The biology of 3-iodothyronamine...Riccardo Zucchi University of Pisa, Italy The biology of...

Riccardo ZucchiUniversity of Pisa, Italy

The biology of 3-iodothyronamine

83rd ATA Annual Meeting – Puerto Rico, October 17, 2013

PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)

Disclosure

Nothing to disclose


3-Iodothyronamine (T1AM)


T1AM as a chemical messenger

• found in brain and other tissues

• agonist of TAAR1• interacts with amine transporters• interacts with mitochondrial targets• interacts with apoB-100

• hypothermia• decreased cardiac contractility• decreased insulin secretion• increased gluconeogenesis• shift to lipid catabolism• neuromodulatory action• behavioral effects

• endogenous compound, which

• by acting on specific receptors

• produces functional effects


0

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D4-T1AM

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T1AM

D4-T1AM

T1AM

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T1AM

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T1AMliver

kidney muscle

heart

stomach

lung

serum

T1AM assay in rat tissues

Saba et al, Endocrinology 151:5063, 2010


T1AM T3 T4

Serum (nM) 0.3±0.1 1.4±0.1 49.6±4.8Heart 6.6±1.4 0.5±0.1 0.7±0.2Liver 92.9±28.4 4.7±0.8 14.5±3.0Kidney 36.1±10.4 7.1±0.9 13.0±2.8Muscle 25.0±6.9 0.8±0.2 1.8±0.4Stomach 15.5±6.9 3.3±0.7 16.0±9.2Lung 5.6±1.5 4.4±1.5 24.8±12.2

T1AM concentration in rat tissues (pmol/g)



Tissue distribution of [125I]-T1AM in mouse

30 min

adip

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t.bl

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bone

brai

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test

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kidn

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stom

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oid

0

10

20

30

*

**

**

* *

radi

oact

ivity

(%ID

/g)

* P<0.05 vs blood** P<0.01 vs blood

Chiellini et al, J Endocrinol 213:223, 2012


1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in0

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nsity

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1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in0

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nsity

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T 1A M D 4- T 1 A M

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Inte

nsity

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1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in0

0 . 6 e 5

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nsity

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T 1A M D 4- T 1 A M A

B

human serum

rat liver

T1AM in human blood



T1AM in human blood

Galli et al, J Clin Endocrinol Metab 97:E69, 2012


T1AM assay in tissuesReference species tissue concentration

Scanlan et al, Nat Med 2004 rat brain < 1 pmol/g

Chiellini et al, FASEB J 2007 rat heart ≈ 68 pmol/g

Braulke et al, J Comp Physiol 2008 hamster blood 6 nM

Ackermans et al, J Endocrinol 2010 rat & human blood none (<0.25 nM)human thyroid none (<0.3 pmol/g)

Saba et al, Endocrinology 2010 rat many 0.3 – 92 pmol/g

Hoefig et al, JCEM, 2011 human blood 66 nM*

Galli et al, JCEM, 2012 human blood 0.2 nM

Hackenmuller et al, Endocrinology 2012 mouse liver 2 pmol/g

* immunological assay


Messages to take home (1)

• T1AM can be detected in blood and in most tissues at nanomolarconcentrations.

• A few technical issues must still be solved before quantitative correlationsbetween blood T1AM and other clinical variables can be reliablyinterpreted.


T1AM as a chemical messenger

• found in brain and other tissues

• agonist of TAAR1• interacts with amine transporters• interacts with mitochondrial targets• interacts with apoB-100

• hypothermia• decreased cardiac contractility• decreased insulin secretion• increased gluconeogenesis• shift to lipid catabolism• neuromodulatory action• behavioral effects

• endogenous compound, which

• by acting on specific receptors

• produces functional effects


Endocrine and metabolic effects of T1AM

Reference adm. dose effect

Braulke et al, J Comp Physiol 2007 ip 128 mol/Kg ↓ respiratory quotient, ↓ body fat

Regards et al, J Clin Invest 2007 ip 128 mol/Kg ↑ glucose, ↓ insulin, ↑ glucagon

Klieverik et al, J Endocrinol 2009 icv 1.2 mol/Kg ↑ glucose, ↑ glucagonip 128 mol/Kg ↑ glucose, ↑ glucagon

Manni et al, Br J Pharmacol 2012 icv 3.3 nmol/Kg ↑ glucose

Manni et al, Br J Pharmacol 2013 icv 0.3 nmol/Kg ↑ glucose

Haviland et al, Obesity 2013 ip 25 mol/kg/day ↓ body weight, lipolysis


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0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Bod

y w

eigh

t cha

nge

(%)

Study day

SHAMT1AM

Effects of chronic T1AM treatment on body weight

10 mg/Kg/day T1AM

Haviland et al, Obesity, 2013


p=0.0170 p=0.0166

p=0.0221

p=0.129

p=0.0121

p=0.162

p=0.152 p=0.140

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Aver

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Effects of chronic T1AM treatment on lipid metabolism

Haviland et al, Obesity, 2013


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Glucose Lactate

Co

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•Control •Day 4 •Day 7

Metabolic effects of chronic T1AM treatment


T1AM and sirtuin expression in liver

qPCR

Western blot


•Lipolysis•Fatty Acid •Biosynthesis

•Cholesterol •Uptake

T1AM and gene expression in adipose tissue


liver WAT

control 24±8 0.5±0.2

T1AM (10 mg/Kg/day) 2041±119 -

T1AM (25 mg/Kg/day) 8513±1746 14.6±5.5

Assay of tissue T1AM (pmol/g)


• Administration of exogenous T1AM decreases insulin secretion and/orproduces anti-insulin effects.

• Chronic administration of exogenous T1AM induces lipolysis anddecreases body weight. This likely involves complex modulation of geneexpression.



Gompf et al, Brain Res 1351:130, 2010

Neuromodulatory action of T1AM


Behavioral effects of T1AM

Reference adm. dose effect

Dhillo et al, Diabetes Obes Metab 2009 icv 1.2 nmol/Kg ↑ food intakeip 4 nmol/Kg ↑ food intake

Manni et al, Br J Pharmacol 2012 icv 3.3 nmol/Kg ↓ food intake 51 nmol/Kg ↑ food intake

Haviland et al, Obesity 2013 ip 25 mol/kg/day = food intake

James et al, Horm Behav 2013 icv 10 nmol/kg nREM sleep reduction

Manni et al, Br J Pharmacol 2013 icv 3.3 nmol/Kg pro-learning effect1.0 nmol/Kg ↓ pain threshold


i.c.v. injection

15 min

Training

1 hour

Acquisition

24 hours

Retention

MS assay of T1AM/TA1Western blot for pERK

mouse

Effect of T1AM on learning


Pro-learning effect of T1AM

Manni et al, Br J Pharmacol 168:354, 2013

0

100

200

300

400

Ste

p-th

roug

h la

tenc

y (s

ec)

Training Acquisition (1 h) Retention (24 h)

P<0.05 vs vehicle

P<0.01 vs vehicle

VehicleT1AM 0.13 g/Kg

T1AM 0.4 g/Kg

T1AM 1.32 g/KgT1AM 4 g/Kg


Anti-amnestic effect of T1AM

0

100

200

300

Vehicle + scop.Vehicle

*

scopolamine

T1AM 0.4 g/Kg + scopT1AM 1.32 g/Kg + scop

Training Acquisition (1 h) Retention (24 h)

**

* P<0.05 vs vehicle

** P<0.01 vs vehicle

scopolaminescopolamine

*

§§ P<0.01 vs vehicle + scop

§§*

§§ §§ §§


• Mesencephalon

•T1AM (gkg-1)

•Amygdala

•Hippocampus

•0.044 •0.132•Veh.

•α-tubulin•p-ERK 1/2

•Hypothalamus

•Veh. •0.044 •0.132

•T1AM (gkg-1)

ERK activation by T1AMp/

ER

K 2

exp

ress

ion

(Arb

irary

Uni

ts)


T1AM TA1

Baseline 48.6±17.7 0.8±0.2

Vehicle 33.6±6.0 0.7±0.3

T1AM icv (1.32 g/Kg) 1008.6±313.0 22.2±4.8

Brain assay for T1AM and TA1 (pmol/g)


• Intracerebral administration of T1AM has pro-learning and anti-amnesticeffects, at doses increasing endogenous concentration by about oneorder of magnitude.

• T1AM might have physiological and/or pathophysiological importance inthe regulation of metabolism and of CNS function.



The biology of 3-iodothyronamine...Riccardo Zucchi University of Pisa, Italy The biology of...

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