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

“Classical” Endocrine Glands

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

Exocrine and Endocrine Glands

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

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

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)

Assay and Measurement of Hormones

BioassayChemical assayRadioimmunoassay (1977 Nobel prize)

Receptor binding assay (Scatchard plot)

[hormone] (ng/ml)

% *H

orm

one

boun

d

#

Action of nuclear hormones

Actions of PPARγ, a nuclear hormone receptor

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

Structure of an islet

How glucose and therapeutic drugs cause insulin secretion

Two general principles of hormone action

Acts on cells containing the receptor

Action is regulated by a feedback mechanism

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%

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

Tissue distribution of leptin

Leptin gene mutation in ob/ob mouse

R105 (CGA→TGA)

ob/ob R105 (CGA→TGA)

167

Leptin Receptor Isoforms

1162

894

805

Extracellular TMR Intracellular

892

900

OB-Rb

OB-Ra

OB-Rc

OB-Rd

OB-Re

Long

Short

Soluble

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

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

Leptin Levels in Lean and Obese Rodents

+/+ db/db +/+ fa/faLeptin western

Leptin northern

β-actin

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

Soluble Leptin Receptor Levels in Lean and ZDF Rats

100 1 2 5 10 20ZDFLean

OB-Re

203

116M.W

. (kD

a)

Plasma (µl)

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

Hypothalamic signaling pathways regulating energy homeostasis

Severe postnatal obesity of a child with leptin mutation

Age (years)

One example of human leptin mutation

Leptin treatment of a girl with leptin deficiency

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