticoid deficiency at adrenal level**
- **congenital adrenal hyperplasia** = deficiency of enzyme P450c21 → not producing enough GC
- causes:
- autoimmune
- infectious
- congenital
- iatrogenic
- symptom: hyperpigmentation
70
5'-deiodinase
activates T3 (converrs T4 ➞ T3)
- D1:
- kidney, liver, skeletal muscle (& small amount in the thyroid gland)
- most abundant
- in PM of cells ➞ ensures adequate circulating levels of T3
- D2:
- brain & pituitary gland
- in ER close to nucleus
- ensures adequate cellular levels of T3 w/in CNS
- sensitive to Δ circulating levels of T4
71
5-deiodinase
removes the I at position 5 to convert it into rT3 & inactivate it
- highly expressed in fetal tissues, placenta, CNS
- inactivates T4 by conversion to rT3
- inactivates T3 by conversion to T2
- ↑ in hyperthyroidism
- ↓ in hypothyroidism
72
TH actions on fetal development
- roles in terminal differentiation of brain cells & neural development (mediated by TR⍺)
- **congenital hypothyroidism** = genetic/iodine deficiency: impairs terminal differentiation process ➔ severe mental & growth retardation (cretinism)
- development of the auditory system: human TH resistance syndrome (Refetoff syndrome) = mutation in TRβ ➔ deafness
- development of sensory systems (auditory, visual)
- neurogenesis
- neural transmission (myelin sheath formation)
73
TH actions on metabolism & thermogenesis
1. stimulates protein expression & turnover
2. ↑ metabolism secondary to thermogenesis (↑ basal body temp)
3. stimulate expression of β-adrenergic receptors & ↑ adrenergic activity
4. ↑ BMR accompanied by ↑ energy expenditure & ↑ need for O2 in tissues to support ↑ activity
74
TH actions to meet ↑ O2 requirements
1. enhances O2 absorption by resp system
2. ↑ expression of erythropoietin to enhance RBC production
3. enhances β-adrenergic receptor-mediated effects in the heart (inotropic & chronotropic effects)
75
TH actions to meet ↑ energy requirements
1. ↑ GI motility tract
2. ↑ GI absorption efficiency
3. stimulate lipolysis
4. ↑ appetite ➔ stimulate CNS satiety/hunger centers
- full signamls in POMC neurons in Arc use ⍺MSH to signal PVN to secrete TRH & begin TH cascade
- insulin & leptin inform brain that body has enough nutrients to ↑ metabolic rate
76
TH actions on thermogenesis
**non-shivering thermogenesis** by UCP1 (uncoupling proteins) in mitochondria of brown adipose tissue
- located in inner mitochondrial membrane
- redirect H+ flow from the ATPase ➞ dissipates energy in the form of heat instead of ATP
77
hashimoto's disease
autoimmune hypothyroidism: body produces antibiodies against TPO, Tg, & TSHR
* progressive destruction of the thyroid gland
* symptoms: fatigue, weight gain, joint/muscle pain, feeling cold, bradycardia, slow metabolism
* may present w/ goiter
78
grave's disease
**continuous activation of TSHR by antibodies**
- autoimmune hyperthyroidism
- LATS: long-acting thyroid stimulating antibody
- symptoms consistent with hyperthyroidism: insomnia, weight loss, heat intolerance, tachycardia, exopthalmos
- commonly presents with goiter
79
iodination of TG
* iodination occurs at apical colloid border
* iodination of the tyrosyl residues (iodotorosines) forms monoiodotyrosine (MIT) & diiodotyrosine (DIT)
* these are coupled to form T3/T4
* iodide must be oxidized by TPO to be able to iodinate tyrosine residues
80
D1 5’-deiodinase
- kidney, liver, skeletal muscle (& small amount in the thyroid gland)
- converts T4 to T3
- most abundant
- in PM of cells ➞ ensures adequate circulating levels of T3
81
D2 5’-deiodinase
- brain & pituitary gland
- in ER close to nucleus
- ensures adequate cellular levels of T3 w/in CNS
- very sensitive to changing circulating levels of T4
- low levels of T4 ↑ [5'-deiodinase]
- high levels of T4 ↓ [5'-deiodinase]
82
systemic effects of chronic synthetic glucocorticoids (hyperadrenocorticism)
**↑**
1. PEPCK, myostatin, lipase
2. circulating AA
3. BG (↑ 50%)
**↓**
1. body weight (visceral fat accumulation)
2. muscle mass
3. endogenous cortisol
83
AVP deficiency model
brattleboro rat has a genetic mutation in neurophysin II ➔ cannot fold AVP protein properly ∴ cannot synthesize AVP (neurogenic)
NPB 130
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