A DEEPER LOOK // 1. THE ENDOCRINE SYSTEM

A DEEPER LOOK // 1. THE ENDOCRINE SYSTEM Peptide C: pancreas f pts with type 1 diabetes is unable t prduce insulin and therefre have less peptide C Amin acid hrmnes Catechlamines: derived frm tyrsine dpamine nrepinephrine epinephrine; adrenal gland Thyrxine (T4): derived frm tyrsine; prhrmne fr T3; made frm idinatin f thyrglbulin Sterid hrmnes: all are derived frm chlesterl whse side chains are cleaved by P450scc int pregnenlne then int prgesterne Final prduct depends n the cell type and the enzymes lcated there: adrenal glmerulsaaldsterne, adrenal fasiculatacrtisl, variesestradil, testesteststerne Prstaglandins: lipid, derived frm fatty acids; an eicsanid; autcrine and paracrine mediatrs Prstaglandin bisynthesis: arachadnic acid is cnverted t prstaglandin via COX (inhibited by NSAIDs) and then frms either thrmbxane, prstacyclin, r prstaglandins Kd: dissciatin cnstant; cncentratin needed t ccupy 50% f receptrs; the smaller the Kd, the higher the affinity and mre tightly bund hrmne is t receptr Membrane receptrs: fr hydrphilic hrmnes G-prtein cupled receptrs Think New Hampshire Creepy Guy NH-CG : N tail binds hrmne, G-prtein binds t C tail Inactive GDP f alpha subunit is phsphrylated by GRK t GTP, cmplex is activated, beta and gamma subunits mve and bind t adenylyl cyclase, ATP camp, camp binds t RU which activates PKA, PKA phsphrylates CREB (transcriptin factr) t regulate gene expressin Gαs: activates adenylyl cyclase Gαi: inhibits ATPcAMP Gαq: phsphlipase C (PLC) Tyrsine kinase receptrs http://www.wiley.cm/cllege/fb/quiz/quiz21/21-15.html Starts ff as tw mnmeric receptrs Binding f 2 grwth factr causes the mnmeric receptrs t dimerize Autphsphrylatin leads t the phsphrylatin f the tyrsine kinase dmains which activates the receptr, allwing ther prteins t bind and lead t a cellular respnse MAPK cascade Substrates: grwth factrs EGF and IGF Cytkine receptrs http://www.yutube.cm/watch?v=g4k6iqzghjc&feature=related JAK: janus kinases STAT: signal transducers and activatrs f transcriptin JAKs bind t the intracellular part f the receptr, a cytkine ligand binds t the extracellular receptr, which activates the JAKs, wh phsphrylate the receptr, which attract STATs t dck at the receptr, wh becme phsphrylated t, and the STATs dimerize, nw able t accumulate in the nucleus and regulate gene transcriptin N kinase activity Substrates: prlactin, leptin Serine threnine receptrs When a TGF-B binds t the extracellular dmain, the mnmeric units dimerize, the tyrsine kinase site phsphrylates the OH grup f serine/threnine, which recruits SMAD transcriptin factrs, wh themselves becme phsphrylated, dimerize, and regulate gene transcriptin Substrates: TGF-B Intracellular nuclear receptrs: fr lipphilic hrmnes Hrmne crsses membrane and binds t the receptr, which crsses the nuclear membrane and binds t a genmic sequence t regulate gene expressin Three dmains frm N-terminal t C-terminal: Transactivatin dmain: activates the prmter Zinc finger dmain: binds the DNA Hrmne binding dmain: binds the particular hrmne

A DEEPER LOOK // 2. HYPOTHALAMIC & PITUITARY INTERACTION Hypthalamus: cnnects nervus system t endcrine system Paraventricular nucleus (PVN): releases xytcin Ventrmedial nucleus: assciated with satiety Supraptic nucleus (SON): releases ADH/vaspressin Arcuate nucleus: dpamine and GHRH, regulates hunger Embrynic rigins: Neural: infundibulum f the primitive brain (third ventricle) grws dwn and becmes the pars nervsa (psterir pituitary) Epithelial: Rathke s puch f the ral cavity grws upward and separates t becme the pars distalis (anterir pituitary) Cmmunicatin & cnnectins: Prtal system vessels begin and end in capillaries Hypthalam-hypphyseal prtal system: hypthalamus secretes 1 st hrmnes int the superir hypphyseal artery at the primary prtal plexus in the median eminence which flws t the anterir pituitary int the secndary prtal plexus t act n endcrine cells causing the anterir pituitary t secrete the 2 nd hrmnes int circulatin Neural cnnectins: the axns f the supraptical nuclei (SON) and paraventricular nuclei (PVN) extend int the psterir pituitary and release their hrmnes there int a plexus frmed by the inferir hypphyseal artery Hypthalam-Pituitary-Adrenal Axis Hypthalamus secretes CRH nt the crtictrphs which secretes ACTH nt the adrenal glands which secrete crtisl Hypthalam-Pituitary-Liver Axis Hypthalamus secretes GHRH nt and stimulates smattrphs which secrete GH nt liver stimulating prductin f IGF Hypthalamus secretes smatstatin nt and inhibits smattrphs, inhibiting GH secretin Hypthalam-Pituitary-Thyrid Axis Hypthalamus secretes TRH nt thyrtrphs, stimulating them t secrete TSH nt thyrid t prduce T4 and T3 Hypthalam-Pituitary-Gnad Axis (depends n sex) Hypthalamus secretes GnRH nt gnadtrphs which secretes FSH & LH nt testes (teststerne, inhibin) r varies (estradil, prgesterne, inhibin) Hypthalam-Pituitary-Mammary Gland Axis Secretin f dpamine inhibits the secretin f prlactin Lacttrphs cnstantly prduce prlactin in the absence f dpamine Psterir pituitary Structure: amin acids, ring Made in the hypthalamus by magncellular cells (SON, PVN) Frmed as preprhrmnes: neurphysin and glycprtein cmpnents ADH aka vaspressin Osmreceptrs: senses increase in smlality, secretes ADH, leading t vascnstrictin and increased water retentin in kidneys Barreceptrs: senses decreased bld pressure, inf sent t hypthalamus via vagus nerve, secretes ADH Oxytcin Mymetrial cntractins f the uterus is sensed and sent t hypthalamus via brain stem, causing xytcin secretin, which increases cntractins (psitive feedback lp) Milk ejectin: suckling sensed and carried t brain via vagus nerve, xytcin secretin, increased milk ejectin; als secretes prlactin t induce milk prductin

A DEEPER LOOK // 3. GROWTH HORMONE GHRH: G-prtein cupled receptr GH: cytkine receptr (JAK-STAT) Ghrelin receptr: 7 transmembrane, cupled t PLC, Ca2+, bth synthesizes and secretes GH IGF-I: tyrsine kinase; insulin like effect r increases prtein, cell, and bne grwth; MAPK pathway; increases bne grwth either thrugh liver r directly at the level f chndrcytes in the cartilage Effect f GH: lyplysis: shifts metablism t lipid use fr energy while cnserving carbhydrates and prteins, therefre aka hyperglycemic hrmne ; increases lean bdy mass Interactin with insulin: insulin prmtes the frmatin f glycgen frm glucse whereas GH prmtes the breakdwn f glycgen int glucse; ppsing frces After a meal (high calries, lw prtein): insulin dminates s glucse uptake increases, GH secretin inhibited s lyplysis decreases; verall decrease grwth During fasting: GH dminates s lyplysis is stimulated, FFAglucse, but there is a decrease in IGF s verall grwth als decreases During fasting yu dn't want t waste energy grwing, because yu dn't really have the nutrients required, and s all yu want t d is keep yur brain and bdy metablism ging A DEEPER LOOK // 4. THYROID Thyrid perxidase: liberates idine fr additin nt tyrsine residues f thyrglbulin t make T4/T3; PTU inhibits this by blcking the idinatin f thryglbulin Organificatin: bichemical prcess in thyrid glands; xidatin f idide by perxide t frm reactive species, then binding t a tyrsine residue within thyrglbulin Effect f TSH n T4/T3 release Increased expressin f Na+I- symprter (NIS), therefre increasing idine uptake Stimulates rganificatin, which allws the activating and binding f idine t thyrglbulin Stimulates the actin f prtease n thyrglbulin, which cleaves it int T4 (mstly) r T3 (little) Increases grwth and vascularity f thyrid gland (pathlgy: t much TSH means huge thyrid) Mechanism f actin Nuclear receptr (i.e. thyrid hrmne is lipphilic) T4/T3 crss the membrane and enter int the cell T3 can directly enter the nucleus, but T4 needs t be cnverted int T3 first by 5 deidinase (D1, D2) Bth hyper- and hyp-thyridism prduce giters A DEEPER LOOK // 5. ADRENAL GLAND Think GFR MGS : t memrize adrenal crtex znes and their steridal hrmnes GRF : znas glmerulsa, fasiculata, reticularis MGS : mineralcrticids, gluccrticids, sex hrmnes Aldsterne Mineralcrticid, zna glmerulsa Thrugh the angitensin-renin system, it causes the retentin f water t increase bld pressure Crtisl Gluccrticid, zna fasiculata Secretin: circadian rhythm CRH ACTH crtisl Estrgen effect: causes the liver t prduce binding prteins which availability f active crtisl Effects n cell: camp, StAR, HDL-R, pregnenlne, size and quantity f cells Nuclear receptr: free crtisl crsses membrane and binds t chaperne-receptr cmplex, chaperne prtein dissciates, receptr-crtisl cmplex crsses membrane int the nucleus and binds with cactivatrs, resulting in regulatin f gene expressin

Physilgical effect: bld sugar (gluccrticid activity), H 2 O retentin (mineralcrticid activity) There is a very high plasma cncentratin f crtisl flating arund; therefre we shuld theretically be hypertensive due t its mineralcrticid activity (similar t aldsterne). Hwever, the enzyme 11βHSD2 cnverts active crtisl int inactive crtisne, decreasing its actin in cells that express the mineralcrticid receptr and where its actin is undesired. In cells with gluccrticid receptrs, its actin is desired, therefre 11βHSD1 catalyzes the cnversin f inactive crtisne t active crtisl. Licrice: inactivates 11βHSD2, s crtisl has mineralcrticid actin and causes hypertensin Physilgical effects as a respnse t stress Inhibits glucse uptake in adipse tissue In cases f lw insulin, induces lyplysis, which frees up FFA Enhances lyplytic effects f GH and epinephrine Liver cnverts the FFA int glucse release f epinephrine & glucagn, which stimulates glucnegenesis and glycgenlysis, bth f which glucse prductin Depresses immune system and has anti-inflammatry effects Cushing s Syndrme Hypercrticism : a disease caused by high levels f crtisl in bld Cause: adenma in pituitary gland ACTH secretin crtisl Effect: crtisl appetite eat glucse intake insulin liplysis fat retentin centrally and in the face pudginess Addisn s Disease Hypcrticism : a disease caused by crtisl deficiency, primary adrenal insufficiency Causes weakness, rapid weight lss, hypglycemia Because f the lack f crtisl, there is n negative feedback at the level f the pituitary gland, therefre ACTH levels, causing darker skin Treatment: replacement therapy DHEA (dehydrepiandrsterne) The mst abundant sterid in humans Des nt have the duble bnd at the 4C, therefre nt as active as ther sterids, and s it serves as a precursr/prhrmne t ther sterids DHEA andrstendine teststerne Has n negative feedback n pituitary (unlike crtisl) Cngenital adrenal hyperplasia Excess r deficiency f sex hrmnes as a result f prtein malfunctin Bad P450c21: Althugh ACTH is secreted, the adrenal crtex cannt prduce crtisl and aldsterne This causes excessive salt excretin and results in hyptensin Hwever, it can prduce lts f DHEA, and accumulatin f this sterid causes the masculinizatin f wmen Bad P45011β1: Crtisl but crticsterne can still be prduced, which can be cnverted int aldsterne This results in salt retentin and hypertensin, as well as masculinizatin frm DHEA Lipid cngenital adrenal hyperplasia Defective StAR N sterid prductin N DHEA: n masculinizatin f females N andrgens: males dn t lk like males N negative feedback at pituitary: ACTH, accumulatin f lipid drplets, cell damage Adrenal medulla Catechlamines: nrepinephrine, epinephrine (amin acid derived hrmnes) Medulla chrmaffin cells Cntrlled by the autnmic nervus system, which releases ACh nt the chrmaffin cells, which then secrete epinephrine int circulatin

Even thugh the sympathetic system secretes epinephrine, we need the adrenal medulla chrmaffin cells t als secrete epinephrine because f its lnger duratin, prlnged stimulatin, and its ability t reach cells that lack innervatins G-prtein cupled receptrs α receptrs: respnds better t epinephrine β receptrs: respnds better t nrepinephrine Effects: fight r flight Bld flw Glucse = energy Oxygen frm brnchidilatin GI use A DEEPER LOOK // 6. CALCIUM & PHOSPHATE METABOLISM IMPORTANT HORMONES PTH Secreted by chief/principle cells Ca2+ = PTH Ca2+and calcitril inhibits the synthesis f PTH by inhibiting the PTH gene Calcitril stimulates the CaSR gene t express mre CaSR (calcium sensing receptr) at the membrane, allwing a greater intake f Ca2+ PTH receptr: G-prtein cupled receptr (mstly in kidneys) Calcitnin Secreted by parafllicular C cells Nt a big rle in human metablism Ca2+ = Calcitnin Calcitril/Vitamin D Prduced frm chlesterl (i.e. sterid hrmne), metablized by liver and kidney (hydrxylases) Mst active frm is 1,25-dihydrxyvitamin D3 Prhrmne Calcifedil hydrxylase Calcitril PTH stimulates calcitril prductin Ca2+ inhibits prductin VDR: nuclear receptr: sterid crsses membrane easily, binds t nuclear receptr, chaperne prtein dissciates, cuples with cfactrs, needs heterdimer, binds t genes Regulatin PTH stimulates cnversin f califedil t calcitril ( Ca2+ inhibits the gene) Negative feedback: calcitril itself inhibits the gene Prtein binding extends its half life ORGANS INVOLVED Small intestine Mst f calcium regulatin is paracellular and hrmnally regulated and favred by a large cncentratin gradient, like in the case f a high calcium diet, which easily diffuses t be blcked In the case f lw Ca2+ cncentratins, can t be hrmnally regulated, absrptin f Ca2+ is very specific, and ne f the transprters that is used is a TrpV 5/6 epithelial channel frm luminal t apical/enteral side Once it gets in, it is bund by Calbindin-D9k, which facilitates the transfer f Ca2+ frm luminal t enteral side Serves as a shuttle frm cytplasm t PMCA (plasma membrane calcium ATPase) Calcitril regulates this at all three levels PTH mediates absrptin frm the gut indirectly by stimulating calcitril prductin Kidney Almst all Ca2+ reabsrbed by kidneys, <1% excreted Mst reabsrbed passively by prximal tubule, sme reabsrbed actively in ascending Lp f Henle thrugh TrpV channel

Bnes Tw transprters that mve Ca2+ t basal/apical side: PMCA and NCX (sdium calcium exchanger) Reabsrptin in ascending lp can be increased by PTH Phsphate is cntinually reabsrbed by a Sdium-Phsphate Transprter (NPT) frm the luminal side This transprter is stimulated by calcitril but inhibited by PTH (excess PTH = decrease phsphate) Bne is a dynamic prcess (steclasts break dwn rapidly, steblasts frm slwly) Osteblasts differentiate frm strmal cells Osteblasts express PTH receptr and VDR PTH stimulates the steblast t prduce M-CSF (mncyte clny stimulating factr) which binds t mnctyes/macrphages induce its differentiatin int a presteclasts Osteblast als prduces anther cytkine, RANKL (receptr activatr fr nuclear factr), which binds t presteclasts fr its final differentiatin int a plykarynic steclast (a big cell with many nuclei) which initiates the bne s break dwn, frms a very tight seal between the steclast and bne Prtelytic enzymes break dwn the bne and causes the secretin f Ca2+ int the serum Osteblasts can als prduce anther cytkine, OPG, which binds and inhibits RANKL, inhibiting resrptin Causes the cell t apptsis r mve t anther lcatin Once the steclast dies r mves away, it can be replaced by an steblast that secretes steid and salts t frm new bne matrix Osteclast actin is stimulated by PTH A DEEPER LOOK // 8. ENERGY HOMEOSTASIS INSULIN Helps the uptake f glucse n the cells (e.g. liver) Activates Prtein Phsphatase 1 (PP-1) which activates glycgen synthase by dephsphrylatin Muscle/liver is a very limited strage During lw levels f glucse, glucagn and epinephrine get t wrk Only the liver regulates glucse synthesis by dephsphrylatin G-6P t glucse INSULIN SECRETION Glucse enters via GLUT2 and is phsphrylated by gluckinase t G6P which can t leave the cell Glucse sensr: amunt f G6P inside cell is directly prprtinal t amunt f glucse utside Rati f ATP/ADP in the cell is vey imprtant: if ATP increases, it will blck the ptassium channel and deplarize the membrane, which will activate vltage dependent Ca2+ channel which will lead t an increase in intracellular Ca2+, favring the excytsis f secretry granules f insulin Ach and FFA can act thrugh receptrs and increase Ca2+ and insulin secretin (less imprtant than glucse) Epinephrine and nrepinephrine prevent the increase f camp Every cell is invlved in insulin secretin except in the brain INSULIN RECEPTOR AND SIGNALING GLUCAGON Insulin receptr is part f the tyrsine kinase family Once insulin binds, causes crss phsphrylatin, serving as a dcking site fr intracellular mlecule IRS (insulin receptr substrate) It is again phsphrylated as a result, and nw serves as a dcking site fr the prtein P13K which will becme phsphrylated by the receptr due t its prximity This allws the cnversin f PIP2 t PIP3 PIP3 is a dcking site fr PKB, which stimulates the mvement f GLUT4 vesicles t the membrane, which can nw transprt glucse int the cell MAPK grwth Prduced in alpha cells in pancreas and L cells in intestines Prduced frm preprglucagn L cells prduce glucagn-like peptide (GLP-1) which augments insulin release Glucagn secretin inhibited by glucse and insulin Glucagn secretin stimulated by amin acids and catechlamines

Glucagn secreted int hepatic prtal vein and ges directly thrugh the liver where it is stred, less than 20% makes it ut Glucagn receptr is a G-prtein cupled receptr Glucse = alpha cells = glucagn = glucagn glucse Glucse = beta cells = insulin = glucse glucagn Nrmal: 90 mg/100ml METABOLISM AFTER A MEAL Fd = tns f excess glucse Glycgen strage is limited (100g) Acetyl CA cnverted t free fatty acids and then t triglycerides in lipid synthesis Increase in insulin causes increase in GLUT 4 expressin t increase uptake f glucse in adipse, liver, and muscle Liver: fr glycgen strage and t prduce CA fr lipgenesis : FFA TG VLDL, which is transprted int adipse tissue fr strage Adipse: lipprtein lipase (LPL) is stimulated/activated which takes chylmicrns frm intestines and releases FF; Glyclysis prduces G3P which is used t make triglycerides Muscle: glucse used fr energy and strage as glucagn Insulin als increases prtein synthesis in all the tissues METABOLISM DURING FASTING STATE Insulin = Glucagn (since insulin is the main inhibitr f glucagn) Glycgen G1P G6P glucse Glyclysis prduct pyruvate can be used t frm G6P in glucnegenesis Amin acids can be invlved in varius levels Lactate frmed int pyruvate fr glucnegenesis Glucse-sparing effect: using ther surces f energy like amin acids and FFA Fast fr lng perids f time: glycgen depleted: acetyl Ca ketne bdies, which are used by the brain and incrprated int the TCA cycle Fasting causes insulin glycgen and epinephrine Epinephrine stimulates the breakdwn f glycgen int G6P but there s n phsphatase present s it cannt be cnverted in t glucse fr use in circulatin In the liver, phsphatase is present: glycgen G6P glucse feed the bdy Lack f insulin and glucagn stimulate liplysis t prduce FFA which ges t the liver t create acetyl CA and then ultimately ketne bdies Glucse sparing: liver and muscle start using FFA as main surce f energy, allwing glucse t be used primarily fr the brain camp activates phsphrylase kinase which activates glycgen phsphrylase glycgen degradatin glucse camp inactivates glycgen synthase glycgen synthesis glucse A DEEPER LOOK // 8. ENERGY HOMEOSTASIS Regulatin f fd intake Arcuate nucleus NPY, AgRP, ghrelin: prmtes hunger (rexigenic) POMC, CART: prmtes satiety (anrexigenic) Shrt-term: use f glucse, FFA, ghrelin, vagal afferents, distentin Lng-term: use f insulin, leptin (satiety) and adipnectin (hunger) frm adipse tissue Leptin receptrs: JAK-STAT cytkine receptrs