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Endocrine Glands and the General Principles

of Hormone Action

Cai Li, Ph.D. Assistant professor Touchstone Center for Diabetes Research Departments of Physiology and Internal Medicine The University of Texas Southwestern Medical Center Dallas, TX 75390-8854 April 6, 2002

“Classical” Endocrine Glands

A more complete listing of the endocrine glands Endocrine gland

Major hormones

Primary target organs

Adipose tissue

Leptin

hypothalamus

Adrenal cortex

Glucocorticoids

liver, muscle

Aldosterone

kidneys

Adrenal medulla

Epinephrine

heart, blood vessels

Heart^

Atrial natriuretic hormones

kidneys

Hypothalamus

Releasing and inhibiting hormones

pituitary

Small intestine

Secretin, cholecystokinin

stomach, liver, pancreas

Islets of Langerhans

Insulin

fat, muscle, brain

glucagon

liver, fat

Kidneys

erythropoietin

bone marrow

Liver^

Somatomedins

cartilage

Ovaries

estradiol, progesterone

repro. tract, mammary glands

Parathyroid glands

Parathyroid hormone

bone, small intestine, kidneys

Pineal gland

Melatonin

hypothalamus, ant. Pituitary

Pituitary, anterior

Trophic hormones

endocrine glands

Pituitary,posterior

Antidiuretic hormone

kidney, blood vessels

oxytocin

uterus, mammary glands

Skin^

1,25-dihydroxy vitamin D

3

small intestine

Stomach

Gastrin

Stomach

Testes

Testosterone

prostate, seminal vesicles

Thymus

Thymosin

lymph nodes

Throid 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 a body surface

Examples:

sweat, tear, saliva

Endocrine Glands:

Secrete (hormone) into the blood Hormone circulates in blood and acts at target organs where hormone receptor is expressed

Examples:

insulin

Exocrine and Endocrine glands:

Endocrine

Exocrine

Liver:

IGF^

Bile

Pancreas

Pancreatic juice

insulin, glucagon, PP

Chemical Structure of Hormones^ 1.^

Amines (amino acid derivatives) Tyrosine derived:

epinephrine, thyroid hormones

Tryptophan derived: melatonin 2. Polypeptides Insulin, leptin, ADH 3. Glycoproteins FSH, 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 surface ƒ^ Polar hormones (insulin, leptin)

-^

Some receptors are located in the cytoplasm ƒ^ Lipophilic hormones (steroids, thyroid hormones)

-^

Some receptors are located in the nucleus ƒ^ Lipophilic hormones (TZDs, Fibrates)

Assay and Measurement of Hormones Bioassay Chemical assay Radioimmunoassay (1977 Nobel prize) Receptor binding assay (Scatchard plot)

[hormone] (ng/ml)

% *Hormone bound

Action of nuclear hormones

Actions of PPAR

γ, 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.

180 150120906030 Millions of People^0

_ _ _ _ _ _

?

60% 2010

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 (C

GA→

TGA)

ob/ob

R105 (C

GA→

TGA)^167

Leptin Receptor Isoforms

1162 894 805

Extracellular

TMR Intracellular^892900

OB-RbOB-RaOB-RcOB-RdOB-Re Long Short Soluble

Tissue distribution of the leptin receptor

HeartBrain

LiverLung

KidneySk. Muscle Spleen

Testis

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/db3J3Jdb/db PasPasdb/db fa/fakkfa/fa

Q269P

Mouse Rat

1162 894 625 281

1162

762

Extracellular

TMR Intracellular

Leptin Levels in Lean and Obese Rodents

+/+^

db/db

+/+

fa/fa

Leptin westernLeptin northern β-actin

14 12 10 8 6 4 2 0

1

2

5

10

25

50

50

ZDF

Lean

Leptin (ng) Plasma ( Leptin levels in lean and ZDF ratsμl)

Soluble Leptin Receptor Levels in Lean and ZDF Rats

100

1

2

5

10

20

ZDF

Lean

OB-Re

(^203116) M.W. (kDa) Plasma (

μl)