Hypothalamic AMPK as a Regulator of Energy Homeostasis

Neural Plasticity

Volumn 2016, Issue , 2016, Pages

  Huynh, My Khanh Q ^a   Kinyua, Ann W ^a   Yang, Dong Joo ^a   Kim, Ki Woo ^a  

^a Yonsei University Wonju College of Medicine   (South Korea)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ADIPONECTIN; ADRENALIN; CANNABINOID DERIVATIVE; CANNABINOID RECEPTOR ANTAGONIST; CORTICOSTERONE; DEXAMETHASONE; ESTRADIOL; GHRELIN; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCOCORTICOID; GLUCOSE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE KINASE ACTIVATOR; INSULIN; LEPTIN; LIRAGLUTIDE; MAMMALIAN TARGET OF RAPAMYCIN; NICOTINE; PIOGLITAZONE; SMALL INTERFERING RNA;

ADIPOCYTE; APPETITE; BRAIN; BRAIN FUNCTION; CALORIC INTAKE; CENTRAL NERVOUS SYSTEM; ENERGY BALANCE; ENERGY EXPENDITURE; ENERGY METABOLISM; ENZYME ACTIVITY; EXERCISE; FEEDING BEHAVIOR; GLUCOSE HOMEOSTASIS; HOMEOSTASIS; HUMAN; HYPOGLYCEMIA; HYPOTHALAMUS; INSULIN BLOOD LEVEL; INSULIN TREATMENT; NONHUMAN; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN STRUCTURE; REVIEW; SKELETAL MUSCLE; THERMOGENESIS; UBIQUITINATION; ANIMAL; EATING; METABOLISM; PHYSIOLOGY;

AMP-ACTIVATED PROTEIN KINASES; ANIMALS; EATING; ENERGY METABOLISM; FEEDING BEHAVIOR; HOMEOSTASIS; HUMANS; HYPOTHALAMUS;

EID: 84982131522     PISSN: 20905904     EISSN: 16875443     Source Type: Journal    
DOI: 10.1155/2016/2754078     Document Type: Review

References (167)

1. G. C. Kennedy, "The central nervous regulation of calorie balance, " Proceedings of the Nutrition Society, vol. 20, pp. 58-64, 1961.
2. G. A. Bray, "Regulation of energy balance: studies on genetic, hypothalamic and dietary obesity, " Proceedings of the Nutrition Society, vol. 41, no. 2, pp. 95-108, 1982.
3. S. C. Woods, R. J. Seeley, D. Porte Jr., and M. W. Schwartz, "Signals that regulate food intake and energy homeostasis, " Science, vol. 280, no. 5368, pp. 1378-1383, 1998.
4. C. C. Cheung, D. K. Clifton, and R. A. Steiner, "Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus, " Endocrinology, vol. 138, no. 10, pp. 4489-4492, 1997.
5. J. G. Mercer, N. Hoggard, L. M. Williams et al., "Coexpression of leptin receptor and preproneuropeptide Y mRNA in arcuate nucleus of mouse hypothalamus, " Journal of Neuroendocrinology, vol. 8, no. 10, pp. 733-735, 1996.
6. M. M. Ollmann, B. D. Wilson, Y.-K. Yang et al., "Antagonismof central melanocortin receptors in vitro and in vivo by agoutirelated protein, " Science, vol. 278, no. 5335, pp. 135-138, 1997.
7. Y. Aponte, D. Atasoy, and S. M. Sternson, "AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training, " Nature Neuroscience, vol. 14, no. 3, pp. 351-355, 2011.
8. N. Wu, B. Zheng, A. Shaywitz et al., "AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1, " Molecular Cell, vol. 49, no. 6, pp. 1167-1175, 2013.
9. C. J. Estler and H. P. Ammon, "The importance of the adrenergic beta-receptors for thermogenesis and survival of acutely coldexposed mice, " Canadian Journal of Physiology and Pharmacology, vol. 47, no. 5, pp. 427-434, 1969.
10. D. G. Hardie and D. Carling, "The AMP-activated protein kinase-fuel gauge of the mammalian cell" European Journal of Biochemistry, vol. 246, no. 2, pp. 259-273, 1997.
11. F. Moore, J. Weekes, and D. G. Hardie, "Evidence that AMP triggers phosphorylation as well as direct allosteric activation of rat liver AMP-activated protein kinase. A sensitive mechanism to protect the cell against ATP depletion, " European Journal of Biochemistry, vol. 199, no. 3, pp. 691-697, 1991.
12. D. G. Hardie, "AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy, " Nature Reviews Molecular Cell Biology, vol. 8, no. 10, pp. 774-785, 2007.
13. A.-S. Marsin, L. Bertrand, M. H. Rider et al., "Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia, " Current Biology, vol. 10, no. 20, pp. 1247-1255, 2000.
14. A.-S. Marsin, C. Bouzin, L. Bertrand, and L. Hue, "The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase, " The Journal of Biological Chemistry, vol. 277, no. 34, pp. 30778-30783, 2002.
15. S. P. Berasi, C. Huard, D. Li et al., "Inhibition of gluconeogenesis through transcriptional activation of EGR1 and DUSP4 by AMP-activated kinase, "The Journal of Biological Chemistry, vol. 281, no. 37, pp. 27167-27177, 2006.
16. S. Horman, G. J. Browne, U. Krause et al., "Activation of AMP-activated protein kinase leads to the phosphorylation of elongation factor 2 and an inhibition of protein synthesis, " Current Biology, vol. 12, no. 16, pp. 1419-1423, 2002.
17. P. R. Clarke and D. G. Hardie, "Regulation of HMG-CoA reductase: identification of the site phosphorylated by theAMPactivated protein kinase in vitro and in intact rat liver, " The EMBO Journal, vol. 9, no. 8, pp. 2439-2446, 1990.
18. D. M. Muoio, K. Seefeld, L. A. Witters, and R. A. Coleman, "AMP-activated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3-phosphate acyltransferase is a novel target, " Biochemical Journal, vol. 338, no. 3, pp. 783-791, 1999.
19. M. López, R. Nogueiras, M. Tena-Sempere, and C. Diéguez, "Hypothalamic AMPK: A canonical regulator of whole-body energy balance, "Nature Reviews Endocrinology, vol. 12, no. 7, pp. 421-432, 2016.
20. Y. Minokoshi, T. Alquier, H. Furukawa et al., "AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus, " Nature, vol. 428, no. 6982, pp. 569-574, 2004.
21. J. Bass and J. S. Takahashi, "Circadian integration of metabolism and energetics, " Science, vol. 330, no. 6009, pp. 1349-1354, 2010.
22. L. E. Landree, A. L. Hanlon, D. W. Strong et al., "C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy Metabolism, " The Journal of Biological Chemistry, vol. 279, no. 5, pp. 3817-3827, 2004.
23. M. S. Kim and K. U. Lee, "Role of hypothalamic 5-AMPactivated protein kinase in the regulation of food intake and energy homeostasis, " Journal ofMolecularMedicine, vol. 83, no. 7, pp. 514-520, 2005.
24. D. Stapleton, K. I. Mitchelhill, G. Gao et al., "Mammalian AMPactivated protein kinase subfamily, " The Journal of Biological Chemistry, vol. 271, no. 2, pp. 611-614, 1996.
25. D. Stapleton, E. Woollatt, K. I. Mitchelhill et al., "AMP-activated protein kinase isoenzyme family: subunit structure and chromosomal location, " FEBS Letters, vol. 409, no. 3, pp. 452-456, 1997.
26. P. C. F. Cheung, I. P. Salt, S. P. Davies, D. G. Hardie, and D. Carling, "Characterization of AMP-activated protein kinase-subunit isoforms and their role in AMP binding, " Biochemical Journal, vol. 346, no. 3, pp. 659-669, 2000.
27. E. R. Hudson, D. A. Pan, J. James et al., "Anovel domain inAMPactivated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias, " Current Biology, vol. 13, no. 10, pp. 861-866, 2003.
28. A. Bateman, "The structure of a domain common to archaebacteria and the homocystinuria disease protein, " Trends in Biochemical Sciences, vol. 22, no. 1, pp. 12-13, 1997.
29. M. C. Towler and D. G. Hardie, "AMP-activated protein kinase in metabolic control and insulin signaling, " Circulation Research, vol. 100, no. 3, pp. 328-341, 2007.
30. M. Vogel and F. Heinz, "Purification and characterisation of the cyclic amp-dependent protein kinase, the C-and the R-protein from bovine liver, " Biochimica et Biophysica Acta (BBA)-Protein Structure, vol. 670, no. 1, pp. 47-55, 1981.
31. G. J. Gowans, S. A. Hawley, F. A. Ross, andD. G. Hardie, "AMP is a true physiological regulator of amp-activated protein kinase by both allosteric activation and enhancing net phosphorylation, " Cell Metabolism, vol. 18, no. 4, pp. 556-566, 2013.
32. D. Carling, C. Thornton, A. Woods, and M. J. Sanders, "AMPactivated protein kinase: new regulation, new roles" Biochemical Journal, vol. 445, no. 1, pp. 11-27, 2012.
33. S. A. Hawley, M. Davison, A. Woods et al., "Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase, " The Journal of Biological Chemistry, vol. 271, no. 44, pp. 27879-27887, 1996.
34. A. Woods, K. Dickerson, R. Heath et al., "Ca2+/calmodulindependent protein kinase kinase-acts upstream of AMPactivated protein kinase in mammalian cells, " Cell Metabolism, vol. 2, no. 1, pp. 21-33, 2005.
35. K. A. Anderson, T. J. Ribar, F. Lin et al., "Hypothalamic CaMKK2 contributes to the regulation of energy balance, " Cell Metabolism, vol. 7, no. 5, pp. 377-388, 2008.
36. M. Claret, M. A. Smith, C. Knauf et al., "Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice, " Diabetes, vol. 60, no. 3, pp. 735-745, 2011.
37. Fei-Wang, D.-R. Tian, P. Tso, andJ.-S. Han, "Diet-inducedobese rats exhibit impaired LKB1-AMPK signaling in hypothalamus and adipose tissue, " Peptides, vol. 35, no. 1, pp. 23-30, 2012.
38. S. A. Hawley, D. A. Pan, K. J. Mustard et al., "Calmodulindependent protein kinase kinase-is an alternative upstream kinase for AMP-activated protein kinase, " Cell Metabolism, vol. 2, no. 1, pp. 9-19, 2005.
39. D. Carling, M. J. Sanders, and A. Woods, "The regulation of AMP-activated protein kinase by upstream kinases, " International Journal of Obesity, vol. 32, supplement 4, pp. S55-S59, 2008.
40. G. Zhou, R. Myers, Y. Li et al., "Role of AMP-activated protein kinase in mechanism of metformin action, " The Journal of Clinical Investigation, vol. 108, no. 8, pp. 1167-1174, 2001.
41. K. V. Doan, C. M. Ko, A. W. Kinyua et al., "Gallic acid regulates body weight and glucose homeostasis through AMPK activation, " Endocrinology, vol. 156, no. 1, pp. 157-168, 2015.
42. D. M. Breen, T. Sanli, A. Giacca, and E. Tsiani, "Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK, " Biochemical and Biophysical Research Communications, vol. 374, no. 1, pp. 117-122, 2008.
43. Y. S. Lee, W. S. Kim, K. H. Kim et al., "Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states, " Diabetes, vol. 55, no. 8, pp. 2256-2264, 2006.
44. P. Pu, X.-A. Wang, M. Salim et al., "Baicalein, a natural product, selectively activating AMPKalpha(2) and ameliorates metabolic disorder in diet-induced mice, " Molecular and Cellular Endocrinology, vol. 362, no. 1-2, pp. 128-138, 2012.
45. J. Ahn, H. Lee, S. Kim, J. Park, and T. Ha, "Theanti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways, " Biochemical and Biophysical Research Communications, vol. 373, no. 4, pp. 545-549, 2008.
46. S.-L. Huang, R.-T. Yu, J. Gong et al., "Arctigenin, a natural compound, activates AMP-activated protein kinase via inhibition of mitochondria complex I and ameliorates metabolic disorders in ob/ob mice, " Diabetologia, vol. 55, no. 5, pp. 1469-1481, 2012.
47. J.-T. Hwang, I.-J. Park, J.-I. Shin et al., "Genistein, EGCG, and capsaicin inhibit adipocyte differentiation process via activating AMP-activated protein kinase, " Biochemical and Biophysical Research Communications, vol. 338, no. 2, pp. 694-699, 2005.
48. W. Pan, H. Yang, C. Cao et al., "AMPK mediates curcumininduced cell death in CaOV3 ovarian cancer cells, " Oncology Reports, vol. 20, no. 6, pp. 1553-1559, 2008.
49. N. K. LeBrasseur, M. Kelly, T.-S. Tsao et al., "Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues, " American Journal of Physiology-Endocrinology and Metabolism, vol. 291, no. 1, pp. E175-E181, 2006.
50. J. M. Corton, J. G. Gillespie, S. A. Hawley, and D. G. Hardie, "5-Aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells" European Journal of Biochemistry, vol. 229, no. 2, pp. 558-565, 1995.
51. B. Xiao, M. J. Sanders, E. Underwood et al., "Structure of mammalian AMPKand its regulation by ADP, " Nature, vol. 472, no. 7342, pp. 230-233, 2011.
52. F. A. Ross, T. E. Jensen, and D. G. Hardie, "Differential regulation by AMP and ADP of AMPK complexes containing different subunit isoforms, " Biochemical Journal, vol. 473, no. 2, pp. 189-199, 2016.
53. J. S. Oakhill, R. Steel, Z.-P. Chen et al., "AMPK is a direct adenylate charge-regulated protein kinase, " Science, vol. 332, no. 6036, pp. 1433-1435, 2011.
54. R. R. Deshmukh and Q. P. Dou, "Proteasome inhibitors induce AMPK activation via CaMKK in human breast cancer cells, " Breast Cancer Research and Treatment, vol. 153, no. 1, pp. 79-88, 2015.
55. Y. Xu, Y. Gu, G. Liu et al., "Cidec promotes the differentiation of human adipocytes by degradation of AMPK through ubiquitin-proteasome pathway, " Biochimica et Biophysica Acta (BBA)-General Subjects, vol. 1850, no. 12, pp. 2552-2562, 2015.
56. A. K. Al-Hakim, A. Zagorska, L. Chapman, M. Deak, M. Peggie, and D. R. Alessi, "Control of AMPK-related kinases by USP9X and atypical Lys29/Lys33-linked polyubiquitin chains, " Biochemical Journal, vol. 411, no. 2, pp. 249-260, 2008.
57. C. T. Pineda, S. Ramanathan, K. Fon Tacer et al., "Degradation ofAMPKby a cancer-specific ubiquitin ligase, " Cell, vol. 160, no. 4, pp. 715-728, 2015.
58. J. Qi, J. Gong, T. Zhao et al., "Downregulation of AMPactivated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue, " The EMBO Journal, vol. 27, no. 11, pp. 1537-1548, 2008.
59. L. M. Ignacio-Souza, B. Bombassaro, L. B. Pascoal et al., "Defective regulation of the ubiquitin/proteasome systemin the hypothalamus of obese male mice, " Endocrinology, vol. 155, no. 8, pp. 2831-2844, 2014.
60. T. L. Martin, T. Alquier, K. Asakura, N. Furukawa, F. Preitner, and B. B. Kahn, "Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle, " The Journal of Biological Chemistry, vol. 281, no. 28, pp. 18933-18941, 2006.
61. T. Kadowaki and T. Yamauchi, "Adiponectin and adiponectin receptors, " Endocrine Reviews, vol. 26, no. 3, pp. 439-451, 2005.
62. N. Kubota, Y. Terauchi, T. Yamauchi et al., "Disruption of adiponectin causes insulin resistance and neointimal formation, " Journal of Biological Chemistry, vol. 277, no. 29, pp. 25863-25866, 2002.
63. N. Maeda, I. Shimomura, K. Kishida et al., "Diet-induced insulin resistance in mice lacking adiponectin/ACRP30, " Nature Medicine, vol. 8, no. 7, pp. 731-737, 2002.
64. C. T. Lim, B. Kola, and M. Korbonits, "AMPK as a mediator of hormonal signalling, " Journal of Molecular Endocrinology, vol. 44, no. 2, pp. 87-97, 2010.
65. I. Klein, M. Sanchez-Alavez, I. Tabarean et al., "AdipoR1 and 2 are expressed on warm sensitive neurons of the hypothalamic preoptic area and contribute to central hyperthermic effects of adiponectin, " Brain Research, vol. 1423, pp. 1-9, 2011.
66. A. Coope, M. Milanski, E. P. Aráujo et al., "AdipoR1 mediates the anorexigenic and insulin/leptin-like actions of adiponectin in the hypothalamus, " FEBS Letters, vol. 582, no. 10, pp. 1471-1476, 2008.
67. N. Kubota, W. Yano, T. Kubota et al., "Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake, " Cell Metabolism, vol. 6, no. 1, pp. 55-68, 2007.
68. E. Guillod-Maximin, A. F. Roy, C. M. Vacher et al., "Adiponectin receptors are expressed in hypothalamus and colocalized with proopiomelanocortin and neuropeptide Y in rodent arcuate neurons, " Journal of Endocrinology, vol. 200, no. 1, pp. 93-105, 2009.
69. T. Kadowaki, T. Yamauchi, and N. Kubota, "The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS, " FEBS Letters, vol. 582, no. 1, pp. 74-80, 2008.
70. H. Shimizu, T. Tsuchiya, N. Sato, Y. Shimomura, I. Kobayashi, and M. Mori, "Troglitazone reduces plasma leptin concentration but increases hunger in NIDDM patients, " Diabetes Care, vol. 21, no. 9, pp. 1470-1474, 1998.
71. M. Lehrke and M. A. Lazar, "The many faces of PPAR, " Cell, vol. 123, no. 6, pp. 993-999, 2005.
72. P. G. F. Quaresma, N. Reencober, T. M. Zanotto et al., "Pioglitazone treatment increases food intake and decreases energy expenditure partially via hypothalamic adiponectin/adipoR1/AMPK pathway, " International Journal of Obesity, vol. 40, no. 1, pp. 138-146, 2016.
73. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, "Ghrelin is a growth-hormone-releasing acylated peptide fromstomach, " Nature, vol. 402, no. 6762, pp. 656-660, 1999.
74. A. M. Wren, L. J. Seal, M. A. Cohen et al., "Ghrelin enhances appetite and increases food intake in humans, " Journal of Clinical Endocrinology andMetabolism, vol. 86, no. 12, pp. 5992-5995, 2001.
75. A. M. Wren, C. J. Small, H. L. Ward et al., "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion, " Endocrinology, vol. 141, no. 11, pp. 4325-4328, 2000.
76. K. Kirsz andD. A. Zieba, "Ghrelin-mediated appetite regulation in the central nervous system, " Peptides, vol. 32, no. 11, pp. 2256-2264, 2011.
77. M. Lopez, R. Lage, A. K. Saha et al., "Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin, " Cell Metabolism, vol. 7, no. 5, pp. 389-399, 2008.
78. S. Gao, N. Casals, W. Keung, T. H. Moran, andG. D. Lopaschuk, "Differential effects of central ghrelin on fatty acid metabolism in hypothalamic ventral medial and arcuate nuclei, " Physiology and Behavior, vol. 118, pp. 165-170, 2013.
79. C. T. Lim, B. Kola, D. Feltrin et al., "Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism, " Molecular and Cellular Endocrinology, vol. 365, no. 2, pp. 303-308, 2013.
80. P. A. Bennett, G. B. Thomas, A. D. Howard et al., "Hypothalamic growth hormone secretagogue-receptor (GHS-R) expression is regulated by growth hormone in the rat, " Endocrinology, vol. 138, no. 11, pp. 4552-4557, 1997.
81. Z. B. Andrews, "Central mechanisms involved in the orexigenic actions of ghrelin, " Peptides, vol. 32, no. 11, pp. 2248-2255, 2011.
82. D. Kohno, H. Sone, Y. Minokoshi, and T. Yada, "Ghrelin raises Ca2+ via AMPK in hypothalamic arcuate nucleus NPY neurons, " Biochemical and Biophysical Research Communications, vol. 366, no. 2, pp. 388-392, 2008.
83. Y. Yang, D. Atasoy, H. H. Su, and S. M. Sternson, "Hunger states switch a flip-flop memory circuit via a synaptic AMPKdependent positive feedback loop, " Cell, vol. 146, no. 6, pp. 992-1003, 2011.
84. N. Jamshidi and D. A. Taylor, "Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats, " British Journal of Pharmacology, vol. 134, no. 6, pp. 1151-1154, 2001.
85. B. Poirier, J.-P. Bidouard, C. Cadrouvele et al., "The anti-obesity effect of rimonabant is associated with an improved serum lipid profile, " Diabetes, Obesity and Metabolism, vol. 7, no. 1, pp. 65-72, 2005.
86. T. C. Kirkhamand C. M. Williams, "Endocannabinoid receptor antagonists: potential for obesity treatment, " Treatments in Endocrinology, vol. 3, no. 6, pp. 345-360, 2004.
87. B. Kola, E. Hubina, S. A. Tucci et al., "Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase, " The Journal of Biological Chemistry, vol. 280, no. 26, pp. 25196-25201, 2005.
88. A. Borgquist, C. Meza, and E. J. Wagner, "The role of AMPactivated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis, " American Journal of Physiology-Endocrinology and Metabolism, vol. 308, no. 6, pp. E482-E495, 2015.
89. V. Di Marzo, S. K. Goparaju, L. Wang et al., "Leptin-regulated endocannabinoids are involved in maintaining food intake, " Nature, vol. 410, no. 6830, pp. 822-825, 2001.
90. B. Kola, I. Farkas, M. Christ-Crain et al., "The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system, " PLoS ONE, vol. 3, no. 3, Article ID e1797, 2008.
91. P. A. Tataranni, D. E. Larson, S. Snitker, J. B. Young, J. P. Flatt, and E. Ravussin, "Effects of glucocorticoids on energy metabolism and food intake in humans, " American Journal of Physiology-Endocrinology andMetabolism, vol. 271, no. 2, part 1, pp. E317-E325, 1996.
92. M. Christ-Crain, B. Kola, F. Lolli et al., "AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: A novel mechanism in Cushing's syndrome, " The FASEB Journal, vol. 22, no. 6, pp. 1672-1683, 2008.
93. S. Di, R. Malcher-Lopes, V. L. Marcheselli, N. G. Bazan, and J. G. Tasker, "Rapid glucocorticoid-mediated endocannabinoid release and opposing regulation of glutamate and-aminobutyric acid inputs to hypothalamic magnocellular neurons, " Endocrinology, vol. 146, no. 10, pp. 4292-4301, 2005.
94. M. Scerif, T. Füzesi, J. D. Thomas et al., "CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus, " Journal of Endocrinology, vol. 219, no. 1, pp. 79-88, 2013.
95. H. Shimizu, H. Arima, M. Watanabe et al., "Glucocorticoids increase neuropeptide Y and agouti-related peptide gene expression via adenosine monophosphate-activated protein kinase signaling in the arcuate nucleus of rats, " Endocrinology, vol. 149, no. 9, pp. 4544-4553, 2008.
96. L. Liu, Z. Song, H. Jiao, and H. Lin, "Glucocorticoids increase NPY gene expression via hypothalamic AMPK signaling in broiler chicks, " Endocrinology, vol. 155, no. 6, pp. 2190-2198, 2014.
97. R. J. McCrimmon, X. Fan, Y. Ding, W. Zhu, R. J. Jacob, and R. S. Sherwin, "Potential role for AMP-activated protein kinase in hypoglycemia sensing in the ventromedial hypothalamus, " Diabetes, vol. 53, no. 8, pp. 1953-1958, 2004.
98. M.-S. Kim, J.-Y. Park, C. Namkoong et al., "Anti-obesity effects of-lipoic acidmediated by suppression of hypothalamicAMPactivated protein kinase, " Nature Medicine, vol. 10, no. 7, pp. 727-733, 2004.
99. T. Alquier, J. Kawashima, Y. Tsuji, and B. B. Kahn, "Role of hypothalamic adenosine 5-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia, " Endocrinology, vol. 148, no. 3, pp. 1367-1375, 2007.
100. R. J. McCrimmon, M. Shaw, X. Fan et al., "Key Role for AMPactivated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia, " Diabetes, vol. 57, no. 2, pp. 444-450, 2008.
101. X. Fan, Y. Ding, S. Brown et al., "HypothalamicAMP-activated protein kinase activation with AICAR amplifies counterregulatory responses to hypoglycemia in a rodentmodel of type 1 diabetes, " American Journal of Physiology-Regulatory Integrative and Comparative Physiology, vol. 296, no. 6, pp. R1702-R1708, 2009.
102. S. R. Salpeter, J. M. E. Walsh, T. M. Ormiston, E. Greyber, N. S. Buckley, and E. E. Salpeter, "Meta-analysis: effect of hormonereplacement therapy on components of themetabolic syndrome in postmenopausal women, " Diabetes, Obesity and Metabolism, vol. 8, no. 5, pp. 538-554, 2006.
103. F. S. J. De Souza, S. Nasif, R. López-Leal, D. H. Levi, M. J. Low, and M. Rubinsten, "The estrogen receptor colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conservedmotif present in the neuron-specific enhancer nPE2, " European Journal of Pharmacology, vol. 660, no. 1, pp. 181-187, 2011.
104. T. A. Roepke, "Oestrogen modulates hypothalamic control of energy homeostasis through multiple mechanisms, " Journal of Neuroendocrinology, vol. 21, no. 2, pp. 141-150, 2009.
105. P. B. Martnez de Morentin, I. González-Garcá, L. Martins et al., "Estradiol regulates brown adipose tissue thermogenesis viahypothalamic AMPK, " CellMetabolism, vol. 20, no. 1, pp. 41-53, 2014.
106. Y.-C. Tsai, Y.-M. Lee, K.-K. Lam, Y.-C. Wu, M.-H. Yen, and P.-Y. Cheng, "The role of hypothalamic AMP-activated protein kinase in ovariectomy-induced obesity in rats, " Menopause, vol. 17, no. 6, pp. 1194-1200, 2010.
107. B. A. Ibrahim, P. Tamrakar, A. D. Gujar, A. K. Cherian, and K. P. Briski, "Caudal fourth ventricular administration of the AMPK activator 5-aminoimidazole-4-carboxamide-riboside regulates glucose and counterregulatory hormone profiles, dorsal vagal complex metabolosensory neuron function, and hypothalamic fos expression, " Journal of Neuroscience Research, vol. 91, no. 9, pp. 1226-1238, 2013.
108. P. Tamrakar and K. P. Briski, "Estradiol regulation of hypothalamic astrocyte adenosine 5-monophosphate-activated protein kinase activity: role of hindbrain catecholamine signaling, " Brain Research Bulletin, vol. 110, pp. 47-53, 2015.
109. P. B. Martnez de Morentin, R. Lage, I. González-Garcá et al., "Pregnancy induces resistance to the anorectic effect of hypothalamic malonyl-COA and the thermogenic effect of hypothalamic AMPK inhibition in female rats, " Endocrinology, vol. 156, no. 3, pp. 947-960, 2015.
110. Y. Minokoshi, Y.-B. Kim, O. D. Peroni et al., "Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase, " Nature, vol. 415, no. 6869, pp. 339-343, 2002.
111. U. Andersson, K. Filipsson, C. R. Abbott et al., "AMP-activated protein kinase plays a role in the control of food intake, " The Journal of Biological Chemistry, vol. 279, no. 13, pp. 12005-12008, 2004.
112. M. Tanida, N. Yamamoto, T. Shibamoto, and K. Rahmouni, "Involvement of hypothalamicAMP-activated protein kinase in leptin-induced sympathetic nerve activation, " PLoS ONE, vol. 8, no. 2, article e56660, 2013.
113. M. A. Cowley, J. L. Smart, M. Rubinstein et al., "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus, " Nature, vol. 411, no. 6836, pp. 480-484, 2001.
114. S. Obici, B. B. Zhang, G. Karkanias, and L. Rossetti, "Hypothalamic insulin signaling is required for inhibition of glucose production, " Nature Medicine, vol. 8, no. 12, pp. 1376-1382, 2002.
115. C. S. Solon, D. Franci, L. M. Ignacio-Souza et al., "Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats, " Amino Acids, vol. 42, no. 6, pp. 2403-2410, 2012.
116. C. Namkoong, S. K. Min, G. J. Pil et al., "Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats, " Diabetes, vol. 54, no. 1, pp. 63-68, 2005.
117. S.-M. Han, C. Namkoong, P. G. Jang et al., "Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats, " Diabetologia, vol. 48, no. 10, pp. 2170-2178, 2005.
118. I. Shimizu, M. Hirota, C. Ohboshi, and K. Shima, "Identification and localization of glucagon-like peptide-1 and its receptor in rat brain, " Endocrinology, vol. 121, no. 3, pp. 1076-1082, 1987.
119. M. D. Turton, D. O'Shea, I. Gunn et al., "A role for glucagon-like peptide-1 in the central regulation of feeding, " Nature, vol. 379, no. 6560, pp. 69-72, 1996.
120. A. P. Goldstone, I. Morgan, J. G. Mercer et al., "Effect of leptin on hypothalamic GLP-1 peptide and brain-stem preproglucagon mRNA, " Biochemical and Biophysical Research Communications, vol. 269, no. 2, pp. 331-335, 2000.
121. V. Hurtado-Carneiro, C. Sanz, I. Roncero, P. Vazquez, E. Blazquez, and E. Alvarez, "Glucagon-like peptide 1 (GLP-1) can reverse AMP-activated protein kinase (AMPK) and S6 kinase (P70S6K) activities induced by fluctuations in glucose levels in hypothalamic areas involved in feeding behaviour, " Molecular Neurobiology, vol. 45, no. 2, pp. 348-361, 2012.
122. P.-E. Poleni, S. Akieda-Asai, S. Koda et al., "Possible involvement of melanocortin-4-receptor and AMP-activated protein kinase in the interaction of glucagon-like peptide-1 and leptin on feeding in rats, " Biochemical and Biophysical Research Communications, vol. 420, no. 1, pp. 36-41, 2012.
123. D. Beiroa, M. Imbernon, R. Gallego et al., "GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK, " Diabetes, vol. 63, no. 10, pp. 3346-3358, 2014.
124. M. López, C. Diéguez, and R. Nogueiras, "Hypothalamic GLP-1: The control of BAT thermogenesis and browning of white fat, " Adipocyte, vol. 4, no. 2, pp. 141-145, 2015.
125. N. Fujii, T. Hayashi, M. F. Hirshman et al., "Exercise induces isoform-specific increase in 5' AMP-activated protein kinase activity in human skeletal muscle, " Biochemical and Biophysical Research Communications, vol. 273, no. 3, pp. 1150-1155, 2000.
126. U. Andersson, J. T. Treebak, J. N. Nielsen et al., "Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity, " Biochemical and Biophysical Research Communications, vol. 329, no. 2, pp. 719-725, 2005.
127. S. Park, S. J. Jin, W. J. Dong, and M. H. Sang, "Exercise enhances insulin and leptin signaling in the cerebral cortex and hypothalamus during dexamethasone-induced stress in diabetic rats, " Neuroendocrinology, vol. 82, no. 5-6, pp. 282-293, 2006.
128. E. R. Ropelle, M. F. A. Fernandes, M. B. S. Flores et al., "Central exercise action increases the AMPK and mTOR response to leptin, " PLoS ONE, vol. 3, no. 12, Article IDe3856, 2008.
129. M. Claret, M. A. Smith, R. L. Batterham et al., "AMPK is essential for energy homeostasis regulation and glucose sensing by POMCandAgRP neurons, "The Journal of Clinical Investigation, vol. 117, no. 8, pp. 2325-2336, 2007.
130. D. G. Hardie, F. A. Ross, and S. A. Hawley, "AMPK: A nutrient and energy sensor that maintains energy homeostasis, " Nature Reviews Molecular Cell Biology, vol. 13, no. 4, pp. 251-262, 2012.
131. D. Kohno, H. Sone, S. Tanaka, H. Kurita, D. Gantulga, and T. Yada, "AMP-activated protein kinase activates neuropeptide Y neurons in the hypothalamic arcuate nucleus to increase food intake in rats, " Neuroscience Letters, vol. 499, no. 3, pp. 194-198, 2011.
132. T. M. Loftus, D. E. Jaworsky, C. L. Frehywot et al., "Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors, " Science, vol. 288, no. 5475, pp. 2379-2381, 2000.
133. J. L. Beverly and R. J. Martin, "Influence of fatty acid oxidation in lateral hypothalamus on food intake and body composition, " American Journal of Physiology-Regulatory Integrative and Comparative Physiology, vol. 261, no. 2, part 2, pp. R339-R343, 1991.
134. T. R. Kasser and R. J. Martin, "Induction of ventrolateral hypothalamic fatty acid oxidation in diabetic rats, " Physiology and Behavior, vol. 36, no. 2, pp. 385-388, 1986.
135. Z. Hu, S. H. Cha, S. Chohnan, andM. D. Lane, "Hypothalamic malonyl-CoA as a mediator of feeding behavior, " Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 22, pp. 12624-12629, 2003.
136. S. Obici, Z. Feng, A. Arduini, R. Conti, and L. Rossetti, "Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production, " Nature Medicine, vol. 9, no. 6, pp. 756-761, 2003.
137. Z. Hu, Y. Dai, M. Prentki, S. Chohnan, andM. D. Lane, "A role for hypothalamic malonyl-CoA in the control of food intake, " The Journal of Biological Chemistry, vol. 280, no. 48, pp. 39681-39683, 2005.
138. M. J. Wolfgang and M. D. Lane, "The role of hypothalamic malonyl-CoA in energy homeostasis, " Journal of Biological Chemistry, vol. 281, no. 49, pp. 37265-37269, 2006.
139. M. J. Wolfgang, S. H. Cha, D. S. Millington et al., "Brainspecific carnitine palmitoyl-transferase-1c: role in CNS fatty acid metabolism, food intake, and body weight, " Journal of Neurochemistry, vol. 105, no. 4, pp. 1550-1559, 2008.
140. S. Ramrez, L. Martins, J. Jacas et al., "Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin, " Diabetes, vol. 62, no. 7, pp. 2329-2337, 2013.
141. R. Lage, M. J. Vázquez, L. Varela et al., "Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender, " The FASEB Journal, vol. 24, no. 8, pp. 2670-2679, 2010.
142. Z. Song, L. Liu, Y. Yue et al., "Fasting alters protein expression of AMP-activated protein kinase in the hypothalamus of broiler chicks (Gallus gallus domesticus), " General and Comparative Endocrinology, vol. 178, no. 3, pp. 546-555, 2012.
143. L. Lei and Z. Lixian, "Effect of 24 h fasting on gene expression of AMPK, appetite regulation peptides and lipometabolism related factors in the hypothalamus of broiler chicks, " Asian-Australasian Journal of Animal Sciences, vol. 25, no. 9, pp. 1300-1308, 2012.
144. D. Cota, K. Proulx, K. A. Blake Smith et al., "Hypothalamic mTOR signaling regulates food intake, " Science, vol. 312, no. 5775, pp. 927-930, 2006.
145. K. Inoki, T. Zhu, and K.-L. Guan, "TSC2 mediates cellular energy response to control cell growth and survival, " Cell, vol. 115, no. 5, pp. 577-590, 2003.
146. M. P. Byfield, J. T. Murray, and J. M. Backer, "hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase, " The Journal of Biological Chemistry, vol. 280, no. 38, pp. 33076-33082, 2005.
147. Y. Dagon, E. Hur, B. Zheng, K. Wellenstein, L. C. Cantley, and B. B. Kahn, "P70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake, " Cell Metabolism, vol. 16, no. 1, pp. 104-112, 2012.
148. E. R. Ropelle, J. R. Pauli, M. F. A. Fernandes et al., "A central role for neuronal AMP-activated protein kinase (AMPK) and mammalian target of rapamyein (mTOR) in high-protein dietinduced weight loss, " Diabetes, vol. 57, no. 3, pp. 594-605, 2008.
149. B. B. Lowell and B. M. Spiegelman, "Towards a molecular understanding of adaptive thermogenesis, " Nature, vol. 404, no. 6778, pp. 652-660, 2000.
150. M. N. Perkins, N. J. Rothwell, M. J. Stock, and T. W. Stone, "Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus, " Nature, vol. 289, no. 5796, pp. 401-402, 1981.
151. S. J. Holt, H. V. Wheal, and D. A. York, "Hypothalamic control of brown adipose tissue in Zucker lean and obese rats. Effect of electrical stimulation of the ventromedial nucleus and other hypothalamic centres, " Brain Research, vol. 405, no. 2, pp. 227-233, 1987.
152. T. Yoshida and G. A. Bray, "Catecholamine turnover in rats with ventromedial hypothalamic lesions, " American Journal of Physiology, vol. 246, no. 4, part 2, pp. R558-R565, 1984.
153. M. Saito, Y. Minokoshi, and T. Shimazu, "Ventromedial hypothalamic stimulation accelerates norepinephrine turnover in brown adipose tissue of rats, " Life Sciences, vol. 41, no. 2, pp. 193-197, 1987.
154. T. Hugie, I. Halvorson, and J. Thornhill, "Brown adipose tissue temperature responses following electrical stimulation of ventromedial hypothalamic and lateral preoptic areas or after norepinephrine infusion to long evans or sprague-dawley rats, " Brain Research, vol. 575, no. 1, pp. 57-62, 1992.
155. K. W. Kim, L. Zhao, J. Donato Jr. et al., "Steroidogenic factor 1 directs programs regulating diet-induced thermogenesis and leptin action in the ventral medial hypothalamic nucleus, " Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 26, pp. 10673-10678, 2011.
156. K. W. Kim, J. Donato Jr., E. D. Berglund et al., "FOXO1 in the ventromedial hypothalamus regulates energy balance, " The Journal of Clinical Investigation, vol. 122, no. 7, pp. 2578-2589, 2012.
157. S. F. Morrison, "RVLM and raphe differentially regulate sympathetic outflows to splanchnic and brown adipose tissue, " American Journal of Physiology-Regulatory Integrative and Comparative Physiology, vol. 276, no. 4, pp. R962-R973, 1999.
158. T. Uno and M. Shibata, "Role of inferior olive and thoracic IML neurons in nonshivering thermogenesis in rats, " American Journal of Physiology-Regulatory Integrative and Comparative Physiology, vol. 280, no. 2, pp. R536-R546, 2001.
159. M. Shibata, T. Uno, andM. Hashimoto, "Disinhibition of lower midbrain neurons enhances non-shivering thermogenesis in anesthetized rats, " Brain Research, vol. 833, no. 2, pp. 242-250, 1999.
160. M. López, L. Varela, M. J. Vázquez et al., "Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance, " Nature Medicine, vol. 16, no. 9, pp. 1001-1008, 2010.
161. A. J. Whittle, S. Carobbio, L. Martins et al., "BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions, " Cell, vol. 149, no. 4, pp. 871-885, 2012.
162. P. Seoane-Collazo, P. B. Martnez de Morentin, J. Fernø, C. Diéguez, R. Nogueiras, and M. López, "Nicotine improves obesity and hepatic steatosis and ERstress in diet-induced obese male rats, " Endocrinology, vol. 155, no. 5, pp. 1679-1689, 2014.
163. C. S. Yang, C. K. L. Lam, M. Chari et al., "Hypothalamic AMP-activated protein kinase regulates glucose production, " Diabetes, vol. 59, no. 10, pp. 2435-2443, 2010.
164. M. Ikegami, H. Ikeda, T. Ohashi et al., "Olanzapine increases hepatic glucose production through the activation of hypothalamic adenosine 5-monophosphate-activated protein kinase, " Diabetes, Obesity and Metabolism, vol. 15, no. 12, pp. 1128-1135, 2013.
165. B. Brunmair, K. Staniek, F. Gras et al., "Thiazolidinediones, like metformin, inhibit respiratory complex I: A common mechanism contributing to their antidiabetic actions" Diabetes, vol. 53, no. 4, pp. 1052-1059, 2004.
166. L. G. D. Fryer, A. Parbu-Patel, andD. Carling, "The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways, " Journal of Biological Chemistry, vol. 277, no. 28, pp. 25226-25232, 2002.
167. W. Sun, T.-S. Lee, M. Zhu et al., "Statins activate AMP-activated protein kinase in vitro and in vivo, " Circulation, vol. 114, no. 24, pp. 2655-2662, 2006.