endocrine glands and the general principles of - dallas, · pdf fileendocrine glands and the...
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Endocrine Glands and the General Principles of Hormone Action
Cai Li, Ph.D.Assistant professorTouchstone Center for Diabetes Research Departments of Physiology and Internal MedicineThe University of Texas Southwestern Medical CenterDallas, TX 75390-8854
April 6, 2002
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“Classical” Endocrine Glands
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A more complete listing of the endocrine glands
Endocrine gland Major hormones Primary target organsAdipose tissue Leptin hypothalamusAdrenal cortex Glucocorticoids liver, muscle
Aldosterone kidneysAdrenal medulla Epinephrine heart, blood vesselsHeart Atrial natriuretic hormones kidneysHypothalamus Releasing and inhibiting hormones pituitarySmall intestine Secretin, cholecystokinin stomach, liver, pancreasIslets of Langerhans Insulin fat, muscle, brain
glucagon liver, fatKidneys erythropoietin bone marrowLiver Somatomedins cartilageOvaries estradiol, progesterone repro. tract, mammary glandsParathyroid glands Parathyroid hormone bone, small intestine, kidneysPineal gland Melatonin hypothalamus, ant. PituitaryPituitary, anterior Trophic hormones endocrine glandsPituitary,posterior Antidiuretic hormone kidney, blood vessels
oxytocin uterus, mammary glandsSkin 1,25-dihydroxy vitamin D3 small intestineStomach Gastrin StomachTestes Testosterone prostate, seminal vesiclesThymus Thymosin lymph nodesThroid gland T3, T4, calcitonin Many
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Exocrine and Endocrine Glands
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Exocrine Glands and Endocrine glands
Exocrine Glands: Secrete into a duct and to the outside of abody surface
Examples: sweat, tear, saliva
Endocrine Glands: Secrete (hormone) into the bloodHormone circulates in blood and actsat target organs where hormone receptor is expressed
Examples: insulin
Exocrine and Endocrine glands:Endocrine Exocrine
Liver: IGF BilePancreas Pancreatic juice insulin, glucagon, PP
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Chemical Structure of Hormones
1. Amines (amino acid derivatives)Tyrosine derived: epinephrine, thyroid hormones Tryptophan derived:melatonin
2. PolypeptidesInsulin, leptin, ADH
3. GlycoproteinsFSH, LH
4. Steroids (cholesterol derived)Glucocorticoids, testosterone, vitamine D
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Mechanisms of Actions of Hormones
All hormones act by binding to their receptors
• Some receptors are located on the cell surfacePolar hormones (insulin, leptin)
• Some receptors are located in the cytoplasmLipophilic hormones (steroids, thyroid hormones)
• Some receptors are located in the nucleusLipophilic hormones (TZDs, Fibrates)
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Assay and Measurement of Hormones
BioassayChemical assayRadioimmunoassay (1977 Nobel prize)
Receptor binding assay (Scatchard plot)
[hormone] (ng/ml)
% *H
orm
one
boun
d
#
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Action of nuclear hormones
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Actions of PPARγ, a nuclear hormone receptor
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Regulation of hormone secretion:A simple feedback loop
↑ Blood glucose↓
β cells in the pancreas↓
↑ Insulin secretion↓
↑Uptake of blood glucose
↓ blood glucose
LiverMuscle Fat
Glucose Glucose↓ ↓
Glycogen Triglyceride
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Structure of an islet
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How glucose and therapeutic drugs cause insulin secretion
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Two general principles of hormone action
Acts on cells containing the receptor
Action is regulated by a feedback mechanism
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Overweight and NIDDM in the U.S.M
illio
ns o
f Peo
ple
180
150
120
90
60
30
0
_
_
_
_
_
_
?
1980 1990 2000 2010
60%54%
33%
28%
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Leptin: a new hormone from fat
•Made in the adipose tissues•A polypeptide of 167 amino acids•Product is secreted into blood•Its receptor is found in many tissues•Leptin deficiency causes obesity, infertility, and many other •complications
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Tissue distribution of leptin
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Leptin gene mutation in ob/ob mouse
R105 (CGA→TGA)
ob/ob R105 (CGA→TGA)
167
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Leptin Receptor Isoforms
1162
894
805
Extracellular TMR Intracellular
892
900
OB-Rb
OB-Ra
OB-Rc
OB-Rd
OB-Re
Long
Short
Soluble
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Tissue distribution of the leptin receptor
Hea
rtBr
ain
Lung
Live
rSk
. Mus
cle
Kidn
ey
Sple
en
Test
is
Common
Ob-Ra
Ob-Rb
Actin
Probe Length (kb)
0.60
0.25
0.20
2.00
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Rodent Mutations at the db Locus
Ob-Rb
C57BL/KsJ db/db
db3J/db3J
dbPas/dbPas
fa/fa
fak/fak
Q269P
Mouse
Rat
1162
894
625
281
1162
762
Extracellular TMR Intracellular
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Leptin Levels in Lean and Obese Rodents
+/+ db/db +/+ fa/faLeptin western
Leptin northern
β-actin
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0
2
4
6
8
10
12
14
1 2 5 10 25 50 50
ZDF Lean
Lept
in (n
g)
Plasma (µl)
Leptin levels in lean and ZDF rats
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Soluble Leptin Receptor Levels in Lean and ZDF Rats
100 1 2 5 10 20ZDFLean
OB-Re
203
116M.W
. (kD
a)
Plasma (µl)
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Jak-STAT Pathway of Leptin Receptor Signal Transduction
Ob-Ra Ob-Rb
YYY
YYY
Leptin
YYY
YYY
P
P
P P
P
Jak2 Jak2
YYY
YYYP
P P
PP
P
SHP-2P
Jak2 Jak2 Jak2 Jak2P PP
STAT3
Moves to Nucleus
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Hypothalamic signaling pathways regulating energy homeostasis
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Severe postnatal obesity of a child with leptin mutation
Age (years)
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One example of human leptin mutation
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Leptin treatment of a girl with leptin deficiency
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SUMMARY
• Most tissues are endocrine glands and have the capacity to secrete molecules that act on other tissues
• All hormones act by interaction with their receptors
• The action of most hormones are regulated by a negative feedback mechanism