Horm Metab Res 2015; 47(08): 605-610
DOI: 10.1055/s-0034-1394380
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

3-Iodothyronamine-Mediated Metabolic Suppression Increases the Phosphorylation of AMPK and Induces Fuel Choice Toward Lipid Mobilization

H. Ju
1   Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju, Gangwon-Do, Republic of Korea
,
H. Shin
1   Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju, Gangwon-Do, Republic of Korea
,
C. Son
2   Medical Research Institute, Sungkyunkwan University, Clinical Research Center, Samsung Biomedical Research Institute, Irwon-dong 50, Gangnam-gu, Seoul, Republic of Korea
,
K. Park
2   Medical Research Institute, Sungkyunkwan University, Clinical Research Center, Samsung Biomedical Research Institute, Irwon-dong 50, Gangnam-gu, Seoul, Republic of Korea
,
I. Choi
1   Division of Biological Science and Technology, College of Science and Technology, Yonsei University, Wonju, Gangwon-Do, Republic of Korea
› Author Affiliations
Further Information

Publication History

received 28 July 2014

accepted 01 October 2014

Publication Date:
05 November 2014 (online)

Abstract

Despite broad medical application, induction of artificial hypometabolism in vitro and its biochemical consequence have been rarely addressed. This study aimed to elucidate whether 3-iodothyronamine (T1AM) induces hypometabolism in an in vitro model with activation of AMP-activated protein kinase (AMPK) and whether it leads to a switch in primary fuel from carbohydrates to lipids as observed in in vivo models. Mouse C2C12 myotube and T1AM, a natural derivative of thyroid hormone, were used in this study. The oxygen consumption rate (OCR) decreased in a dose-dependent manner in response to 0–100 μM T1AM for up to 10 h. Upon 6-h of exposure to 75 μM T1AM, the OCR was reduced to 60 vs. ~ 95% for the control. The intracellular [AMP]/[ATP] was 1.35-fold higher in T1AM-treated cells. RT-PCR and immunoblotting analyses revealed that treated cells had upregulated p-AMPK/AMPK (1.8-fold), carnitine palmitoyl transferase 1 mRNA, and pyruvate dehydrogenase kinase, and downregulated acetyl CoA carboxylase (0.4-fold) and pyruvate dehydrogenase phosphatase. The treated cells had darker periodic acid-Schiff staining with 1.2-fold greater glycogen content than controls. Taken together, the hypometabolic response of myotubes to T1AM was dramatic and accompanied by increases in both the relative abundance of AMP and AMPK activation, and fuel choice favoring lipids over carbohydrates. These results are consistent with the general trends observed for rodent models and true hibernators.

 
  • References

  • 1 Bolling SF, Benedict MB, Tramontini NL, Kilgore KS, Harlow HH, Su TP, Oeltgen PR. Hibernation triggers and myocardial protection. Circulation 1998; 98: II220-II223 discussion II223–II224
  • 2 Lee CC. Is human hibernation possible?. Annu Rev Med 2008; 59: 177-186
  • 3 Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 2004; 10: 638-642
  • 4 Braulke LJ, Klingenspor M, DeBarber A, Tobias SC, Grandy DK, Scanlan TS, Heldmaier G. 3-Iodothyronamine: a novel hormone controlling the balance between glucose and lipid utilisation. J Compar Physiol B 2008; 178: 167-177
  • 5 Ju H, So H, Ha K, Park K, Lee JW, Chung CM, Choi I. Sustained torpidity following multi-dose administration of 3-iodothyronamine in mice. J Cell Physiol 2011; 226: 853-858
  • 6 Panas HN, Lynch LJ, Vallender EJ, Xie Z, Chen GL, Lynn SK, Scanlan TS, Miller GM. Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res 2010; 88: 1962-1969
  • 7 Zucchi R, Chiellini G, Scanlan TS, Grandy DK. Trace amine-associated receptors and their ligands. Br J Pharmacol 2006; 149: 967-978
  • 8 Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem Soc Trans 2011; 39: 1-13
  • 9 Nader GA. Molecular determinants of skeletal muscle mass: getting the "AKT" together. Inter J Biochem Cell Biol 2005; 37: 1985-1996
  • 10 Saha AK, Ruderman NB. Malonyl-CoA and AMP-activated protein kinase: an expanding partnership. Mol Cell Biochem 2003; 253: 65-70
  • 11 Folmes CD, Lopaschuk GD. Role of malonyl-CoA in heart disease and the hypothalamic control of obesity. Cardiovasc Res 2007; 73: 278-287
  • 12 Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS. Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. J Med Chem 2006; 49: 1101-1112
  • 13 Kim J-G, Song Y-K, Jo Y-H, Yu M-R, Ju H, Choi I, Chung C-H. A new efficient synthetic method for 3-iodothyronamine involving sonication and its potent hypometabolic efficacy. Bull Korean Chem Soc 2011; 32: 1131-1133
  • 14 Bos EM, Leuvenink HG, Snijder PM, Kloosterhuis NJ, Hillebrands JL, Leemans JC, Florquin S, van Goor H. Hydrogen sulfide-induced hypometabolism prevents renal ischemia/reperfusion injury. J Am Soc Nephrol 2009; 20: 1901-1905
  • 15 Doyle KP, Suchland KL, Ciesielski TM, Lessov NS, Grandy DK, Scanlan TS, Stenzel-Poore MP. Novel thyroxine derivatives, thyronamine and 3-iodothyronamine, induce transient hypothermia and marked neuroprotection against stroke injury. Stroke 2007; 38: 2569-2576
  • 16 Zhang J, Kaasik K, Blackburn MR, Lee CC. Constant darkness is a circadian metabolic signal in mammals. Nature 2006; 439: 340-343
  • 17 Hofmann S, Cherkasova V, Bankhead P, Bukau B, Stoecklin G. Translation suppression promotes stress granule formation and cell survival in response to cold shock. Mol Biol Cell 2012; 23: 3786-3800
  • 18 Oakhill JS, Scott JW, Kemp BE. AMPK functions as an adenylate charge-regulated protein kinase. Trends Endocrinol Metab 2012; 23: 125-132
  • 19 Belke DD, Wang LC, Lopaschuk GD. Acetyl-CoA carboxylase control of fatty acid oxidation in hearts from hibernating Richardson’s ground squirrels. Biochim Biophys Acta 1998; 1391: 25-36
  • 20 Carey HV, Andrews MT, Martin SL. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature. Physiol Rev 2003; 83: 1153-1181
  • 21 Healy JE, Gearhart CN, Bateman JL, Handa RJ, Florant GL. AMPK and ACC change with fasting and physiological condition in euthermic and hibernating golden-mantled ground squirrels (Callospermophilus lateralis). Comp Biochem Physiol Part A 2011; 159: 322-331
  • 22 Andrews MT, Squire TL, Bowen CM, Rollins MB. Low-temperature carbon utilization is regulated by novel gene activity in the heart of a hibernating mammal. Proc Natl Acad Sci USA 1998; 95: 8392-8397
  • 23 Buck MJ, Squire TL, Andrews MT. Coordinate expression of the PDK4 gene: a means of regulating fuel selection in a hibernating mammal. Physiol Genom 2002; 8: 5-13