Hypothalamic mTOR pathway mediates thyroid hormone-induced hyperphagia in hyperthyroidism

Journal of Pathology

Volumn 227, Issue 2, 2012, Pages 209-222

  Varela, Luis ^a,b   Martínez Sánchez, Noelia ^a,b   Gallego, Rosalía ^c   Vázquez, María J ^a,b   Roa, Juan ^b,d,e   Gándara, Marina ^c   Schoenmakers, Erik ^f   Nogueiras, Rubén ^a,b   Chatterjee, Krishna ^f   Tena Sempere, Manuel ^b,d,e   Diéguez, Carlos ^a,b   López, Miguel ^a,b  

^a Universidade de Santiago de Compostela and Instituto de Investigación Sanitaria de Santiago de Compostela   (Spain)

^b Instituto de Salud Carlos III   (Spain)

^c UNIVERSITY OF SANTIAGO DE COMPOSTELA   (Spain)

^d UNIVERSITY OF CÓRDOBA   (Spain)

^e Maimonides Institute for Research in Biomedicine of Cordoba   (Spain)

^f UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

AMPK; energy balance; food intake; hyperthyroidism; hypothalamus; mTOR

Indexed keywords

ADENYLATE KINASE; AGOUTI RELATED PROTEIN; MAMMALIAN TARGET OF RAPAMYCIN; MESSENGER RNA; NEUROPEPTIDE; NEUROPEPTIDE Y; PROOPIOMELANOCORTIN; RAPAMYCIN; THYROID HORMONE; THYROID HORMONE RECEPTOR; THYROID HORMONE RECEPTOR ALPHA;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARCUATE NUCLEUS; ARTICLE; CONTROLLED STUDY; DRUG EFFECT; ENERGY EXPENDITURE; EUTHYROIDISM; FOOD INTAKE; HYPERPHAGIA; HYPERTHYROIDISM; HYPOTHALAMUS; MALE; NONHUMAN; PRIORITY JOURNAL; PROTEIN LOCALIZATION; RAT; UPREGULATION; WEIGHT REDUCTION;

AGOUTI-RELATED PROTEIN; AMP-ACTIVATED PROTEIN KINASES; ANIMALS; DISEASE MODELS, ANIMAL; EATING; FEEDING BEHAVIOR; HYPERPHAGIA; HYPERTHYROIDISM; HYPOTHALAMUS; MALE; NEURAL PATHWAYS; NEUROPEPTIDE Y; PHOSPHORYLATION; PRO-OPIOMELANOCORTIN; PROTEIN KINASE INHIBITORS; RATS; RATS, SPRAGUE-DAWLEY; RNA, MESSENGER; SIGNAL TRANSDUCTION; SIROLIMUS; THYROID HORMONE RECEPTORS ALPHA; TIME FACTORS; TOR SERINE-THREONINE KINASES; TRIIODOTHYRONINE; WEIGHT LOSS;

EID: 84860671774     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.3984     Document Type: Article

References (51)

1. Silva JE,. Thermogenic mechanisms and their hormonal regulation. Physiol Rev 2006; 86: 435-464.
2. Lõpez M, Varela L, Vázquez MJ, et al., Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010; 16: 1001-1008.
3. Ingbar SH,. The thyroid gland. In Williams Textbook of Endocrinology, Wilson JD, Foster DW, (eds). W.B. Saunders Company, Philadelphia, 7th ed. 1985; 975-1170.
4. Lõpez M, Seoane L, Señarís R, et al., Prepro-orexin mRNA levels in the rat hypothalamus, and orexin receptors mRNA levels in the rat hypothalamus and adrenal gland are not influenced by the thyroid status. Neurosci Lett 2001; 300: 171-175.
5. Pijl H, de Meijer PH, Langius J, et al., Food choice in hyperthyroidism: potential influence of the autonomic nervous system and brain serotonin precursor availability. J Clin Endocrinol Metab 2001; 86: 5848-5853.
6. Lõpez M, Seoane LM, Tovar S, et al., Thyroid status regulates CART transcript but not AgRP mRNA levels in the rat hypothalamus. NeuroReport 2002; 13: 1775-1779.
7. Dennis PB, Jaeschke A, Saitoh M, et al., Mammalian TOR: a homeostatic ATP sensor. Science 2001; 294: 1102-1105.
8. Wullschleger S, Loewith R, Hall MN,. TOR signaling in growth and metabolism. Cell 2006; 124: 471-484.
9. Guertin DA, Sabatini DM,. Defining the role of mTOR in cancer. Cancer Cell 2007; 12: 9-22.
10. Sarbassov DD, Guertin DA, Ali SM, et al., Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098-1101.
11. Proud CG,. Role of mTOR signalling in the control of translation initiation and elongation by nutrients. Curr Top Microbiol Immunol 2004; 279: 215-244.
12. Wang X, Proud CG,. Nutrient control of TORC1, a cell-cycle regulator. Trends Cell Biol 2009; 19: 260-267.
13. Kahn BB, Alquier T, Carling D, et al., AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 2005; 1: 15-25.
14. Carling D, Sanders MJ, Woods A,. The regulation of AMP-activated protein kinase by upstream kinases. Int J Obes (Lond) 2008; 32 (suppl 4): S55-59.
15. Hardie DG,. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond) 2008; 32 (suppl 4): S7-12.
16. Lage R, Diéguez C, Vidal-Puig A, et al., AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol Med 2008; 14: 539-549.
17. Bolster DR, Crozier SJ, Kimball SR, et al., AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 2002; 277: 23977-23980.
18. Krause U, Bertrand L, Hue L,. Control of p70 ribosomal protein S6 kinase and acetyl-CoA carboxylase by AMP-activated protein kinase and protein phosphatases in isolated hepatocytes. Eur J Biochem 2002; 269: 3751-3759.
19. Kimura N, Tokunaga C, Dalal S, et al., A possible linkage between AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) signalling pathway. Genes Cells 2003; 8: 65-79.
20. Inoki K, Zhu T, Guan KL,. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115: 577-590.
21. Shaw RJ, Bardeesy N, Manning BD, et al., The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004; 6: 91-99.
22. Ropelle ER, Pauli JR, Fernandes MF, et al., A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in high-protein diet-induced weight loss. Diabetes 2008; 57: 594-605.
23. Gwinn DM, Shackelford DB, Egan DF, et al., AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30: 214-226.
24. Cheng SW, Fryer LG, Carling D, et al., Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status. J Biol Chem 2004; 279: 15719-15722.
25. Cota D, Proulx K, Smith KA, et al., Hypothalamic mTOR signaling regulates food intake. Science 2006; 312: 927-930.
26. Cota D, Matter EK, Woods SC, et al., The role of hypothalamic mammalian target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci 2008; 28: 7202-7208.
27. Ropelle ER, Fernandes MF, Flores MB, et al., Central exercise action increases the AMPK and mTOR response to leptin. PLoS ONE 2008; 3: e3856.
28. Blouet C, Ono H, Schwartz GJ,. Mediobasal hypothalamic p70 S6 kinase 1 modulates the control of energy homeostasis. Cell Metab 2008; 8: 459-467.
29. Mori H, Inoki K, Munzberg H, et al., Critical role for hypothalamic mTOR activity in energy balance. Cell Metab 2009; 9: 362-374.
30. Cao R, Li A, Cho HY, et al., Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock. J Neurosci 2010; 30: 6302-6314.
31. Lembke V, Goebel M, Frommelt L, et al., Sulfated cholecystokinin-8 activates phospho-mTOR immunoreactive neurons of the paraventricular nucleus in rats. Peptides 2011; 32: 65-70.
32. Hahn TM, Breininger JF, Baskin DG, et al., Coexpression of AgRP and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1998; 1: 271-272.
33. Inhoff T, Stengel A, Peter L, et al., Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats. Peptides 2010; 31: 257-262.
34. Reed AS, Unger EK, Olofsson LE, et al., Functional role of suppressor of cytokine signaling 3 upregulation in hypothalamic leptin resistance and long-term energy homeostasis. Diabetes 2010; 59: 894-906.
35. Villanueva EC, Munzberg H, Cota D, et al., Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 2009; 150: 4541-4551.
36. Morton GJ, Blevins JE, Kim F, et al., The action of leptin in the ventral tegmental area to decrease food intake is dependent on Jak-2 signaling. Am J Physiol Endocrinol Metab 2009; 297: E202-210.
37. Roa J, García-Galiano D, Varela L, et al., The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 2009; 150: 5016-5026.
38. Lõpez M, Lelliott CJ, Tovar S, et al., Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes 2006; 55: 1327-1336.
39. Lõpez M, Lage R, Saha AK, et al., Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab 2008; 7: 389-399.
40. Vázquez MJ, González CR, Varela L, et al., Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology 2008; 149: 4534-4543.
41. Lage R, Vázquez MJ, Varela L, et al., Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J 2010; 24: 2670-2679.
42. Sangiao-Alvarellos S, Varela L, Vázquez MJ, et al., Influence of ghrelin and growth hormone deficiency on AMPK and hypothalamic lipid metabolism. J Neuroendocrinol 2010; 22: 543-556.
43. Kelly JF, Elias CF, Lee CE, et al., Ciliary neurotrophic factor and leptin induce distinct patterns of immediate early gene expression in the brain. Diabetes 2004; 53: 911-920.
44. Minokoshi Y, Alquier T, Furukawa N, et al., AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004; 428: 569-574.
45. Huang J, Manning BD,. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412: 179-190.
46. Lõpez M, Tovar S, Vázquez MJ, et al., Peripheral tissue-brain interactions in the regulation of food intake. Proc Nutr Soc 2007; 66: 131-155.
47. Gao Q, Horvath TL,. Neurobiology of feeding and energy expenditure. Annu Rev Neurosci 2007; 30: 367-398.
48. Ishii S, Kamegai J, Tamura H, et al., Hypothalamic neuropeptide Y/Y1 receptor pathway activated by a reduction in circulating leptin, but not by an increase in circulating ghrelin, contributes to hyperphagia associated with triiodothyronine-induced thyrotoxicosis. Neuroendocrinology 2003; 78: 321-330.
49. Wolfgang MJ, Lane MD,. Control of energy homeostasis: role of enzymes and intermediates of fatty acid metabolism in the central nervous system. Annu Rev Nutr 2006; 26: 23-44.
50. Saha AK, Xu XJ, Lawson E, et al., Downregulation of AMPK accompanies leucine- and glucose-induced increases in protein synthesis and insulin resistance in rat skeletal muscle. Diabetes 2010; 59: 2426-2434.
51. Cao X, Kambe F, Moeller LC, et al., Thyroid hormone induces rapid activation of Akt/protein kinase B-mammalian target of rapamycin-p70S6K cascade through phosphatidylinositol 3-kinase in human fibroblasts. Mol Endocrinol 2005; 19: 102-112.