The biology of 3-iodothyronamine Riccardo Zucchi University of - - PowerPoint PPT Presentation

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The biology of 3-iodothyronamine Riccardo Zucchi University of - - PowerPoint PPT Presentation

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

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SLIDE 1

Riccardo Zucchi University 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)

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SLIDE 2

Disclosure

Nothing to disclose

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

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SLIDE 3

3-Iodothyronamine (T1AM)

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

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SLIDE 4

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

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

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SLIDE 5

1.0e5 Intensity, cps

A

1.0e4

B

1.5e5

C

4.0 Time, min 2.0 4.1e5

E

4.0 Time, min 2.0 5.6e4

F

Intensity, cps 4.0 Time, min 2.0 2.2e4

G

Intensity, cps 3363

D

T1AM D 4-T1AM T1AM D4-T1AM T1AM D4-T1AM D 4-T1AM T1AM D4-T1AM T1AM D4-T1AM T1AM D4-T1AM T1AM 1.0e5 Intensity, cps

A

1.0e4

B

1.5e5

C

4.0 Time, min 2.0 4.1e5

E

4.0 Time, min 2.0 5.6e4

F

Intensity, cps 4.0 Time, min 2.0 2.2e4

G

Intensity, cps 3363

D

T1AM D 4-T1AM T1AM D4-T1AM T1AM D4-T1AM D 4-T1AM T1AM D4-T1AM T1AM D4-T1AM T1AM D4-T1AM T1AM

liver kidney muscle heart stomach lung serum

T1AM assay in rat tissues

Saba et al, Endocrinology 151:5063, 2010

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

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SLIDE 6

T1AM T3 T4

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

T1AM concentration in rat tissues (pmol/g)

Saba et al, Endocrinology 151:5063, 2010

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

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SLIDE 7

Tissue distribution of [125I]-T1AM in mouse

30 min

adipose t. blood bone brain gallbladder heart intestine kidney liver lung muscle pancreas skin spleen stomach thyroid 10 20 30

* ** ** * *

radioactivity (%ID/g)

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

Chiellini et al, J Endocrinol 213:223, 2012

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

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SLIDE 8

1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in 2 . 0 e 5 4 . 0 e 5 Intensity, cps 3 . 0 9 D 4 -T 1A M T 1 A M 1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in 0 . 6 e 5 1 . 2 e 5 Intensity, cps 3 . 0 8 T 1A M D 4- T 1 A M 1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in 2 . 0 e 5 4 . 0 e 5 Intensity, cps 3 . 0 9 D 4 -T 1A M T 1 A M 1 . 0 2 . 0 3 . 0 4 .0 5 .0 6 .0 T im e , m in 0 . 6 e 5 1 . 2 e 5 Intensity, cps 3 . 0 8 T 1A M D 4- T 1 A M

A B

human serum rat liver

T1AM in human blood

Saba et al, Endocrinology 151:5063, 2010

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

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SLIDE 9

T1AM in human blood

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

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

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SLIDE 10

T1AM assay in tissues

Reference 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

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

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SLIDE 11

Messages to take home (1)

  • T1AM can be detected in blood and in most tissues at nanomolar

concentrations.

  • A few technical issues must still be solved before quantitative correlations

between blood T1AM and other clinical variables can be reliably interpreted.

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

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SLIDE 12

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

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

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SLIDE 13

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, ↑ glucagon ip 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

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

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SLIDE 14
  • 12
  • 10
  • 8
  • 6
  • 4
  • 2

2 4

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

Body weight change (%)

Study day SHAM T1AM

Effects of chronic T1AM treatment on body weight

10 mg/Kg/day T1AM

Haviland et al, Obesity, 2013

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

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SLIDE 15

p=0.0170 p=0.0166 p=0.0221 p=0.129 p=0.0121 p=0.162 p=0.152 p=0.140

  • 4.5
  • 4
  • 3.5
  • 3
  • 2.5
  • 2
  • 1.5
  • 1
  • 0.5

1 2 3 4 5 6 7

Study day

Average change in 13C  value

Effects of chronic T1AM treatment on lipid metabolism

Haviland et al, Obesity, 2013

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

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SLIDE 16

0.2 0.4 0.6 0.8 1 1.2 1.4 Glucose Lactate

Concentration (mM)

  • Control
  • Day 4
  • Day 7

Metabolic effects of chronic T1AM treatment

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

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SLIDE 17

T1AM and sirtuin expression in liver

qPCR Western blot

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

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SLIDE 18
  • Lipolysis
  • Fatty Acid
  • Biosynthesis
  • Cholesterol
  • Uptake

T1AM and gene expression in adipose tissue

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

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SLIDE 19

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)

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

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SLIDE 20
  • Administration of exogenous T1AM decreases insulin secretion and/or

produces anti-insulin effects.

  • Chronic

administration

  • f

exogenous T1AM induces lipolysis and decreases body weight. This likely involves complex modulation of gene expression.

Messages to take home (2)

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

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SLIDE 21

Gompf et al, Brain Res 1351:130, 2010

Neuromodulatory action of T1AM

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

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SLIDE 22

Behavioral effects of T1AM

Reference adm. dose effect

Dhillo et al, Diabetes Obes Metab 2009 icv

1.2 nmol/Kg ↑ food intake ip 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 effect 1.0 nmol/Kg ↓ pain threshold

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

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SLIDE 23

i.c.v. injection 15 min Training 1 hour Acquisition 24 hours Retention MS assay of T1AM/TA1 Western blot for pERK

mouse

Effect of T1AM on learning

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

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SLIDE 24

Pro-learning effect of T1AM

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

100 200 300 400

Step-through latency (sec) Training Acquisition (1 h) Retention (24 h)

P<0.05 vs vehicle P<0.01 vs vehicle Vehicle T1AM 0.13 g/Kg T1AM 0.4 g/Kg T1AM 1.32 g/Kg T1AM 4 g/Kg

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

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SLIDE 25

Anti-amnestic effect of T1AM

100 200 300 Vehicle + scop. Vehicle

* scopolamine

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

Training Acquisition (1 h) Retention (24 h) ** * P<0.05 vs vehicle ** P<0.01 vs vehicle scopolamine scopolamine * §§ P<0.01 vs vehicle + scop §§ * §§ §§ §§

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

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SLIDE 26
  • 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 T1AM

p/ERK 2 expression (Arbirary Units)

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

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SLIDE 27

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)

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

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SLIDE 28
  • Intracerebral administration of T1AM has pro-learning and anti-amnestic

effects, at doses increasing endogenous concentration by about one

  • rder of magnitude.
  • T1AM might have physiological and/or pathophysiological importance in

the regulation of metabolism and of CNS function.

Messages to take home (3)

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