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 Zucchi)
Disclosure Nothing to disclose PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
3-Iodothyronamine (T 1 AM) PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
T 1 AM as a chemical messenger • found in brain and other tissues • endogenous compound, which • by acting on specific receptors • agonist of TAAR1 • interacts with amine transporters • interacts with mitochondrial targets • interacts with apoB-100 • hypothermia • produces functional effects • decreased cardiac contractility • decreased insulin secretion • increased gluconeogenesis • shift to lipid catabolism • neuromodulatory action • behavioral effects PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
T 1 AM assay in rat tissues 1.0e5 1.0e5 1.0e4 1.0e4 1.5e5 1.5e5 C C A A B B serum heart liver T 1 AM T 1 AM D 4 -T 1 AM D 4 -T 1 AM D 4 -T 1 AM D 4 -T 1 AM Intensity, cps Intensity, cps D 4 -T 1 AM D 4 -T 1 AM T 1 AM T 1 AM T 1 AM T 1 AM 0 0 0 0 0 0 3363 3363 4.1e5 4.1e5 5.6e4 5.6e4 D D E E F F T 1 AM T 1 AM kidney muscle stomach D 4 -T 1 AM D 4 -T 1 AM T 1 AM T 1 AM Intensity, cps Intensity, cps D 4 -T 1 AM D 4 -T 1 AM T 1 AM T 1 AM D 4 -T 1 AM D 4 -T 1 AM 0 0 0 0 0 0 2.0 2.0 Time, min Time, min 4.0 4.0 2.0 2.0 Time, min Time, min 4.0 4.0 2.2e4 2.2e4 G G lung T 1 AM T 1 AM Intensity, cps Intensity, cps D 4 -T 1 AM D 4 -T 1 AM 0 0 Saba et al, Endocrinology 151:5063, 2010 2.0 2.0 Time, min Time, min 4.0 4.0 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
T 1 AM concentration in rat tissues (pmol/g) T 1 AM T 3 T 4 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 Saba et al, Endocrinology 151:5063, 2010 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Tissue distribution of [ 125 I]-T 1 AM in mouse 30 min 30 ** radioactivity (%ID/g) * P<0.05 vs blood ** P<0.01 vs blood 20 ** * * * 10 0 adipose t. blood bone brain gallbladder heart intestine kidney liver lung muscle pancreas skin spleen stomach thyroid 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)
T 1 AM in human blood 3 . 0 8 3 . 0 8 A human serum 1 . 2 e 5 1 . 2 e 5 D 4 - T 1 A M D 4 - T 1 A M T 1 A M T 1 A M Intensity, cps Intensity, cps 0 . 6 e 5 0 . 6 e 5 0 0 1 . 0 1 . 0 2 . 0 2 . 0 3 . 0 3 . 0 4 .0 4 .0 5 .0 5 .0 6 .0 6 .0 T im e , m in T im e , m in 3 . 0 9 3 . 0 9 B 4 . 0 e 5 4 . 0 e 5 rat liver T 1 A M T 1 A M Intensity, cps Intensity, cps 2 . 0 e 5 2 . 0 e 5 D 4 -T 1 A M D 4 -T 1 A M 0 0 1 . 0 1 . 0 2 . 0 2 . 0 3 . 0 3 . 0 4 .0 4 .0 5 .0 5 .0 6 .0 6 .0 T im e , m in T im e , m in Saba et al, Endocrinology 151:5063, 2010 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
T 1 AM 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)
T 1 AM 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)
Messages to take home (1) • T 1 AM 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 T 1 AM 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)
T 1 AM as a chemical messenger • found in brain and other tissues • endogenous compound, which • by acting on specific receptors • agonist of TAAR1 • interacts with amine transporters • interacts with mitochondrial targets • interacts with apoB-100 • hypothermia • produces functional effects • decreased cardiac contractility • decreased insulin secretion • increased gluconeogenesis • shift to lipid catabolism • neuromodulatory action • behavioral effects PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Endocrine and metabolic effects of T 1 AM Reference adm. dose effect 128 mol/Kg ip ↓ respiratory quotient, ↓ body fat Braulke et al, J Comp Physiol 2007 128 mol/Kg ip ↑ glucose, ↓ insulin, ↑ glucagon Regards et al, J Clin Invest 2007 1.2 mol/Kg icv ↑ glucose, ↑ glucagon Klieverik et al, J Endocrinol 2009 128 mol/Kg ip ↑ glucose, ↑ glucagon icv 3.3 nmol/Kg ↑ glucose Manni et al, Br J Pharmacol 2012 icv 0.3 nmol/Kg ↑ glucose Manni et al, Br J Pharmacol 2013 25 mol/kg/day ip ↓ body weight, lipolysis Haviland et al, Obesity 2013 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Effects of chronic T 1 AM treatment on body weight 10 mg/Kg/day T1AM 4 2 Body weight change (%) 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 -2 -4 -6 -8 SHAM -10 T1AM -12 Study day Haviland et al, Obesity, 2013 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Effects of chronic T 1 AM treatment on lipid metabolism 0 Average change in 13 C value 0 1 2 3 4 5 6 7 -0.5 -1 p=0.152 p=0.140 -1.5 -2 p=0.162 -2.5 p=0.129 -3 -3.5 p=0.0166 p=0.0221 p=0.0170 -4 p=0.0121 -4.5 Study day Haviland et al, Obesity, 2013 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Metabolic effects of chronic T 1 AM treatment 1.4 1.2 Concentration (mM) 1 0.8 0.6 0.4 0.2 0 Glucose Lactate •Control •Day 4 •Day 7 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
T 1 AM 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)
T 1 AM and gene expression in adipose tissue •Cholesterol •Uptake •Fatty Acid •Lipolysis •Biosynthesis PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Assay of tissue T 1 AM (pmol/g) liver WAT control 24 ± 8 0.5 ± 0.2 T 1 AM (10 mg/Kg/day) 2041 ± 119 - T 1 AM (25 mg/Kg/day) 8513 ± 1746 14.6 ± 5.5 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Messages to take home (2) • Administration of exogenous T 1 AM decreases insulin secretion and/or produces anti-insulin effects. • Chronic administration of exogenous T 1 AM induces lipolysis and decreases body weight. This likely involves complex modulation of gene expression. PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Neuromodulatory action of T 1 AM Gompf et al, Brain Res 1351:130, 2010 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Riccardo Zucchi)
Behavioral effects of T 1 AM Reference adm. dose effect Dhillo et al, Diabetes Obes Metab 2009 icv 1.2 nmol/Kg ↑ food intake ip 4 nmol/Kg ↑ food intake icv 3.3 nmol/Kg ↓ food intake Manni et al, Br J Pharmacol 2012 51 nmol/Kg ↑ food intake 25 mol/kg/day ip = food intake Haviland et al, Obesity 2013 icv 10 nmol/kg nREM sleep reduction James et al, Horm Behav 2013 icv 3.3 nmol/Kg pro-learning effect Manni et al, Br J Pharmacol 2013 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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