BIOCHEMISTRY  
 
HORMONAL   REGULATION  OF  METABOLISM  I  
 

 
 
 
     Dr.  Floro  B.  Madarcos  |  March  1,  2019    
LE5 TRANS3  
 
OUTLINE   Cortisol   Adrenal  Cortex  (zona  fasciculata)  
I.   Introduction     V.   Cortisol  
A.   Classification  of   Synthesis   Thyroid  
Hormones   A.   Regulation  of  synthesis   Hormones     Thyroid  gland  (follicular  cells)  
B.   Chemical  Composition     &  secretion   (T3  &  T4)  
II.   Somatostatin   B.   Mechanism  of  action    
III.   Growth  Hormone   C.   Metabolic  effects   Anabolic  (Hypoglycemic)  
A.   Structure   D.   Clinical  correlation  
B.   Control  of  Secretion   VI.   Thyroid  Hormones   Insulin   β  cells  of  pancreas  
C.   Mechanism  of  Action   A.   Synthesis    
D.   Metabolic  Effects   B.   Metabolism   II.  SOMATOSTATIN  
E.   Clinical  Correlation   C.   Regulation    

IV.  Catecholamines   D.   Mechanism  of  action   •   Chemical  formula:  C76H104N18O19S2  +  nH2O  

A.   Synthesis  and   E.   Metabolic  effects   •   Also  known  as:  
secretion   F.   Clinical  correlation   →  Growth  Hormone  Releasing-­Inhibiting  Hormone  (GHRIH)  
B.   Mechanism  of  action   VII.   Adipose  tissue  as  an   →  Somatotropin  Releasing-­Inhibiting  Hormone  (SRIH)  
C.   Effects  on  metabolism   endocrine  organ   →  Somatotropin  Releasing-­Inhibiting  Factor  (SRIF)  
D.   Degradation     VIII.   Hormones  that  control   •   A  cyclic  polypeptide  hormone  made  up  of  14  amino  acids,  with  
E.   Clinical  correlation   appetite   a  disulfide  bond  between  cysteine  residues  3  and  14  
 

OBJECTIVES  
 

•   Discuss   the   major   hormones   that   regulate   fuel   metabolism   in  

terms  of:  
→  Synthesis  and  structure  
→  Factors  affecting  synthesis  and  secretion/release  
→  Signaling  pathways  
→  Metabolic  and  physiologic  defects  
•   Comparing   the   effect   of   hormones   for   appetite   control   and  
eating  behavior    
Figure  1.  Structure  of  Somatotastin  [Lecture  PPT]    
→  Leptin    
→  Insulin   A.  SYNTHESIS  AND  SECRETION  
 
→  Ghrelin  
•   Involves   the   biosynthesis   of   a   larger   116   amino   acid  
→  PYY   preprosomatostatin  precursor  molecule  
→  Adiponectin  
•   Proteolytic   cleavages   subsequently   produce   the   smaller  
 
prosomatostatin   molecule   and   then   the   2   bioactive   peptide  
I.  INTRODUCTION  
isoforms:  
•   Hormones  
→  Class   of   signaling   molecules   synthesized   by   endocrine   −   the  originally  discovered  14  amino  acid-­peptide  
organs   and   transported   in   the   bloodstream   to   target   distant   SST-­14   −   more  abundant  in  hypothalamus  and  exocrine  
organs  and  provide  homeostatic  responses     pancreas  
§   can  also  act  on  adjacent  cells  (paracrine)  
§   can   also   act   on   the   cells/tissues   in   which   they   were   −   the  C-­terminally  extended  form  with  28  amino  
synthesized  (autocrine)   acids  
 
SST-­28   −   predominant  in  the  GIT  
A.  CLASSIFICATION  OF    HORMONES   −   7-­10x  more  potent  in  inhibiting  the  release  of  
•   Chemical  Composition   GH  and  insulin  than  SST-­14  
•   Solubility  Properties    

•   Location  of  Receptors   •   Mechanism  of  secretion:  mediated  by  membrane  depolarization  
•   Nature  of  Intracellular  Messenger  or  Signal  used   and/or  increasing  cytosolic  Ca2+  
*See  Appendix    
 

B.  MAJOR  HORMONES  IN  FUEL  METABOLISM  

 
Table  1.  Major  Hormones  that  regulate  fuel  metabolism  
Catabolic  (Hyperglycemic;;  Counterregulatory)  
Glucagon   α  cells  of  pancreas  
Hypothalamus  (major  site)    
D  (or  α)  cells  of  pancreas  
CNS  outside  of  hypothalamus  
Somatostatin  
gastric  &  duodenal  mucosal  cells    
Others:  placenta,  kidney,  retina,  immune  
cells                  
Growth  Hormone   Somatotrophs  of  anterior  pituitary  gland    
 
Figure  2.  Synthesis  and  Secretion  of  Somatotastin  [Lecture  PPT]    
Catecholamines:  
 
Epinephrine  &   Adrenal  Medulla  
 
NE  
 
L.E.  #  5  -­  Trans  #  3   Group  T:  Trinidad,  Y.,  Triviño,  Tuazon,  Ursulom,  Valeros       1  of  20  
 
  

Regulators  of  Somatostatin  Secretion   First  Signaling  Pathway  

  •   Inhibition   by   all   receptors   of   the   G-­protein   (guanine  
Stimulators  (+)   nucleotide  binding  protein)  à  inactivation  of  adenylyl  cyclase  
Nutrients   Glucose,  Amino  Acids  (Arg,  Leu),  FA   à   decrease   cAMP   synthesis   from   ATP   à   inactivation   of  
protein  kinase  A    
Hormones   Glucagon,  GNRH,  CRH,  Neurotensin   →  Decreased   GH   and   TSH   secretion   from   the   anterior  
pituitary  gland  
CCK  –  Cholecystokinin    
→  Decreased   insulin   and   glucagon   secretion   from   the  
GIP  –  Gastric  Inhibitory  Polypeptide    
GIT  Hormones   pancreatic  islets  
GIP  1  –  Glucagon-­like  Peptide  I  
 
VIP  –  Vasoactive  Intestinal  Peptide  
Second  Signaling  Pathway  
Neurotransmitters   IL1,  IL6,  TNFα       •   Activation   of   G-­protein   regulated   inward   K   channel   à   cell  
membrane   depolarization   à   decrease   in   Ca   flux   through  
 
voltage-­dependent   Ca   channels   à   decrease   intracellular  
Inhibitors  (  -­  )   Ca2+  
Neurotransmitters   GABA   •   Decreased  cytosolic  cAMP  and  intracellular  Ca2+  à  inhibition  
Cytokines   TNFβ,  Leptin   of   neurotransmitter   and   hormone   secretion   from   cells   in  
different  tissues  (pituitary  gland,  endocrine  pancreas,  GIT)  
   
B.  MECHANISM  OF  ACTION   Third  Signaling  Pathway  
•   Activation  (upon  binding  of  a  somatostatin  to  its  receptor)  of  
a  number  of  protein  phosphatases  from  different  families  like:  
→  Phosphotyrosine  Phosphatase  (PTPase)    
§   SHP1  and  SHP2  
→  Serine/Threonine/Tyrosine  phosphatases    
→  Ca2+  dependent  phosphatases  
•   Regulation   of   more   distal   signaling   pathways   like   Mitogen-­
Activated  Protein  Kinase  (MAPK)  pathway  
•   Also  PDK1  (Phosphoinositide-­dependent  Protein  Kinase  1)  
•   Net   effect:   apoptosis   and   decreased   cell   growth   and  
  proliferation  (cytostatic  action)  
Figure  3.  Signaling  Pathway  for  Lipophobic  Hormones  [Lecture  PPT]    
 
•   Lipophobic  Hormones  (Class  II)   NOTE  
→  Aqueous  in  nature     o   The  1st  and  2nd  signaling  pathways  inhibit  neurotransmitter  
→  Cannot  penetrate  lipid  bilayer  of  cell  membranes   and  hormone  secretion.  
→  2nd  messengers  inside  the  cell  cytoplasm  are  needed   o   The  3rd  signaling  pathway  produces  anti-­proliferative  
  effects.  
•   There  are  5  identified  somatostatin  receptors  
→  All  are  from  GPCR  superfamily    
•   Receptors  for  somatostatin  are  trimeric-­GPCRs  (SSTR1-­ C.  PHYSIOLOGIC  EFFECTS  OF  SOMATOSTATIN  
 

SSTR5)   •   Somatostatin  inhibits  the  secretion  of  many  other  hormones  

•   Somatostatin   binds   to   its   cell   membrane   receptors   on   multiple   •   Acts   by   both   endocrine   and   paracrine   pathways   to   affect   its  
target  cells   target  cells  
•   It  suppresses  the  release  of  the  following  hormones:  
•   The   activated   receptors   interact   with   multiple   intracellular  
signaling  pathways  depending  on:  
Anterior   −   GH  
→  The  cell  type  expressing  the  receptor   Pituitary   −   TSH,  Thyrotropin  
→  The  specific  somatostatin  receptor  being  expressed   hormones   −   Prolaction  (PRL)  
•   There  are  3  signaling  pathways  for  somatostatin  
−   Gastrin  /  Secretin  /  Pancreozymin  
−   Cholecystokinin  (CCK)  
GIT  
−   Vasoactive  Intestinal  Peptide  (VIP)  
hormones  
−   Gastric  Inhibitory  Polypeptide  (GIP)  
−   Motilin  /  Enteroglucagon  

Pancreatic   −   Insulin  
hormones   −   glucagon  

•   Decreases  rate  of  nutrient  via:  

→  Decreasing  gastric  acid  and  pepsin  secretion  via  suppression  
of  parietal  cells  
→  Prolonging  or  decreasing  gastric  emptying  time  
→  Reducing   smooth   muscle   contraction   and   blood   flow   within  
the  intestines  
→  Diminishing   pancreatic   exocrine   secretions   (digestive  
enzymes,  HCO3,  H2O)  
 
 
   
Figure  4.  Signaling  Pathway  for  Somatostatin  [Lecture  PPT]    
Biochemistry   Hormonal  Regulation  of  Metabolism  I   2  of  20  
 
 
  

D.  CLINICAL  APPLICATION   •   Release  is  also  modulated  by  plasma  levels:  

 

Somatostatin  and  its  synthetic  long-­acting  analogues  (Octreotide,   →  ↓  Glucose  =  ↑  GH  secretion  
Lanreotide)   are   used   clinically   to   treat   various   secretory   §   ↑  blood  glucose  =  ↓  GH  secretion  
neoplasms   →  ↑  AA  =  ↑  GH  secretion  
→  ↑  FA  (prolonged  fasting)  =  ↑  GH  secretion      
Gigantism  and  acromegaly    
•   Maximum  level  of  GH  secretion  is  during  deep  sleep,  and  lower  
•   GH-­secreting  tumor  of  the  anterior  pituitary  gland   level  during  daytime  
•   Due  to  its  own  inhibition  of  growth  hormone   →  Circadian  rhythm  
→  Secretory  burst  most  frequently  in  children  and  young  adult  
Carcinoid  tumor   •   Ghrelin  induces  GHRH  and  directly  stimulates  GH  release  
↓"Bld."glucose
•   Due   to   serotonin-­secreting   carcinoid   tumors   anywhere   along   ↑"Bld."AAs Stress
the  GIT  and  the  lungs   ↑"FAs" + +
1Sleep
Exercise
•   A   well-­differentiated,   malignant   neuroendocrine   tumor   of   the   rhythms
small  intestine   + 2Ghrelin
+
•   Production  of  hormones  like  serotonin,  substance  P,  gastrin   Hypothalamus
•   Octreotide   (Sandostatin®)   is   adjunct   in   the   treatment   plan   of   +
carcinoid  tumors  
"
→   neutralizes  serotonin  and  decreases  urinary  5-­HIAA)  (2021A)   GHRH *Somatos"
  tatin5(GHRIH)
+
III.  GROWTH  HORMONE  
  "
•   GH;;  Human  Growth  Hormone  (HGH)     Anterior
•   Somatotropin;;  Somatropin   pituitary
"
•   Secreted   by   the   somatotropic   cells   present   in   the   lateral   areas  
1Children5&5
of  the  anterior  pituitary  gland   Growth5hormone
young5adults
•   Most  abundant  trophic  hormone  in  the  anterior  pituitary   IGF"1
  + IGF"1
A.  STRUCTURE  OF  GROWTH  HORMONE   *Primary5regulatory IGF"1
 
mechanism (Somatomedin)5
•   Single   water-­soluble   polypeptide   chain   initially   produced   as   a  
217  preGH.  [Madarcos  Notes]   Liver5and5other5cells
•   191   AA   with   two   strong   intramolecular   disulfide   bonds   that    
Figure  6.  Control  of  GH  Secretion    
keeps  the  helical  structure:    
→  Cys  53  –  Cys  165   Table  2.  Some  factors  affecting  Growth  Hormone  Secretion  
→  Cys  182  –  Cys  189  
    Stimulate  (+)   Suppress  (-­)  
↑  Blood  glucose  after  
217$AA$precursor$ Physio-­
Exercise,  Sleep,  Stress   meals  
protein logic  
↓  Blood  Fatty  Acids  

GHRH,  Estrogens  
26$AA$signal$ Somatostatin  
α-­Adrenergic  agonists  
peptide Progesterone    
Pharmaco-­ β-­adrenergic  antagonists  
α-­Adrenergic  antagonists  
logic   Dopamine  agonists  
191$AA$mature$ β-­adrenergic  agonists,  
Serotonin  precursors  
HGH Dopamine  antagonists  
  K  infusion  
Figure  5.  Human  Growth  Hormone    
 
B.  CONTROL  OF  SECRETION  OF  GH   Starvation,  Anorexia  
 

nervosa,  Ectopic  GHH  

Obesity,  Hypothyroidism,  
 

•   Somatostatin   release   is   the   primary   mechanism   of   regulating   Pathologic   production,  Acromegaly,  

Hyperthyroidism  
growth  hormone  secretion   Chronic  renal  failure,  
Hypoglycemia  
→  Release   is   stimulated   by   Growth   Hormone-­Releasing  
Hormone   (GHRH),   also   called   as   somatocrinin   from   the    
hypothalamus    
C.  MECHANISM  OF  ACTION  
→  Release   is   suppressed   by   Growth   Hormone   Release-­  

Inhibiting  Hormone  (GHR-­IH),  also  called  somatostatin  from   •   GH   is   a   Lipophobic   hormone,   thus   it   binds   to   the   extracellular  
the  hypothalamus   domain  of  the  2  GH  receptor  to  produce  its  effects.  
•   Growth  hormone  causes  the  release  of  Insulin  Growth  Factor-­ →  GHRs   are   abundant,   hence   it   stimulates   a   variety   of  
1   (IGF-­1)   from   the   liver   and   other   tissues.   It   inhibits   GNRH   metabolic  processes  in  all  cell    
release   and   stimulates   somatostatin   release   (negative   •   Janus   Kinase   (JAK)   family   is   the   predominant   (JAK2   in  
feedback)     particular)  tryrosine  kinase  that  can  associate  with  GHR  
→  JAK2   –   docking   point   for   the   phosphorylation   of   other  
Hormones   Other  name   Source   Effect  
signaling  proteins  in  a  cascade  manner  
GHRH   Somatocrinin   Hypothalamus   ↑  GH   •   GH-­bound   receptor   induces   JAK2   phosphorylation   →   activate  
GHR-­IH   Somatostatin   Hypothalamus   ↓  GH   various  signaling  molecules,  different  cellular  response  
(-­)  GNRH   •   Activation  of  Mitogen-­Activated  Protein  Kinase  (MAPK)  pathway  
↓  GH     →  transcription  of  target  genes    
IGF   Somatomedin   Liver  
Negative   •   Phosphorylated   Insulin   Receptor   Substrate   (IRS)   →   activated  
feedback   Phosphoinositol  3-­kinase  (PI3K)  →  ↑  glucose  transport  
Biochemistry   Hormonal  Regulation  of  Metabolism  I   3  of  20  
 
 
  

D.  METABOLIC  EFFECTS  
 

Table  4.  General  Effects  of  GH  on  energy  metabolism  

Nutrient   Effects  
Fatty  acids   ↑  availability  for  energy  synthesis  
Glucose  &  
↓  oxidation  due  to  sparing  effect  of  fatty  acids  
Amino  acids  

 
Figure  7.  Mechanism  of  Action  of  GH    

STAT   Signal  Transducer  and  Activator   IRS   Insulin  Receptor  

of  Transcription   Substrate  
SHC   Src  Homology  2alpha  collagen   PI3’K   Phosphoinositol  
related   3’Kinase  
MAPK   Mitogen  Activated  Protein   JAK2   Janus  Kinase  2  
Kinase  
 
Table  3.  GH-­bound  receptor  induced  JAK2  phosphorylation  and  its  cellular  responses  
MOA   (+)   Effects  
GH-­induced  JAK2   Transcription   ↑  metabolism  and  growth  
 
phosphorylation  →   of  target   Figure  9.  Metabolic  effects  of  GH    
activation  of  STAT   genes  
and  SHC     Liver  
•   Increased  Ketogenesis  
JAK2  phosphorylation   Activates   Produce  various  metabolic   →  Enhanced  fatty  acid  oxidation  →  ↑  Acetyl  CoA  →  ↑  energy  
→  activation  of  SHC   MAPK   and  growth  promoting   •   Increased  Gluconeogenesis  
pathway   effects  
→  Increased  amount  of  glycerol  reaching  the  liver  because  of  
MAPK  also  promote   enhanced  lipolysis  (in  the  fasting  state)  
transcription  of  target  genes   •   Increased  Glycogenesis  
JAK2-­induced   Activates   ↑  glucose  transport   →  Results  to  hyperglycemia  (accompanied  with  ↑  
phosphorylated  IRS   PI3K     Gluconeogenesis)  
•   Decreased  Glycolysis  
  •   Increased  Synthesis  and  release  of  IGFs  
Signaling  Pathways  Activated  by  GHR   →  Both  IGF-­1  and  IGF-­2  promote  growth;;  have  structural  
 
homologues  with  proinsulin  
→  More  potent  than  insulin  in  their  growth-­promoting  actions  
§   Children:  IGF1  promotes  proliferation  of  chondrocytes  →    
↑  bone  length  and  height  
§   Puberty:  cartilage  at  the  ends  of  most  long  bones  is  
converted  to  bone;;  IGF1  cannot  increase  their  length  
→  IGF1  more  concentrated  in  liver  >  kidney  and  heart  
Growth  Plate  
•   Simulation  of  chondrocytes  →    induces  growth  of  long  bones  
(linear  growth)  
 

Adipose  Tissues  
•   Increased  Lipolysis  
→  Anti-­insulin  effect  of  GH  
 
Figure  8.  Signaling  pathways  activated  by  GHR   →  ↑  sensitivity  of  adipocyte  to  catecholamines  →  ↑  FFA  and  
•   GH   bind   to   receptor   →   dimerization   of   hormone-­receptor   glycerol  →  ↑  energy  supply  
complex   →   tyrosine   residues   (intracellular   domains   of   the   •   Increased  β-­oxidation  →  ↑  Energy  supply  
receptor)   are   phosphorylated   by   JAK2   →   activation   of   Signal   •   Decreased  Lipogenesis  
Transducers   and   Activators   of   Transcription   (STAT)   and   Src   →  Due  to  ↓  sensitivity  to  insulin  
Homology   2α   Collagen-­related   protein   (SHC)   →   ↑   metabolism   •   Decreased  TAG  Synthesis  
and  growth   →  Due  to  ↓  esterified  FAs  
•   Other   signaling   molecules   involved   in   transcription   of   target  
genes:   Muscle  
→  GRB2  (Growth  Factor  Receptor  Bound  2)   •   Decreased  Glucose  uptake  
→  SOS  (Son  of  Sevenless)   →  Due  to  utilization  of  FFA  as  energy  source    
→  SHP-­2  (Protein  Tyrosine  Phosphatase)   •   Decreased  Glycolysis  
→  RAS  (Proto-­oncogene  protein  P21)   •   Increased  Protein  Synthesis  
→  RAF  (Proto-­oncogene  protein  raf)   →  Due  to  ↑  uptake  of  amino  acids  into  muscle  cells  
→  MAPKK  (Mitogen  Activated  Protein  Kinase  Kinase)   •   Positive  Nitrogen  Balance  
  →  Due  to  protein  sparing  effect  of  fatty  acids  on  proteins  
  •   Increased  DNA  and  RNA  Synthesis  
   

Biochemistry   Hormonal  Regulation  of  Metabolism  I   4  of  20  

 
 
  

Anabolic  effects  of  GH   Manifestation  of  GH  Excess  

•   Currently  in  illicit  use  in  sports    

•   Gigantism  (Children)  
→  Considered  as  a  doping  practice  
→  Excessive  amounts  of  GH  before  closure  of  epiphyseal  
→  Increases  muscle  mass  and  strength  
plates  of  the  long  bones  
→  Performance  enhancing  substance  
→  Abnormal  increase  in  height  but  proportionate  
→  There  is  a  risk  of  developing  acromegaly  with  prolonged  
→  S/S:  Delayed  puberty,  double  vision  headache,  ↑  sweating,  
intake  
  large  hands  and  feet  
E.  CLINICAL  CORRELATION   •   Acromegaly  (Adults)  
  →  Increased  GH  levels  
Disorders  of  GH  Secretion:  Deficiency   →  Frontal  bossing  –  increased  epiphyseal  closure  
 

CONGENITAL   ACQUIRED   →  S/S:    

  §   Body  odor;;  carpal  tunnel  syndrome;;    
−   Anterior  pituitary  gland   −   Infection   §   fatigue,  weakness,  ↑  sweating,  joint  pains,    
disease   −   Brain  tumors  /  surgery  /   §   bone  overgrowth  and  thickening  of  tissues  →  large  hands  
−   Part  of  a  syndrome   radiation  therapy   and  feet,  altered  facial  features  (enlarged  lips  and  tongue  
with  lower  jaw  overgrowth,  widely  spaced  teeth),    
−   Congenital  deficiency  of   −   Injury  –  birth  or  at  later  
§   thick  &  dry  skin;;  organ  enlargement;;  sleep  apnea;;  widely  
GH   stage     spaced  teeth;;  unintentional  weight  loss;;    
  §   HPN,  DM  &  heart  disease  
Manifestations  of  GH  Deficiency    

 
GH  among  athletes  and  body  builders  
CHILDREN   ADULTS  
GH  increase  muscle  mass  and  strength.  It  is  a  performance-­
−   Short  and  proportionate   −   ↓  Energy,  strength,  and   enhancing  substance.  This  effect  has  been  abused  among  
stature   muscle  mass   athletes  and  body  builders.  Prolonged  intake  increases  the  risk  
−   Slow  growth     −   Weight  gain  (esp.  around   of  developing  acromegaly.  
−   Delayed  onset  of  puberty   the  waist)    
and  tooth  development   −   Thin  and  dry  skin    Treatment  of  Gigantism  or  Acromegaly  
−   ↑  Fat  around  the  waist   −   Anxiety  and  depression   1.   Surgery  
  −   ↑  Total  cholesterol,  LDL,   →  Surgical  removal  of  ant  pituitary  gland  tumor  to  stop  
Apoprotein  B  and  &  TAG     excess  release  of  GH  (60%  successful)  
−   ↓  Bone  density   →  Large  tumors  cannot  always  be  completely  removed  
−   No  increase  in  height     2.   Radiation  
  →  Used  in  tandem  with  surgery  
Genetic  Deficiencies  of  GH   →  Can  help  reduce  levels  of  hormone  release  by  killing  
•   GH-­deficient  dwarfs   tumor  cells    
→  Lack  the  ability  to  synthesize  or  secrete  GH  (pituitary   →  A  slow  process  and  not  as  successful  as  surgery  
dwarfism)   3.   Pharmacological  
→  Treated  by  GH  administration  (IM)  before  fusion  of    
 
epiphyseal  plates   Table  5.  Pharmacologic  Treatment  of  Gigantism  of  Acromegaly  
§   Applied  anywhere  from  once  a  day  to  several  times  per  
week   Drugs   Description  
→  Further  care  involves  psychological  therapy   longer  half-­life  than  native  somatostatin  
§   Help  deal  with  social  ramifications  of  such  a  short  stature   •   Octreotide-­  long  acting  release    
Somatostatin  
 
(IM  once  a  month)  
•   Pygmies   Agonists  
•   Lanreotide-­  slow  release    
→  Lack  of  the  IGF-­1  response  to  GH  but  not  its  metabolic  effect   (IM  once  every  other  week)  
→  Deficiency  is  post-­receptor  
 
Dopamine   •   Cabergoline  –  inhibits  GH  
•   Laron  Dwarfs   Agonists   secretion    
→  Decreased  IGF-­1;;  Receptor  defect  
→  Treated  with  biosynthetic  IGF-­1  before  puberty  to  be  effective   Competitively  binds  to  GHR  without  
  GH  receptor   activating  them  
Treatment  of  Dwarfism   Antagonists   •   Pegvisomant  –  blocks  binding  to  
1.   GH  injections   GHR  receptor  
→  Soonest  possible  time    

→  Once/day  to  several/week    

→  Until  age  25    
 
→  No  increase  in  height  during  adult  intake  
 
2.   Psychotherapy  
 
→  Psychological  therapy  to  deal  with  social  ramifications  of  
 
short  stature    
 
   
Disorders  of  GH  Secretion:  Excess    
   
•   Congenital    
→   Anterior  pituitary  gland  disease  (most  common;;  benign)    
→   Part  of  a  syndrome:  Carney  Complex,  McCune-­Albright    
syndrome,  Multiple  Endocrine  Neoplasia,    
Neurofibromatosis    
•   Acquired    
   
Biochemistry   Hormonal  Regulation  of  Metabolism  I   5  of  20  
 
 
  

IV.  CATECHOLAMINES   B.  MECHANISM    OF  ACTION  OF  EPINEPHRINE  

   

A.  SYNTHESIS  AND  SECRETION   Note:   Epinephrine   is   lipophobic   and   impermeable   to   the   cell  
 
membrane   that’s   why   it   produces   its   effect   via   synthesis   of   a  
•   Epinephrine,  Dopamine,  and  Norepinephrine  
second  messenger  upon  binding  to  its  membrane  receptor  
•   Synthesized  in  the  adrenal  medulla  from  tyrosine  (essential  AA)  
 
β-­ADRENERGIC  PATHWAY  (β1  or  β2  receptors)  
•   Β  adrenergic  receptors  are  found  in  liver,  muscle  and  adipose  
tissue  

 
Figure  10.  Synthesis  of  Catecholamines  [Lecture  PPT]  

Table  6.  Synthesis  of  Catecholamines  –  Mechanism    

 
Step   Description   Mechanism   Figure  11.  Signal  transduction  for  beta  receptors  [Lecture  PPT]  
L-­Tyrosine  (immediate  precursor)  
à  L-­DOPA  (3,4-­dihydroxyphenyl-­ 1)   Epinephrine  binds  to  β-­adrenergic  receptor  à  H-­R  complex  
alanine)   2)   Activation  of  stimulatory  G-­protein  (Gs)  
 
→  Gs  –  trimeric  protein  made  of  α,  β,  γ  subunits  
•  Enzyme:  tyrosine  hydroxylase  
1   •  Rate  limiting  step   Hydroxylation   →  GDP  (inactive)  attaches  to  α-­subunit;;  GTP  (active)  
•  Cofactor:  tetrahydrobiopterin   3)   Activation  of  adenylate  cyclase  
(abundant  in  CNS,  sympathetic   4)   Adenylate  cyclase  catalyzes  cAMP  synthesis  from  ATP  
ganglia  and  the  adrenal  medulla)   5)   cAMP  allosterically  activates  protein  kinase  A  
•  Regulated  by  feedback  mechanism   6)   PKA  catalyzes  phosphorylation  of  target  proteins  =  cellular  
response  of  epinephrine  
L-­DOPA  à  Dopamine  (3,4-­
dihydroxyphenylethylamine)   7)   Termination  of  β-­adrenergic  response  by  degrading  cAMP  into  
  5-­AMP  via  cyclic  nucleotide  phosphodiesterase  
2   Decarboxylation  
•  Enzyme:  DOPA-­decarboxylase    
•  Cofactor:  PLP  (pyridoxal   α-­ADRENERGIC  PATHWAY  (α1  and  α2  receptors)  
phosphate)   •   Produces  3  second  messengers:  IP3,  DAG,  and  Ca2+  
Dopamine  à  Norepinephrine  
 
•  Enzyme:  Dopamine  β-­hydroxylase  
•  Cofactors:     Side-­chain  
3  
•  Ascorbic  acid  (electron  donor)   hydroxylation  
•  Cu2+  (at  active  site)  
•  Fumarate  (modulator)  
•  Site:  adrenal  medulla  

Norepinephrine  à  Epinephrine  

 
•  Enzyme:  PNMT    
Phenylethanolamine-­N-­methyl  
transferase;;  synthesis  of  PNMT  is  
4   N-­methylation  
induced  by  glucocorticoid  hormones  
•  occurs  at  the  cytoplasm  of    
   epinephrine-­forming  cells    
•  conversion  of  the  methyl  group       Figure  12.  Signal  transduction  for  alpha  receptors  [Lecture  PPT]  
   donor;;  SAM,  to  SAH   1)   Epinephrine  binds  to  α-­adrenergic  receptor  à  E-­R  complex  
  2)   Activation  of  G  protein  complex  (Gq)  
•   Dopamine  is  the  active  neurotransmitter  in  the  part  of  the  brain   →  Replacement  of  GDP  with  GTP  
(substancia  nigra)   3)   Gq  with  bound  GTP  activates  Phospholipase  C  (PLC)  
→  Failure   to   synthesize   dopamine   results   to   Parkinson’s   4)   PLC  cleaves  PIP2  into  secondary  messengers  IP3  and  DAG  
disease.  Treatment:  administration  of  L-­DOPA   →  IP3  –  water  soluble;;  diffuses  into  the  cytoplasm  and  ER  
•   Dopamine,   Epinephrine   and   Norepinephrine   are   termed   →  DAG  –  lipid  soluble;;  moves  along  plasma  membrane  
catecholamines  because  they  are  amine  derivatives  of  catechol   5)   IP3  binds  to  receptor  à  intracellular  Ca2+  is  released  
•   Secretion   is   stimulated   by   a   variety   of   stresses   (fright,   6)   DAG  and  Ca2+  activate  protein  kinase  C  (PKC)  
hemorrhage,  pain,  cold,  exercise,  hypoglycemia,  hypoxia)   7)   PKC   phosphorylates   target   signal   transduction   proteins   on  
•   Catecholamines  are  contra-­insulin  and  catabolic   serine   or   threonine   residues   à   production   of   cellular  
•   Mediated  by  stress-­induced  transmission  of  nerve  impulses     responses    
Biochemistry   Hormonal  Regulation  of  Metabolism  I   6  of  20  
 
 
  

C.  EFFECTS  ON  FUEL  METABOLISM     D.  DEGRADATION  OF  CATECHOLAMINES  

 
 

DEGRADATION  OF  NOREPINEPHRINE  

 
Figure  14.  Degradation  pathway  –  Norepinephrine  [Lecture  PPT]  
Table  8.  Degradation  of  Norepinephrine    
Step   Description   Reaction  
 
Figure  13.  Effects  of  Epinephrine  and  Norepinephrine  on  Fuel  Metabolism   Norepinephrine  à  aldehyde  product  
 [Lecture  PPT]  
•  Enzyme:  MAO  (monoamine  oxidase)    
•   Secretion  of  catecholamine  are  stimulated  by  a  variety  of  stress:   o   Present  in  the  outer  mitochondrial   Oxidative  
→  Fright,   hemorrhage,   pain,   cold,   exercise,   hypoglycemia,   and   1  
membrane  of  neural  and  other   Deamination  
hypoxia   tissues  (GIT  and  liver)  
•   Catecholamines  are  contrainsulin  and  catabolic  hormones   •  Release  of  NH4  
•   Metabolic   effects   of   catecholamines   are   directed   towards   the  
mobilization  of  fuel  from  their  storage  sites  for  oxidation  by  cells  
to  meet  increased  energy  requirement  when  acute  and  chronic   Aldehyde  product  à  dihydromandelic  
2   Oxidation  
stresses  are  present   acid  
•   Norepinephrine  
→  Affects   the   sympathetic   nervous   system;;   fight   or   flight   Dihydromandelic  acid    
reaction   ↓  
→  Increased  HR,  CO,  BP,  and  dilation  of  respiratory  passages   Vanillylmandelic  acid  (VMA)  
O-­
  3   •  Enzyme:  COMT  
methylation  
Table  7.  Effects  on  various  metabolic  organs     •  Cofactor:  SAM  à  SAH  
Organ   Effects   Results   S-­adenosyl  methionine  (SAM)    
S-­adenosyl  homocysteine  (SAH)  
Decreased  insulin  secretion   Prevent  fuel  storage  
 
Ensure  fuel  flux  and   Step   Description   Reaction  
Pancreas  
further  reinforce   Norepinephrine  à  Normetanephrine  
Increased  glucagon  secretion   O-­
catabolic  effects  of   1   •  Enzyme:  COMT  
epinephrine   Methylation  
 
•  Cofactor:  SAM  

−   Increased  glycogenolysis   ↑  blood  glucose   Normetanephrine  à  VMA   Oxidative  

−   Increased   2  
•  Enzyme:  MAO   Deamination  
gluconeogenesis  
Liver  
−   Increased  blood  glucose    
(in  patients  with  
 

Final  degradation  product  of  Epinephrine  and  Norepinephrine:  

pheochromocytoma)  
VANILLYLMANDELIC  ACID  or  VMA  
   

Increased  TAG  degradation   Glycerol  used  as    

(via  activation  of  sensitive   substrate  for  hepatic   DEGRADATION  OF  EPINEPHRINE  
Adipose   TAG  lipase)   gluconeogenesis  
tissues  
Increased  B-­oxidation  of  FAs   ↑  ATP  synthesis  
 

−   Increased  glycogenolysis   ↑  glucose  for  fuel  

(activation  of  adenylate  
cyclase)  
Muscles   −   Increased  proteolysis  
(Glucogenic  amino  acids  
used  as  substrates  for  
hepatic  gluconeogenesis)  
 
   
Figure  15.  Degradation  pathway  –  Norepinephrine  AND  Epinephrine  [Lecture  PPT]  
Biochemistry   Hormonal  Regulation  of  Metabolism  I   7  of  20  
 
 
  

•   Epinephrine  à  aldehyde  product  via  MAO   •   Diagnosis  

•   Aldehyde  product  is  oxidized  to  dihydromandelic  acid     →  measurement  of  plasma  metanephrine  
•   3,4-­dihydroxymandelic  acid  à  VMA  via  COMT   →  Urine  VMA  or  homovanlic  acid  
  •   Treatment    
•   Epinephrine  à  metanephrine  via  COMT   →  Adrenalectomy  
•   Metanephrine  à  VMA  acid  via  MAO   →  Preoperative   α   &   ß-­catecholamine   antagonists  
  (Phenoxybenzamine,   Propanolol)   to   prevent   hypertensive  
 
crises  –  blood  pressure  elevations  during  intubation  or  tumor  
If  via  MAO  –  mechanism  is  oxidative  deamination  
manipulation.      
If  via  COMT  –  mechanism  is  O-­methylation  
 
NTK:  
Measurement  of  VMA  in  the  urine  –  adrenal  medullary  function  
Metanephrine  –  most  sensitive  and  less  susceptible  to  a  false-­
positive  result  
 

 
DEGRADATION  OF  DOPAMINE  
 

 
Figure  17.  Pheochromocytoma  [Lecture  PPT]  
 
 

V.  CORTISOL  
 

•   Steroid  hormone  
→  Precursor:  Cholesterol  (C27)  
•   Cleavage   of   the   side   chain   of   cholesterol   in   the   following   parts  
produces  specific  products:  
→  Zona  Glomerulosa  –  Aldosterone  
→  Zona  Fasciculata  –  Cortisol  
→  Zona  Reticularis  –  Testosterone  
  →  Peripheral   aromatization   of   the   A   ring   produces   estradiol  
Figure  16.  Degradation  pathway  –  Dopamine    [Lecture  PPT]   (female  hormone)  
 
•   Dopamine  à  dihdroxymandelic  acid  via  MAO   Adrenal  Cortex   Produces   Hormone  
•   Dihydroxymandelic  acid  à  homovanillic  acid  via  COMT  
Mineralocorticoid  
  Zona  Glomerulosa   Aldosterone  
(C21)  
•   Dopamine  à  3-­methoxytyramine  via  COMT  
•   3-­methoxytyramine  à  homovanillic  acid  via  MAO   Corticosteroids  
  Zona  Fasciculata   Cortisol  
  (C21)  
Final  degradation  product  of  Dopamine:  HOMOVANILLIC  ACID  
 
Androgen  (C19)   Testosterone  
  Zona  Reticularis  
Estrogen  (C18)   Estradiol  
MONOAMINE  OXIDASE  INHIBITORS  
 
•   MAO  is  found  in  neural  and  other  tissues  (intestine  and  liver)   •   The  major  glucocorticoid  synthesized  by  the  adrenal  cortex  
•   Neuron:   MAO   Inhibitors   oxidatively   deaminates   and   →  Followed  by  cortisone  and  then  corticosterone  
inactivates   any   excess   neurotransmitter   molecules   •   Effect  is  basically  on  glucose  metabolism  
(norepinephrine,   dopamine,   or   serotonin)   that   may   leak   out   of  
synaptic  vesicles  when  the  neuron  is  at  rest  [Lippincott]  
→   MAO  inhibitors  may  irreversible  or  reversibly  inactivate  the  
enzyme,   permitting   neurotransmitter   molecules   to   escape  
degradation   à   both   accumulate   within   the   presynaptic  
neuron  and  to  leak  into  the  synaptic  space  
→   This   causes   activation   of   norepinephrine   and   serotonin  
receptors.  
→   It   may   be   responsible   for   antidepressant   action   of   these  
drugs  
 
E.  CLINICAL  CORRELATION  
 
PHEOCHROMOCYTOMA  
•   Tumor  of  adrenal  medulla;;  excess  catecholamine  secretion  
•   Sympathetic  signs  and  symptoms  
→  HPN,   plus   classic   triad   of   episodic   headache,   diaphoresis  
and  palpitations  
 
→  Others:  anxiety,  tremors,  wt.  loss   Figure  18.  Biosynthesis  of  Adrenal  Cortical  Hormones  [PPT]  

Biochemistry   Hormonal  Regulation  of  Metabolism  I   8  of  20  

 
 
  

A.  SYNTHESIS  
 

STEPS  IN  CORTISOL  SYNTHESIS  

Table  9.  Cortisol  Synthesis    
Step   Description   Reaction  
Transport  of  Free  cholesterol  
1   •   Transported  into  the  inner   RATE  
Inner   mitochondrial  membrane  by  the   LIMITING  
MM   carrier  protein,  Steroidogenic  Acute   STEP  
Regulatory  (StAR)  protein  

Cholesterol  (C27)    
↓  
Pregnenolone  (C21)  
 
•   Enzyme:  P450  SCC    
→   side  chain  cleavage  enzyme;;  
2   other  names:  20,22-­ Cleavage  
desmolase,  CYP11A  
•   Cofactors:    
 
→   NADPH  (from  PPP)   Figure  19.  Cortisol  Synthesis  [PPT]  
→   O2    
→   ACTH  (from  anterior  pituitary   •   ACTH  stimulates  synthesis  of  steroid  hormones  by  activating  
gland)     desmolase  à  increasing  availability  of  pregnenolone  
 
 

Pregnenolone  (returns  to  the  cytosol)     Cellular  Route  for  Cortisol  Synthesis  
 

↓   1.   Cholesterol   is   stored   in   the   adrenal   cortex   as   cholesterol  

Progesterone   ester  
  →   Cholesterol   are   synthesized   from   acetyl   coA   or   from  
•  Enzymes:     lysosomal  digestion  of  lipoproteins  
→   3-­β-­hydroxysteroid   Oxidation  and   2.   Cholesterol  esterase  acts  on  the  stored  cholesterol  converting  
3   dehydrogenase  (3-­  β  HSD)    
cytosol   Isomerization   it  to  free  cholesterol  and  fatty  acids  
–  converts  OH  group  of  C3  to  a   3.   Free   cholesterol   goes   to   the   inner   mitochondrial   membrane  
keto  group   via  the  StAR  protein  
→   Δ5,4  isomerase  –  transfer   →   Converted  into  pregnenolone  by  P450SCC  
double  bond  from  B  ring  (C5-­ 4.   Pregnenolone   goes   to   the   cytosol   and   is   oxidized   and  
C6)  to     isomerized  into  progesterone    
A  ring  (C4-­C5)   5.   Progesterone   is   then   hydroxylated   forming   17-­α-­
hydroxyprogesterone,   which   is   further   hydroxylated   to  
Progesterone     become  11-­Deoxycortisol  
↓   6.   11-­Deoxycortisol   goes   back   into   inner   mitochondrial  
17-­  α-­hydroxyprogesterone   membrane  where  it  is  converted  into  cortisol  
4     Hydroxylation  
•   Enzyme:  17-­α-­hydoxyprogesterone  
(CYP17)  
•   Addition  of  –OH  group  at  C17  

17-­  α-­hydroxyprogesterone  
↓  
11-­Deoxycortisol  
5   Hydroxylation  
 
•   Enzyme:  21-­α-­hydroxylase  (CYP21)  
•   Addition  of  –OH  group  at  CH2  of  C21  

11-­deoxycortisol    
(transported  back  in  the  inner  
mitochondrial  membrane)  
↓  
Cortisol  
6    
Inner   Hydroxylation    
MM   •   Enzyme:  11-­β-­hydroxylase  
Figure  20.  Cellular  Route  for  Cortisol  Synthesis  
(CYP11β1)    
catalyzes  β-­hydroxylation  at  C11    
•   Cofactor:    
→   NADPH    
 
→   O2    
 
•   Reactions  are  affected  by  hydroxylation    
 
•   Hydroxylases  are  NADPH-­dependent    

Biochemistry   Hormonal  Regulation  of  Metabolism  I   9  of  20  

 
 
  

B.  REGULATION   Mechanism  
 
  1.   Cortisol   is   transported   in   the   blood   bound   to   its   carrier  
protein   transcortin   from   adrenal   cortex,   the   site   of  
synthesis.   Enters   nucleus   and   binds   to   its   receptor   (Rec)   in  
the  nucleus    
→   Forms  a  cortisol  receptor  complex  (CRC)  
2.   The   CRC   will   try   to   stimulate   certain   segments   of   the   DNA  
called   cortisol   response   element   or   hormone-­response  
elements  (HREs)  
3.   Promotes   synthesis   of   protein   through   transcription   and  
translation.  
→   Receptor   attracts   coactivator   or   corepressor   proteins  
à  regulates  the  transcription  à  increase  rate  of  mRNA  
synthesis  à  synthesis  of  new  proteins  via  translation  
4.   Synthesized   proteins   are   responsible   for   the   effects   of  
cortisol  on  the  target  organs  
 

D.  METABOLIC  EFFECTS  

Figure  21.  Regulation  of  Cortisol  Synthesis  and  Secretion  

 
•   Regulation   via   the   Hypothalamic-­Pituitary-­Adrenocortical   Axis  
and  Negative  Feedback  Inhibition  
•   Diurnal   variation   of   cortisol   secretion   follows   the   marked  
pulsatile  release  of  ACTH  from  the  anterior  pituitary  gland  
→  Early  morning:  highest  
→  Night:  minimum  or  almost  undetectable  

•   Regulation  Process  
1.   Non-­specific  stressors  stimulate  the  hypothalamus  
2.   Increased   secretion   of   neurotransmitters,   serotonin   and  
acetylcholine  
3.   Stimulation   of   hypothalamus   to   synthesize   and   release    
Figure  23.  Metabolic  Effects  of  Glucocorticoids  
corticotropin  releasing  hormone  (CRH)    
4.   CRH   induces   synthesis   and   secretion   of   ACTH   from   the   •   Glucocorticoids  –  mainly  affects  glucose  homeostasis  
anterior  pituitary  
Adipose  Tissues  
5.   ACTH   would   stimulate   the   adrenal   cortex   (zona  
•   Stimulate  TAG  degradation  (lipolysis)    
fasciculata)  to  synthesize  and  secrete  cortisol  
6.   High   cortisol   levels   in   the   blood   inhibit   CRH   and   ACTH   →  FA  –  undergo  Beta  oxidation  à  Acetyl  CoA  à  ↑  energy  
release   à   inhibit   hypothalamus   and   anterior   pituitary   à   →  Glycerol  à  hepatic  gluconeogenesis  à  ↑  glucose  
less  CRH  and  ACTH  à  decrease  cortisol   •   Decrease  glucose  utilization  –  a  contradictory  effect  
 

Muscles  
 
 

C.  MECHANISM  OF  ACTION  

  •   Promotes  proteolysis    
→  amino  acids  used  as  substrates  for  hepatic  gluconeogenesis  
•   Decreases  protein  synthesis  
•   Decrease  utilization  of  glucose    
→  Paradoxical   effect   because   it   produces   a   lot   of   glucose   but  
does  not  use  it  

Liver  
•   Increases  glycogenesis  
→  Epinephrine  increases  glycogenolysis  
→  Results:  increase  glucose  available  to  combat  acute  stress  
•   Increases  gluconeogenesis  
→  Increases  RNA  and  protein  synthesis  
 
 

E.  CLINICAL  CORRELATION  
 

Congenital  Adrenal  Hyperplasia  (CAD)  

 
Figure  22.  Mechanism  of  Action  of  Cortisol   •   A   group   of   diseases   due   to   deficiencies   of   steroidogenic  
  enzymes   in   the   synthesis   of   sex   hormones,   cortisol,   and  
•   Cortisol  is  a  Type  I  hormone   mineralocorticoids  (aldosterone)  from  cholesterol  (steroidogenic  
→  Can   penetrate   the   cell   membrane   (lipophilic)   by   simple   pathway)  
diffusion  

Biochemistry   Hormonal  Regulation  of  Metabolism  I   10  of  20  

 
  

→  deficiency   in   the   hormones   cortisol   and   aldosterone   and   an   Cushing’s  Syndrome  

over-­production  of  the  hormone  androgen  [Health  of  Children.com]   •   Hypercorticolism,  primary  disorder,  hyperfunction  
→  Congenital   adrenal   hyperplasia,   also   known   as   androgenital   •   ACTH-­independent  
syndrome,  is  a  disorder  in  which  there  is  an  inherited  defect   •   Causes    
in  one  of  the  enzymes  needed  for  the  production  of  cortisol.   →  Adrenocortical  tumor  
Excessive  amounts  of  adrenal  androgens  must  be  produced   §   Ex.  Adenoma,  carcinoma,  nodular  adrenal  hyperplasia  
to  overcome  the  block  in  cortisol  production  [Brittanica.com]   §   Hyperactivity  of  the  adrenal  cortex  à  ↑  cortisol  
•   Insufficient  amount  or  defect  in  enzymes  lead  to:   →  Iatrogenic  
§   Hormone  synthesis  deficiency  beyond  the  affected  step   §   Prolonged   intake   of   glucocorticoids   (e.g.   Prednisone)   to  
§   Hormone  excess  or  metabolites  before  the  step   treat   inflammatory   illness   (e.g.   chronic   asthma)   and   for  
•   CAD  is  a  primary  disorder:  disorder  of  the  adrenal  cortex   immunosuppression  
→  Secondary  disorders  affect  hypothalamus  or  pituitary   •   Signs   and   symptoms   are   due   to   prolonged   exposure   to   high  
  levels  of  corticosol  (hypercorticolism)  
 
•   Manifestations:  
→  Body  Fat  
§   weight  gain,  central  obesity,    
§   “moon  face”  –  accumulation  of  fats   in  the  cheeks,  jaws,  
and  neck  
§   “buffalo   hump”   –   deposition   of   fats   at   the   center   of   the  
upper  back)  
→  Skin  
§   facial   plethora   (due   party   to   thinning   of   skin   and   cortisol  
induced,  ↑  in  bone  marrow  synthesis  of  RBC)  
§   thin  &  brittle  skin,    
§   easy  bruisability  due  to  catabolic  degradation  of  elastin  of  
the  skin  
−   ↑  fragility  of  capillary  walls  
  §   broad  and  purple  stretch  marks,  acne,  hirsutism    
Figure  24.  Disorders  in  Cortisol  Synthesis  
  →  Bone    
•   Congenital  deficiency  of  steroid  hydroxylase  leads  to:   §   osteopenia,   osteoporosis   (vertebral   fractures),   decreased  
§   Low  cortisol  à  no  feedback  inhibition  on  ACTH  à  adrenal   linear  growth  in  children  
hyperplasia   →  Muscle  
§   ↑  muscle  proteolysis  à  muscle  wasting  and  weakness  
Clinical  Manifestations  
§   proximal  myopathy  –  prominent  atrophy  of  gluteal  &  upper  
Deficiency   Clinical  Manifestation  
leg  muscles  w/  difficulty  climbing  stairs  or  getting  up  from  
→  Female-­like  genitalia  in  males   a  chair  
→  No  glucocorticoids,  mineralocorticoids,   →  CVS  
3-­βHSD     and  ↓  sex  hormones     §   Hypertension;;  decreased  K+,  edema,  atherosclerosis  
→  Salt  retention  in  urine  (excessive  excretion   →  Metabolism  
of  salt  in  urine  or  “salt-­wasting”)  
§   glucose  intolerance  /  diabetes,  dyslipidemia  
→  Female-­like  genitalia  in  males   →  Reproductive  System    
→  No  cortisol  and  ↓  sex  hormone     §   decreased   libido,   amenorrhea   (due   to   cortisol-­mediated  
17-­α-­
inhibition  of  gonadotropin  release)  
hydroxylase     →  Increased  mineralocorticoids  à  
increased  water  retention  and  Na+   →  CNS  
retention   §   irritability,  emotional  lability,  depression,  cognitive  defects,  
paranoid  psychosis  
→  Most  common  CAH  
→  Absent  cortisol  and  glucocorticoids   →  Blood  &  immune  system  
→  Absent  production  of  mineralocorticoids  à   §   increased   susceptibility   to   infections,   WBC,   eosinopenia,  
salt  wasting  and  hyponatremia  in  1st  few   hypercoagulation   w/   increased   risk   for   deep   vein  
days  of  life  glucocorticoids   thrombosis  &  pulmonary  embolism  
21-­α-­
hydroxylase    
→  17-­α-­hydroxyprogesterone  is  converted  to    
 
↑  androgens   Cushing’s  Disease  
o   masculinization  in  females   •   a  secondary  disorder  that  is  ACTH-­dependent  
o   early  virilization  in  males  (due  to   •   Causes    
high  levels  of  estradiol)  
→  Anterior  pituitary  tumor  
→  21-­α-­hydroxylase  measurement  is  part  of  
§   Ex.  Adenoma*,  carcinoma  
routine  newborn  screening   *Cushing’s  Disease  refers  specifically  to  Cushing’s  Syndrome  caused  
by  a  pituitary  corticotrope  adenoma  
→  Most  serious   §   Excess  ACTH  production  à  ↑  cortisol  
→  Low  cortisol,  aldosterone,  and   →  Ectopic  ACTH  Syndrome  
11-­β-­ corticosterone   §   production   by   other   carcinoid   malignant   tumors   (thymus,  
hydroxylase     →  Increased  deoxycorticosterone  à  HPN   thyroid,   bronchial,   pancreatic,   pheochromocytoma)   →  
→  Masculinization  in  females   excess  ACTH  →  ↑  cortisol  
→  Early  virilization  in  males   →  Hypothalamic  resistance  to  cortisol  
   

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•   Same  manifestation  as  Cushing’s  syndrome   •   Thyroid  gland  has  the  greatest  ability  to  trap  iodide  from  the  
•   Manifestations   due   to   Ectopic   ACTH   syndrome:   capillary  blood  
hyperpigmentation   of   the   knuckles,   scars,   or   skin   areas   →  Increase  iodide  concentration  in  the  follicular  cell  to  about  
exposed  to  ↑  friction  due  to  stimulatory  effects  of  x‘s  ACTH  on   20-­30x  that  present  in  the  blood  
melanocyte  pigment  synthesis                 →  About  80%  of  total  iodine  is  stored  here  
 
→  Soil  in  upper  regions  have  less  iodine  à  higher  incidence  
Addison’s  Disease  
of   hypothyroidism   in   mountainous   areas   à   GOITROUS  
•   Hypocorticolism;;  secondary  disorder  
BELTS  
•   Hypofunction  of  adrenal  cortex  
•   May   also   occur   in   the   salivary   glands,   gastric   mucosa,  
•   Caused  by:  
placenta   and   mammary   glands   but   NO   thyroid   hormone  
→  Primary  adrenal  insufficiency:  adrenal  cortex  disease  (TB,  
formation  because  they  cannot  oxidize  iodide  to  iodine  
autoimmune  disease,  hemorrhage,  etc)  
•   Inhibitors:  Perchlorate,  Thiocyanate  
→  Secondary   adrenal   insufficiency:   pituitary   adenoma,  
irradiation,   autoimmune   disease,   hemorrhage,   TB,   •   Congenital  defect  treatment:  large  doses  of  iodine  
actinomycosis    
§   Leads   to   decreased   ACTH   and   cortisol;;   normal   2.  Oxidation  
aldosterone   •   Passive  transport  of  iodide  across  the  luminal  surface  of  the  
follicular   cell   à   oxidized   into   iodine   via   heme-­containing  
•   Manifestations:  
luminal  thyroperoxidase  (TPO)    
→  Tiredness,  muscle  weakness,  diarrhea,  dehydration,    
→  Oxidizing  agent:  H2O2  by  NADPH  from  HMP  
→  postural   hypotension,   hyponatremia,   hyperkalemia,  
hyperpigmentation  (due  to  ↑  ACTH  and  its  MSH  activity)   •   Thyroid   gland   is   the   only   gland   that   can   perform   this  
oxidation  step  
→  loss   of   appetite,   nausea,   vomiting,   irritability,   depression,  
salty-­food  cravings,  hypoglycemia,  irregular  menses   •   Stimulated  by:  TSH  
•   Treatment:   administration   of   glucocorticoid   (plus   •   Inhibited   by   antithyroid   drugs:   Propylthiouracil   (PTU),  
mineralocorticoid)   Thiourea,  Methimazole  
  •   Congenital  defect  treatment:  T4  administration  
VI.  THYROID  HORMONES    
3.  Iodination  /  Organification  
•   Secretory  products  of  the  thyroid  gland:  
→  Tetraiodothyroxine  (T4,  Thyroxine)  
→  Triiodothyronine  (T3)  
 

A.  SYNTHESIS  
•   A   follicular   cell   faces   the   follicular   lumen   (top)   and   the  
extracellular  space  in  contact  with  the  blood  capillaries  (bottom)  
[Madarcos  Notes]  
•   Stimulated   by   thyroid   stimulating   hormone   (TSH)   secreted   by  
the  anterior  pituitary    
•   Steps  
1.   Concentration  or  Iodide  Trapping  
2.   Oxidation  
3.   Iodination  
4.   Coupling    
5.   Uptake   Figure  26.  Formation  of  MIT  and  DIT  [Lecture  PPT]  
 
6.   Deodination  
•   Iodine  is  incorporated  into  the  tyrosine  ring  of  thyroglobulin  
•   Thyroglobulin  
→  Produce  by  thyroid  follicular  cells    
→  5000  AA  and  10%  CHO  
→  Provides   polypeptide   backbone   for   thyroid   hormone  
synthesis  and  release  
→  Has   115   tyrosine   residues,   out   of   which   15   tyrosine  
residues  can  be  iodinated  
•   Formation  of  MIT  and  DIT  via  thyroperoxidase  
→  3-­monoiodotyrosine   (MIT)   from   iodine   incorporated   into  
a  tyrosine  residue  of  thyroglobulin  
→  3,5-­diiodotyrosine   (DIT)   from   2   molecules   of   iodine  
incorporated  into  a  tyrosine  residue  of  thyroglobulin  
 
 

MIT   =  1  Iodine  +  Tyr  residue  of  Tgb  

DIT   =  2  Iodine  +  Tyr  residueof  Tgb  
   
Figure  25.  Thyroid  hormone  synthesis  [Lecture  PPT]  
T3   =  MIT  +  DIT   (T3  is  biologically  active)  
1.  Concentration  or  Iodine  Trapping   T4   =  DIT  +  SIT  
•   Major  control  point  for  thyroid  hormone  synthesis    
•   In  the  presence  of  TSH,  iodide  (I-­)  enters  the  follicular  cell  via   4.  Coupling  
a   Na+-­I-­   symporter   (NIS)   against   a   strong   concentration   •   1  DIT  +  1  MIT  =  T3    
gradient,  using  the  Na+-­K+-­ATPase  pump  system   •   DIT  +  DIT  =  T4  
Biochemistry   Hormonal  Regulation  of  Metabolism  I   12  of  20  
 
  

•   Catalyzed   by   thyroperoxidase   (TPO),   requires   presence   of   C.  FEEDBACK  REGULATION  OF  THYROID  HORMONE  
H2O2   SECRETION  
•   Stored  and  released  only  when  thyroglobulin  is  taken  up  into  
the  follicular  cell  
 
•   Under  normal  conditions  (production)  
→  90%  -­  T4  
→  10%  -­  T3  
•   Inhibited  by:  Propylthiouracil  (PTU)  
•   Congenital  defect  treatment:  T4  administration  
 
5.  Uptake    
•   Under  the  influence  of  TSH  and  cAMP:  
→  Acinar  colloid  droplets  (T3  and  T4  within  the  thyroglobulin)  
are  internalized  into  the  follicle  cells  via  phagocytosis  and  
pinocytosis  when  there  is  demand  for  thyroid  hormones    
 
•   Fusion   of   colloid   droplets   with   lysosomes   à   Figure  28.  Regulation  of  Thyroid  Hormones  [Lecture  PPT]  
phagolysosomes  
→  Results   in   hydrolysis   of   Tgb   peptide   bonds   by   lysosomal   •   Thyrotropin   releasing   hormone   (TRH)   from   paraventricular  
acid  peptidases  or  proteases   nucleus   of   hypothalamus   stimulates   thyrotrophs   of   anterior  
→  Release  of  MIT,  DIT,  T3  (10%)  and  T4  (90%)   pituitary  to  release  TSH  
  •   TSH  stimulates  thyroid  glands  to  capture  iodine  from  the  blood  
6.  Deiodination   to  synthesize,  store  and  release  T4  
•   MIT   and   DIT   are   deiodinated   into   tyrosine   and   iodide   via   •   As  T4  reaches  its  target  cells,  it  is  deiodinated  to  T3    
thyroid  deiodinase    
•   Once  T4  and  T3  reach  adequate  blood  levels,  they  will  cause  a  
•   Iodide  and  tyrosine  are  reutilized  
negative   feedback   on   the   hypothalamus   and   anterior   pituitary  
→  Tyrosine:  for  incorporation  with  nascent  Tgb  molecules  
gland  to  reduce  TRH  and  TSH  output,  respectively  
→  Several  fold  more  iodide  is  reused  
•   Iodide  depresses  deiodination   →  Much  of  the  feedback  inhibition  by  T4  requires  its  conversion  
→  Reason  why  potassium  iodide  (KI)  is  used  as  an  adjuvant   intracellularly  to  T3  by  type  2  deiodinase  
in  the  treatment  of  hyperthyroidism   •   T3    
•   Congenital  deficiency  of  deiodinase  à  MIT  and  DIT  in  urine   →  Biologically  active  form  
  →  more  potent  feedback  inhibitor  
 

B.  METABOLISM  OF  THYROID  HORMONES   •   Pituitary  gland  –  more  sensitive  to  feedback  inhibition  
•   Ensures  uninterrupted  supply  of  biologically  active  free  T3  in  the  
blood  
Table  10.  Inhibitors  of  Thyroid  Hormone  Synthesis  (Antithyroid  drugs/Goitrogens)    
PATHWAY  INHIBITED   INHIBITORS  
Perchlorate  
1)   Iodide  
Pertechnetate  
trapping/Concentration  
Perrhenate  
2)   Competes  for  transport   Thiocyanate  
3)   Na+-­K+-­ATPase  pump   Oaubain  
PTU  
Methimazole  
4)   Iodination/Organification  
Goitrins  –  some  fruits  and  
vegetables  
 

Figure  27.  Metabolism  of  thyroid  hormones  [Lecture  PPT]   5)   Coupling   PTU,  Methimazole  
•   ~80%  of  T4  released  is  converted  to:   6)   Release   Lithium    
→  T3  (40%)  –  biologically  active  form      
§   From   type   1   and   2   deiodinases   in   peripheral   organs   •   Goitrogenic  foods  prevent  utilization  of  iodine  
(pituitary,  liver,  kidney,  spleen,  muscles)   •   Goitrin  inhibits  iodination  or  organification  
−   Catalyze   the   removal   of   iodine   from   the   outer   (5’)   •   Goitrogenic   foods   that   inhibit   thyroid   hormone   synthesis  
include  [Lecture  PPT]:  
tyrosine  ring  of  T4  
→  Strawberry,   turnip,   cabbage,   cauliflower,   lettuce,   radish,  
§   T4  is  considered  as  a  prohormone   spinach,   broccoli,   peas,   peanuts,   peaches,   rutabaga,   kale,  
§   T3  is  10x  more  potent  than  T4   kohlrabi,    
→  Reverse  T3  (rT3)  –  40%;;  no  significant  or  negligible  biological   →  Sweet  potato,  beans,  maize,  bamboo  shoots  
activity   →  Cassava   –   contains   thiocyanate   that   competes   with   iodide  
§   From   removal   of   iodine   of   the   inner   (5)   tyrosine   ring   by   for  transport  across  the  thyroid  follicle  cell  
Types  1  and  3  deiodinases   →  Avocado  and  coconut  –  stimulates  the  synthesis  of  thyroid  
hormone  synthesis  
•   Inhibited  by:  PTU  (Propylthiouracil)  
•   Sources   of   iodine   include:   seafood,   meat,   fruits,   iodized   salt  
•   Peripheral  conversion  of  T4  to  T3  and  rT3  –  Major  pathway  for  
[Dr.  Madarcos]  
deiodination  of  thyroid  hormones    
 
 

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D.  MECHANISM  OF  ACTION   E.  METABOLIC  EFFECTS  

 
 

Growth  and  Development  

•   Prenatally  
→  Not  required  for  growth  
→  Required  for  normal  skeletal  and  CNS  development  
 

•   Postnatally  
→  Required  for  normal  growth,  maturation,  development  
→  Acts  synergistically  with  GH  for  growth  of  long  bones  
→  Hypothyroidism  can  cause  irreversible  damage  if  
replacement  is  delayed  
 
Calorigenesis  
•   High  heat  production  à  high  O2  consumption/utilization  
→  Measured  as:  high  BMR,  high  CO,  high  HR,  high  RR  
•   Causes  
→  High  Na+-­K+  dependent  ATPase  à  high  ATP  utilization  
→  Avoidance  of  futile  cycles  
   
Figure  29.  Mode  of  action  of  thyroid  hormone  [Lecture  PPT]  
Proteins  
•   Thyroid  hormones:  Group  I  (lipophilic  hormones)  
•   In  general:  
→  Penetrate  the  lipid  cell  membranes   →  High  protein  and  enzyme  synthesis  
•   T3   enters   the   cell   membrane   and   binds   to   the   nuclear   →  Hyperthyroidism:  high  rate  of  proteolysis  à  negative  N  
triiodothyronine  receptor  in  thyroid-­sensitive  tissues     balance  
à  form  T3-­receptor  complex   •   Specific  proteins  
•   The   complex   stimulates   the   specific   regions   of   DNA   called   →    May  show  induction  curve  all  the  way  from  hypothyroid  to  
thyroid   hormone   response   element   (THRE)   and   regulate   hyperthyroid  range  
 
gene  transcription  
Carbohydrates  
→  (+)  synthesis  of  mRNA  à  protein  synthesis  via  translation   •   Glycogen  
→  new   proteins   accounts   for   the   various   effects   of   TH,   →  Increased  glycogenesis  and  glycogenolysis  in  
specifically  growth  and  development   hyperthyroidism    
  •   Glucose    
•   MCT8  protein     →  Increased  oxidation  and  gluconeogenesis  in  hyperthyroidism  
→  Thyroid  transporter      
Lipids  
→  Genetic   deficiency   of   this   protein   leads   to   severe  
•   Cholesterol,  Fatty  acids  
psychomotor  retardation  
→  Increased  synthesis  and  degradation  in  hyperthyroidism    
  •   TAGs  
•   Nuclear  receptors  that  mediate  changes  in  gene  expression  by   →  Increased  lipolysis  in  hyperthyroidism  
effects  of  thyroid  hormones:    
→  Thyroid  hormone  receptor  alpha  (THRα)   Others  
§   Predominate   isoform   in   bone,   GIT,   cardiac   and   skeletal   •   Increased  milk  production  during  lactation  
muscles   •   Increased  calcium  bone  mobilization  
§   More   common   defects:   produce   high   thyroid   hormone   •   Increased  HR  and  muscle  contractility  partly  due  to  increased  
susceptibility  to  effects  of  catecholamines  
levels  with  detectable  TSH  
•   Necessary  for  normal  menstrual  cycle,  fertility  
→  Thyroid  hormone  receptor  beta  (THRβ)    
§   Liver,  kidney,  parts  of  the  hypothalamus   F.  CLINICAL  CORRELATION  
§   Defects:   delayed   skeletal   maturation,   constipation,   mild    
Table  7.  Disorders  of  the  thyroid  function  
mental  retardation  
TYPE   THYROID  STATUS   LAB  
−   high  T3/T4  with  normal  TSH  
  Primary     Hypothyroidism   ↓  T3,  ↓  T4    &  ↑  TSH  
(thyroid  gland  
THR   Location   Effects  of  defects  
defects)   Hyperthyroidism   ↑  T3,  ↑  T4    &  ↓  TSH  
bone,  GIT,  cardiac   ↑  TH  
THRα   Secondary   Hypothyroidism   ↓  T3,  ↓  T4    &  ↓  TSH  
and  skeletal  muscles   with  detectable  TSH  
(hypothalamus/  
pituitary  defects)   Hyperthyroidism   ↑  T3,  ↑  T4    &  ↑  TSH    
delayed  skeletal  maturation,  
Liver,  kidney,  parts   constipation,  mild  mental    
THRβ   HYPOTHYROIDISM  
of  the  hypothalamus   retardation  associated  with    
↑  T3/T4  with  normal  TSH   •   Mild/Moderate  disease:  
  →  Lethargy,  fatigue,  hoarseness,  hearing  loss,  thick/dry/flaky  
  skin,  stiff  gait,  constipation,  cold  intolerance  
  •   Severe  disease:  Myxedema  coma  
 
→  Coma,  refractory  hypothermia,    
 
  →  ↓  HR,  ↑  RR,  pleural  effusion,  electrolyte  imbalance,  seizures    
   
 
 
Biochemistry   Hormonal  Regulation  of  Metabolism  I   14  of  20  
 
  

DISEASES  CAUSING  HYPOTHYROIDISM  (↓TH)   •   Manifestations  

→  Hypometabolic   state   –   fatigue,   muscle   weakness,   ↓   BMR,  
SECONDARY  
PRIMARY   cardiac  degeneration    
(Hypothalamus  /    
(Thyroid  defects)   →  Mental  retardation  
ant  pituitary  defects)  
→  Low  pitch,  hoarse  voice  
•   Hashimoto’s  Thyroiditis   •   Pituitary/hypothalamic   →  Skin  manifestations  
•   Thyroidectomy   tumors   §   Dry   skin   (xeroderma),   yellow   skin   (carotedemia),   non-­
•   Endemic  Goiter     •   Trauma,  surgery,     pitting   edema,   thickened   and   puffy   skin   around   the   lips,  
•   Irradiation,  infiltration   eyes  &  nose,  extremities,  etc.  
•   Viral  Thyroiditis  –  viral  
§   Due   to   accumulation   of   ↑   amounts   of   hyaluronic   acid   &  
infection  of  thyroid  gland         •   Sheehan’s  Syndrome   chondroitin  SO4  in  the  dermis  of  the  skin  secondary  to  TH  
•   Congenital  Hypothyroidism   •   Isolated  TSH  Deficiency     stimulation  of  dermal  fibroblasts.        
•   Radioactive  Therapy    
•   Inadequate  Replacement   HYPERTHYROIDISM  
•   Drugs  –  lithium,  antithyroid    
drugs,  para-­amino     DISEASES  CAUSING  HYPERTHYROIDISM  (↑TH)  
  PRIMARY   SECONDARY  
Hashimoto’s  Thyroiditis  
•   Presence  of  autoimmune  antibodies  directed  against  Tgb  and   •   Grave’s  Disease   •   TSH-­secreting  pituitary  
TPO  or  both   •   Toxic  multinodular  goiter   adenoma  
•   Destruction  of  thyroid  gland   •   Excessive  iodide  intake     •   Thyroid  hormone  resistance  
•   Goiter  formation  in  an  attempt  to  compensate   •   Excessive  intake  of  thyroid   syndrome  
•   Lab:   hormones   •   Gestational  thyrotoxicosis  
→  ↓  T3  &  ↓  T4   •   Functioning  metastatic   •   Chorionic  gonadotropin  
→  ↑  TSH  due  to  lack  of  feedback  effect   thyroid  CA   secreting  tumors    
  •   TSH  receptor  mutation    
Congenital  hypothyroidism:  Cretinism    
•   Congenital  absence  of  thyroid  hormones  in  infants  and  children   •   Clinical  manifestations  
which  can  be  detected  by  newborn  screening     →  Hypermetabolic  States  
•   Causes   §   Tremors,   excessive   sweating,   fast   reflexes,   nervousness,  
→  Absence  or  only  a  rudimentary  thyroid  gland   agitation  
→  Iodine  def  →  no  thyroxine  synthesis   §   ↑  HR,  ↑  RR,  ↑  appetite,  ↑  bowel  movement    (diarrhea)    
→  TSH  receptor  mutation   →  Smooth,  velvety  skin;;  fine  hairs  
→  Maternal  hypothyroidism   →  Mood  swings  –  depression,  panic  attacks,  insomnia,  anxiety  
•   PE     →  Muscle  and  joint  pains  
→  Flat   nose   and   face,   macroglossia,   jaundice,   yellow   /   dry   /   →  Enlarged  thyroid  gland  with  characteristic  stare  
coarse  skin,  choking  episodes  during  feeding,  dry/brittle  hair,   →  Weight  loss,  fatigue,  ↓concentration,  heat  sensitivity  
constipation,   stunted   growth,   umbilical   hernia   secondary   to    
muscle   weakness,   jaundice,   floppiness,   sluggishness,   Grave’s  Disease  
sleepiness     •   Most   common   cause   of   hyperthyroidism   between   ages   25-­50  
years,  female  preponderance  
•   An   autoimmune   antibody   called   Long   Acting   Thyroid  
Stimulator   (LATS)   or   Thyroid   Stimulating   Immunoglobulin  
(TSIg)   binds   to   TSH   receptor   or   Tgb   or   both   →   ↑synthesis   of  
thyroid  hormones  without  feedback  control.    
•   Manifestations:  Goiter,  hyper-­thyroidism,  exophthalmopathy  
•   Lab:  ↑  T3,  ↑  T4,  ↑  TSH;;  TSH  receptor  antibodies  

   
Figure  30.  Children  with  cretinism  [Lecture  PPT]  
•   If  untreated  in  children,  may  cause:  
→  Severe  physical  and  mental  retardation  
→  Stunting  of  growth  or  severe  dwarfism  or  cretinism  –  physical  
stature  of  a  child  when  in  fact  he  is  much  older.      
Figure  31.  Eye  finding  common  in  patients  with  Grave’s  Disease  
   
Endemic  Goiter   •   Associated  eye  findings:  
•   Thyroid  hypertrophy  secondary  to  insufficient  dietary  iodine   →  Periorbital  edema  –  20  to  accumulation  of  
•   Lab:   mucopolysaccharides  and  associated  H2O  
→  ↓  T3  and  T4  
→  Chemosis  –  swelling  and  redness  of  conjunctiva  
→  ↑  TSH  due  to  lack  of  feedback  effect  
  →  Lid  retraction  and  lid  lag  
Myxedema  (adults)   →  Proptosis  or  exophthalmos  –  2o  to  infiltration  of  retroorbital  
•   Most  frequent  causes:   tissues  by  lymphocytes,  macrophages  and  plasma  cells  
→  Atrophy  of  the  gland   together  with  H2O  accumulation  →  staring  or  frightened  look  
→  Surgical  removal   →  Diplopia,  blurring  of  vision,  extra-­ocular  muscle  involvement    
→  Irradiation   →  Dryness  of  the  cornea,  loss  of  vision          
   
 
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Toxic  Multinodular  Goiter   A.  SET-­POINT  MODEL  FOR  MAINTAINING  CONSTANT  MASS  

 

•   Enlarged   thyroid   gland   containing   small   irregular   rounded   •   Our  body  employs  3  mechanisms  to  prevent  storage  of  excess  
masses   called   nodules   →   become   “autonomous”   →   do   not   dietary  calories:  
respond   to   pituitary   regulation   via   TSH   secondary   to   mutations   →  Conversion  of  excess  fat;;  stored  as  TAG  in  the  adipocytes  
in   the   TSH   receptor   →   ↑   independent   synthesis   of   thyroid  
→  Oxidation  of  excess  fuel  by  exercise  
hormones  →  hyperthyroidism  
→  Diversion  or  wasting  of  fuel  to  heat  production  by  uncoupled  
•   Arise  from  long  standing  simple  goiter,  most  often  in  elderlies   mitochondria  
•   Manifestation:   hyperthyroid   state,   less   exophthalmos   seen   in   •   In   mammals,   hormonal   and   neuronal   signals   keep   fuel   intake  
Grave’s  Disease   and  energy  expenditure  balanced  in  order  to  hold  the  amount  of  
•   Lab   adipose  tissue  at  a  suitable  level  
→  ↑  T3  &  T4   →  Excess  fuel  intake,  more  adipose  tissues  à  obesity  
→  ↓  TSH  due  to  feedback  inhibition   →  Excess  energy  expenditure  à  malnutrition  
  •   In   the   presence   of   excess   adipose   tissue,   leptin   is   released   to  
Excessive  Iodide  Intake   inhibit  food  intake  and  fat  synthesis;;  FA  oxidation  is  stimulated  
•   May  cause  hyperthyroidism  as  the  thyroid  gland  uses  iodine  to   •   Decrease   in   adipose   tissue   mass   =   lowered   leptin   production  
produce  thyroid  hormones   favors  food  intake  and  less  FA  oxidation  
•   Amiodarone   (Cordarone)   –   Used   in   the   treatment   of   heart   →  ↑  adipose  tissue  mass,  ↑  amount  of  leptin  released  
problems,   contain   a   large   amount   of   iodine   and   may   be  
→  ↓  adipose  tissue  mass,  ↓  amount  of  leptin  released  
associated  with  thyroid  function  abnormalities  
•   Other   tissues   that   produce     lesser   amounts   of   leptin:   placenta,  
 
ovaries,   skeletal   muscles,   mammary   glands,   bone   marrow   and  
Excessive  Intake  of  Thyroid  Hormones  
gastric  chief  cells  
•   Frequently   go   undetected   due   to   the   lack   of   follow-­up   of    
patients  taking  thyroid  medicine  
•   Other   persons   may   be   abusing   the   drug   in   an   attempt   to  
achieve  other  goals  such  as  weight  loss  
•   Identified  by  having  a  low  uptake  of  radioactively-­labelled  iodine  
(radioiodine)  on  a  thyroid  scan  
 
Abnormal  Secretion  of  TSH  
•   Pituitary   may   produce   an   abnormally   high   TSH   →   excessive  
signaling  to  the  thyroid  gland  →↑  thyroid  hormone  synthesis  →  
hyperthyroidism  
•   Rare;;  can  be  associated  with  other  abnormalities  of  the  pituitary  
gland  
•   Diagnosed  by  tests  that  assess  TSH  release  
 
VII.  ADIPOSE  TISSUE  AS  AN  ENDOCRINE  ORGAN  
 
Figure  33.  Set-­point  model  for  maintaining  constant  mass  [Lecture  PPT]  
 
ADIPOSITY  NEGATIVE  FEEDBACK  
•   Eating  behavior  is  inhibited  and  energy  expenditure  is  increased  
whenever  the  body  weight  exceeds  a  certain  value  (set  point)  
•   Inhibition   is   relieved   when   body   weight   drops   below   the   set  
point  
 
B.  LEPTIN  AND  THE  HYPOTHALAMUS  

Hypothalamus,

 
 
Figure  32.  Adipose  tissue  as  an  endocrine  organ  [Lecture  PPT]  
 
See,p.,
•   The   adipose   tissue   is   one   of   the   organs   involved   in   the   (167,AAs), 767,
maintenance  of  fuel  or  energy  homeostasis   Mathews

•   Adipose   tissue   stores   TAG   when   glucose   is   excessive   with  

intermediate  insulin  
•   When  blood  glucose  levels  are  low,  glucagon  degrades  TAG  à  
glycerol  and  fatty  acids  in  order  to  restore  blood  glucose    
•   Plays  a  critical  role  in  body-­mass  homeostasis      
↑,TAG
 
→  Releases   regulatory   peptide   molecules   called   adipose    Figure  34.  Leptin  regulation  [Lecture  PPT]  
tissue-­derived  hormones  
§   Leptin,  adiponectin,     •   Leptin  is  a  peptide  hormone  of  167  amino  acids,  belong  to  the  
§   Resistin,  TNF-­α,  IL6  =  ↓  insulin  action  on  muscle  and  liver   family  of  adipokines  
  •   Leptin  sends  signals  to  the  brain  
  →  With  enough  energy  reserves  and  increase  in  body  weight  
  §   Increased  appetite  
  →  With  low  energy  reserves  and  decrease  in  body  weight  
  §   Decreased  appetite  
Biochemistry   Hormonal  Regulation  of  Metabolism  I   16  of  20  
 
  

C.  HYPOTHALAMIC  REGULATION  OF  FOOD  INTAKE  AND   −   During  severe  nutritional  deprivation:  
ENERGY  EXPENDITURE   o   Inhibit  thyroid  hormone  synthesis  
 

•   When   there   are   enough   fat   reserves   in   the   adipocytes,   leptin   o   Decrease  sex  hormone  production  
binds   to   its   receptor   in   the   neurons   of   the   arßcuate   nucleus   of   o   Increase  glucocorticoid  synthesis  
the   hypothalamus   àreduction   of   fuel   intake   and   increased   −   Makes   cells   of   liver   and   muscle   more   sensitive   to  
energy  expenditure   insulin  
•   Leptin  stimulates  the  sympathetic  nervous  system  à  increased   −   Leptin   resistance   –   may   develop   in   people   whose  
NE  release   leptin   receptors   become   overstimulated,   making   them  
•   Norepinephrine   binds   to   its   beta-­adrenergic   receptor   in   the   inactivated  à  obesity  [Dr.  Madarcos]  
adipose   tissue   membrane   à   stimulation   of   Gs   à   activation   of    
adenylate   cyclase   à   cAMP   synthesis   à   stimulation   of   PKA,   →  Orexigenic  (appetite-­stimulating)  neurons  
which  results  to:   §   When   leptin   and   insulin   is   bound   to   orexigenic   neuron  à  
→  Increased  expression  of  uncoupling  protein  I  or  thermogenin   inhibits  the  release  of  Neuropeptide  Y    
in  the  nucleus     −   Neurotransmitter  in  the  hypothalamus  and  sympathetic  
↓   nervous  system  
Uncouples   oxidative   phosphorylation   WITH   ATP   −   Hunger  promoter  
SYNTHESIS  in  the  mitochondria   §   Sends  signal  to  the  brain  to  eat  more  and  metabolize  less  
↓   fuel  à  increase  appetite  
Continuous  oxidation  of  fuel  WITHOUT  ATP  SYNTHESIS    
↓   •   Any   stimulus   that   activates   orexigenic   cells   inactivate  
dissipating  energy  as  heat  and  consuming  dietary  calories  or   anorexigenic   cells   à   strengthening   the   input   of   stimulatory  
stored  fats  in  potentially  very  large  amounts   signals  
 
→  Activation  of  HSL  à  degradation  of  TAGs  in  the  lipid  droplets  
àFAs  and  glycerol  à  B-­oxidation  of  FAs  to  produce  energy   •   Ghrelin  
à  thermogenesis   →  Hormone  from  the  stomach,  hypothalamus  
  →  Stimulates  orexigenic  neurons  à  increase  release  of  NPY  à  
 
↑  appetite    
VIII.  HORMONES  THAT  CONTROL  APPETITE  
→  Hunger  hormone  
 
→  Originally  recognized  as  stimulus  for  growth  hormone  
→  Major  stimulus  for  release:  hunger  /  fasting/  hypoglycemia  
§   Concentration  peaks  before  eating  and  decreases  sharply  
after  a  meal  à  shorter  scale  
→  Inhibited  by  food  intake,  hyperglycemia,  obesity  
→  Injection  in  humans  à  immediate  sensation  of  hunger    
§   Might   lead   to   extreme   obesity,   especially   to   those   with  
Prader-­Willi   Syndrome   whose   ghrelin   levels   are  
exceptionally   high   à   uncontrollable   appetite   à   early  
death  
→  Inhibits   insulin   release   and   expression   of   proinflammatory  
cytokines  
→  Controls  gastric  motility  
→  Influences  sleep  patterns  
→  Memory,  anxiety-­like  behavioral  responses  
 
•   PYY3-­36  /  Peptide  tyrosine  tyrosine  
 
Figure  35.  Hormones  that  Control  Appetite  [Lecture  PPT]   →  Pancreatic  peptide  
  →  From  colon  
•   Interlocking   system   of   neuroendocrine   controls   of   food   intake   →  Response  to  food  coming  from  the  stomach  
and  metabolism     →  Inhibit   orexigenic   neurons   à   inhibit   NPY   release   à   slower  
→  protect  us  from  starvation   suppression  of  hunger  between  meals  à  ↓  appetite  
→  eliminate  counterproductive  accumulation  of  fat  or  obesity    
•   There   are   two   types   of   neurosecretory   cells   in   the   arcuate   A.  JAK-­STAT  MECHANISM  OF  LEPTIN  SIGNAL  
nucleus  of  the  hypothalamus     TRANSDUCTION  IN  THE  HYPOTHALAMUS  
 
→  Receive   hormonal   inputs   and   relay   neuronal   signals   of   the  
cells  of  muscles,  adipose  tissues,  and  pancreas,  respectively  
•   ↑  body  fat  mass  à  release  of  leptin  from  adipose  and  insulin  
from  pancreas  
•   Leptin  and  insulin  act  on:  
→  Anorexigenic  (appetite-­suppressing)  neurons  
§   Medial  hypothalamus  
§   Trigger   the   release   of   alpha-­melanocyte   stimulating  
hormone   aka   melanocortin   (hunger-­suppressant  
hormone)   à   neuron   sends   signal   to   eat   less   and  
metabolize  more  fuel  à  inhibits  hunger  
§   Leptin    
−   satiety  hormone  
−   enhances  insulin  sensitivity  
−   plays   a   permissive   role   in   the   resurgence   of  
gonadotropin   releasing   hormone   secretion   at   onset   of  
puberty    
o   Leptin-­deficient  people  fail  to  enter  puberty    
Figure  36.  JAK-­STAT  mechanism  

Biochemistry   Hormonal  Regulation  of  Metabolism  I   17  of  20  

 
  

  B.  POSSIBLE  MECHANISM  FOR  CROSS-­TALK  BETWEEN  

1.   Leptin   receptor   dimerizes   when   leptin   binds   to   the   RECEPTORS  FOR  INSULIN  AND  LEPTIN  
extracellular  domains  of  the  two  monomers  
2.   Phosphorylation   of   specific   Tyr   residues   of   their   intracellular  
domains  by  a  soluble  Janus  Kinase  (JAK),  a  tyrosine  kinase  
3.   Phosphorylated  Tyr  (P-­Tyr)  residues  become  docking  sites  for  
three   proteins   that   are   Signal   Transducers   and   Activators  
of  Transcription  (STATs  3,  5,  6;;  aka  fat-­STATs)  
4.   P-­Tyr   residues   of   leptin   receptor   bind   to   the   SH   (Src  
homology)   2   domain   of   STAT   à   phosphorylation   of   their   Tyr  
residues  catalyzed  by  a  separate  activity  of  JAK  
5.   Phosphorylated   STAT   dimerize   and   moves   to   the   nucleus   à  
bind   specific   DNA   sequences   à   stimulate   expression   of  
target   genes,   including   gene   for   POMC  
(proopiomelanocortin),  the  precursor  of  alpha-­MSH  
6.   Leptin  stimulates  the  release  of  norepinephrine  in  the  adipose  
tissues  
→   Norepinephrine,   through   Beta2-­adrenergic   receptor    
Figure  37.  Possible  mechanism  for  cross-­talk  [Lecture  PPT]  
(adipose   tissue),   stimulates   the   transcription   of    

mitochondrial  UCP  (uncoupling  protein  I  or  thermogenin)   •   Leptin   receptor   bound   to   leptin   à   phosphorylation   of   several  
gene  via  cAMP  and  PKA   Tyr  residues  in  their  intracellular  domains,  catalyzed  by  JAK  
•   Phosphorylated   intracellular   domains   of   insulin   and   leptin  
→   Thermogenin   uncouples   oxidative   phosphorylation   with  
receptors   phosphorylate   and   activate   insulin   receptor  
ATP   synthesis   à   continuous   oxidation   of   fuels,   release   substrate-­2  (IRS-­2)  
of  heat   →  Acts  as  integrator  of  the  input  from  two  receptors  
→   Leptin   promotes   consumption   and   catabolism   of   fats   via   •   Phosphorylated   IRS-­2   activates   PI-­3K   (phosphoinositide-­3-­
AMP-­activated   protein   kinase   (AMPK)   and   kinase)  à  inhibit  food  intake  
thermogenesis   →  Adiponectin   is   another   adipose   tissue   hormone   that  
  sensitizes  other  organs  to  the  effects  of  insulin  
 
Other  functions  /  properties  of  Leptin  
C.  FORMATION  OF  ADIPONECTIN  AND  ITS  ACTIONS  
•   During  periods  of  severe  nutritional  deprivation,  leptin:   THROUGH  AMPK  
→   Inhibits  TH  synthesis  à  slowing  basal  metabolism  
→   Decrease   sex   hormone   production   à   preventing  
reproduction  
→   Increases   glucocorticoid   synthesis   à   mobilize   body’s  
fuel-­generating   sources   à   minimizing   energy  
expenditure  and  maximizing  use  of  endogenous  reserves  
of  energy  à  greater  survival  
•   Leptin  makes  cells  of  liver  and  muscle  more  sensitive  to  insulin  
•   Giving  leptin  to  leptin-­deficient  patient  will  result  to  weight  loss  
→   However,   obese   patients   have   opposite   effects   due   to  
development  of  leptin  resistance  
 
Causes  of  Leptin  Resistance  
•   Constant   stimulation   of   leptin   receptors   in   obese   individuals   à    
receptor  desensitization    
Figure  38.  Formation  of  adiponectin  and  its  actions  [Lecture  PPT]  
•   Leptin   induces   the   synthesis   factors   that   block   leptin-­induced   •   Adiponectin  
signal  transduction   →  Peptide  hormone  (224  AA)  
→   Suppressor   of   cytokine   signaling-­3   (SOCS3)   →  Exclusively  synthesized  and  the  most  abundant  hormone  
synthesized  by  leptin  antagonizes  STAT  activation   from  the  adipocyte  
→   Long  term  leptin  stimulation  lead  to  constant  expression   →  Adipokine  that  sensitizes  other  organs  (i.e.  muscle,  liver)  to  
of  SOCS3  à  diminished  cellular  response  to  leptin   the  effect  of  insulin  
•   Extended  fasting  /  prolong  starvation  à  ↓  TAG  reserves  in  
•   In   the   presence   of   leptin   resistance,   obesity   develops   since  
adipose  à  triggers  adiponectin  production  and  release  
anorexigenic  signal  is  lost   →  Adiponectin  secretion  is  increased  as  the  adipocyte  gets  
→   Hyperleptinemia  ensues  à  obesity  develops  along  with   smaller    
insulin   resistance,   hyperlipidemia,   and   a   plethora   of    
 

cardiovascular   disorder   à   development   of   metabolic   RELATIONSHIPS  

syndrome   Inverse  =  adipose  tissue  mass  :  adiponectin  
Direct   =  adipose  tissue  mass  :  leptin  
 
   
  •   Acts  through  plasma  membrane  receptors  (AdipoR1,  AdipoR2)  
  →  Phosphorylates  and  activates  AMPK  
 
§   AMPK  can  also  be  activated  by  exercise  and  low  [AMP]  
 
  →  Activation  of  nuclear  transcription  factor  Peroxisome  
  Proliferator  Activated  Receptor-­α  (PPAR-­α)  à  increasing  
  insulin  sensitivity  
Biochemistry   Hormonal  Regulation  of  Metabolism  I   18  of  20  
 
  

→  Effect:     REVIEW  QUESTIONS  

§   increased  insulin  sensitivity   1.   T/F:  The  third  signaling  pathway  inhibits  neurotransmitter  
§   stimulates  FA  uptake  and  oxidation   and  hormone  secretion  
§   inhibits  FA  synthesis   2.   Which  of  the  following  statements  is  true:    
  a.   Increased  IGF-­1  causes  a  decrease  in  GHIH  secretion  
Activation  (+)   b.   GH  increases  amount  of  glycerol  reaching  the  liver  
c.   GH  increases  glucose  uptake  
PFK2   ↑  cardiac  glycolysis   d.   GHRH  suppresses  GH  secretion  from  the  anterior  pituitary  
gland  
GLUT  1,  4   ↑  glucose  transport  
3.   Primary  hypothyroidism  manifests  as:  
a.   ↑  T3,  ↑  T4    &  ↓  TSH  
Brain   ↑  food  intake  but  ↓  energy  expenditure   b.   ↓  T3,  ↓  T4    &  ↓  TSH  
c.   ↑  T3,  ↑  T4    &  ↑  TSH  
o   ↑  beta-­oxidation  of  FA       d.   ↓  T3,  ↓  T4    &  ↑  TSH  
Skeletal   o   ↑  glucose  uptake   4.   In  which  pathway  does  the  activation  of  Gq  protein  complex  
muscles   o   ↑  glycolysis   occur?  
o   ↓  FFA  and  blood  glucose   a.   α  adrenergic  pathway  
o   ↑  beta-­oxidation  of  FAs   b.   β  adrenergic  pathway    
Cardiac   o   ↑  glucose  uptake   5.   What  is  the  rate  limiting  step  in  cortisol  synthesis?  
muscles   o   ↑  glycolysis   a.   Hydroxylation  of  progesterone  
o   ↓  FFA,  blood  glucose   b.   Cleavage  of  cholesterol  
c.   Transport  of  free  cholesterol  
Liver   ↑  beta  oxidation  of  FAs   d.   Transport  and  hydroxylation  of  11-­deoxycortisol  
   
 

Inhibiton  (  -­  )   Answers:  False,  B,  D,  A,  C  

 

REFERENCES  
FAS  1  and   Dr.  Madarcos’  Notes  on  Hormones  that  regulate  fuel  metabolism  
↓  FA  synthesis  but  ↑  FA  oxidation   •  
ACC   •   Lecture  PPT  
•   Mark's  Basic  Medical  Biochemistry  (4th  edition)  
HSL   ↓  lipolysis   •   Lippincott  
•   2021  5.02  Hormonal  Regulation  of  Metabolism  I  Trans  
•   http://www.healthofchildren.com/C/Congenital-­Adrenal-­Hyperplasia.html  
HMGR   ↓  cholesterol  synthesis   •   https://www.britannica.com/science/adrenal-­gland#ref105570  
 
GPAT   ↓  TAG  synthesis   APPENDIX  
 

Glycogen  
↓  glycogenesis  
synthase  
regulates  protein  synthesis  based  on  nutrient  
eF2
availability  
mTOR
↓  protein  synthesis  
Pancreatic  
↓  insulin  secretion  à  inhibit  gluconeogenesis  
beta  cell  

↓  FA  and  cholesterol  synthesis  

Liver  
Anti-­atherogenesis  effect  of  adiponectin  

Adipose  
↓  FA  synthesis  and  lipolysis  
tissue  

FAS  1  -­  Fatty  acid  synthase  I    

ACC  -­  Acetyl-­CoA  carboxylase  
HSL  -­  Hormone-­sensitive  lipase    
HMGR  -­  HMG-­CoA  reductase   Figure  1.  Amino-­acid  derived  hormones  [Lecture  PPT]  
 
GPAT  -­  Acyl  transferase    
eF2  -­  Eukaryotic  elongation  factor  2      
mTOR  -­Mammalian  target  of  rapamycin      
 
   
•   Adiponectin,  acting  via  AMPK  which  in  turn  activates  PPARα  à    
stimulates  FA  uptake  and  oxidation      
→  Inhibits  FA  synthesis      
 
→  Sensitizing  muscle  and  liver  to  insulin    
•   Plasma  level  of  adiponectin  parallels  with  HDL  level    
→  Low  in  people  with  metabolic  syndrome  and  diabetes  mellitus    
   
 
   
   
   
   
   
   
 
Biochemistry   Hormonal  Regulation  of  Metabolism  I   19  of  20  
 
  

APPENDIX  
 
CLASSIFICATION  OF  HORMONES     CHEMICAL  CLASSIFICATION  OF  HORMONES  
CRITERIA   CLASSIFICATION     STRUCTURE   EXAMPLES  
 
Amino  acids  –  derived  from  tyrosine   Thyroids:  T3,  T4  (Tyrosine)  
Chemical   Amino  acid  
Polypeptides  –  amino  acids  in  peptide  linkages   Adrenal  Medulla:  Epinephrine,  Norepinephrine  
composition   derivatives  
Steroids  –  derived  from  precursor  cholesterol   (Tyrosine)  

Class  I:  Lipophilic  (Hydrophobic)       Hypothalamus:  Somatostatin,  ADH  

•   Can  penetrate  the  lipid  bilayered  cell   Pituitary:  TSH,  FSH,  LH,  GH,  ACTH  
Solubility   membrane     Thyroid:  Calcitonin  
properties   •   Steroids,  vitamin  D,  thyroids,  retinoids   Heart:  Atrial  Natriuretic  Factor  
Class  II:  Hydrophilic  (Lipophobic)   Polypeptides   Pancreas:  Insulin  and  Glucagon  
•   Cannot  penetrate  the  cell  membrane   Gonads:  Inhibin    
Placenta:  Choriogonadotropin,  Placental  
Class  I:  Intracellular  (in  cytoplasm  or  nucleus)     Lactogen,  Relaxin  
Location  of  
receptor   Class  II:  Extracellular  (membrane-­bound)   Liver:  Angiotensin  
  Adrenal  cortex:  Glucocorticoids,  
Class  I:  Hormone  receptor  complex  
Nature  of   Mineralocorticoids  
Class  II:  
intracellular   Gonads:  Estrogen,  Estradiol,  Estrone,  Progestin,  
•   1st  messenger  –  hormone     Steroids  
messenger   Androgens  
or  signal   •   2nd  messengers  –  cAMP,  cGMP,  PIP3  
Placenta:  Estrogen,  Progestin  
or  Ca,  kinase  phosphatase  cascade  
Kidneys/Liver:  Calcitriol  
 
 
 
SUMMARY  OF  CLASSES  OF  HORMONES  
 
HORMONES   TYPE   SYNTHETIC  PATHWAY   MODE  OF  ACTION  

Proteolytic  processing  of  proinsulin  

Insulin   Plasma  membrane  receptor;;  
Polypeptide   ↓  
ß-­cell,  pancreas   tyrosine  kinase  as  2nd  messenger    
mature  insulin  (51  AAs)  

Proteolytic  processing  of  proglucagon  

Glucagon   Plasma  membrane  receptor;;    
Polypeptide   ↓  
α-­cell,  pancreas   cAMP  as  2nd  messenger  
mature  glucagon  (29  AAs)  

Somatostatin    
Proteolytic  cleavage  of  preprosomatos-­tatin  
Stomach;;  δ  cell,    pancreas;;   Plasma  membrane  receptor;;    
Polypeptide   ↓  
intestines;;  hypothalamus;;  other  CNS   cAMP  as  2nd  messenger  
mature  somatostatin  (14  AAs)  
areas  

Growth  Hormone  
Proteolytic  processing  of  precursor     Plasma  membrane  receptor;;  
[GH,  HGH,  Somatotropin]  
Polypeptide   ↓   tyrosine  kinase  /  phosphatase  as  
somatotrophs  (acidophils)  of  ant.  pit.  
mature  GH  (191  AAs)       2nd  messenger    
gland  

Thyroid  Hormones  (T3  &  T4)   Amino  acid-­   Nuclear  receptor;;  transcriptional  
Tyrosine  as  precursor  
Thyroid  gland   derived   regulation        

Catecholamines    
Amino  acid-­   Plasma  membrane  receptor;;    
[Epi-­  &  Norepinephrine]     Tyrosine  as  precursor  
derived   cAMP  as  2nd  messenger  
adrenal  medulla  

Cortisol     Nuclear  receptor;;  transcriptional  

Steroid   From  cholesterol  
zona  fasciculata,  adrenal  cortex   regulation        

Biochemistry   Hormonal  Regulation  of  Metabolism  I   20  of  20