Review

Hypothalamic AMPK: a canonical regulator of whole-body energy balance

  • Nature Reviews Endocrinology 12, 421432 (2016)
  • doi:10.1038/nrendo.2016.67
  • Download Citation
Published online:

Abstract

AMP-activated protein kinase (AMPK) has a major role in the modulation of energy balance. AMPK is activated in conditions of low energy, increasing energy production and reducing energy consumption. The AMPK pathway is a canonical route regulating energy homeostasis by integrating peripheral signals, such as hormones and metabolites, with neuronal networks. Current evidence has implicated AMPK in the hypothalamus and hindbrain with feeding, brown adipose tissue thermogenesis and browning of white adipose tissue, through modulation of the sympathetic nervous system, as well as glucose homeostasis. Interestingly, several potential antiobesity and/or antidiabetic agents, some of which are currently in clinical use such as metformin and liraglutide, exert some of their actions by acting on AMPK. Furthermore, the orexigenic and weight-gain effects of commonly used antipsychotic drugs are also mediated by hypothalamic AMPK. Overall, this evidence suggests that hypothalamic AMPK signalling is an interesting target for drug development, but is this approach feasible? In this Review we discuss the current understanding of hypothalamic AMPK and its role in the central regulation of energy balance and metabolism.

  • Subscribe to Nature Reviews Endocrinology for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    , , & AMP-activated protein kinase: nature's energy sensor. Nat. Chem. Biol. 7, 512–518 (2011).

  2. 2.

    , & AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell. Biol. 13, 251–262 (2012).

  3. 3.

    AMPK — sensing energy while talking to other signaling pathways. Cell Metab. 20, 939–952 (2014).

  4. 4.

    , & The action of nucleotides in the disruptive phosphorylation of glycogen. J. Biol. Chem. 123, 381–383 (1938).

  5. 5.

    , & Studies on heart phosphofructokinase. Purification, crystallization, and properties of sheep heart phosphofructokinase. J. Biol. Chem. 241, 1512–1521 (1966).

  6. 6.

    & Studies on heart phosphofructokinase. Binding of cyclic adenosine 3′,5′-monophosphate, adenosine monophosphate, and of hexose phosphates to the enzyme. Biochemistry 11, 1478–1486 (1972).

  7. 7.

    , & Adenylate as a metabolic regulator. Effect on yeast phosphofructokinase kinetics. J. Biol. Chem. 239, 3619–3622 (1964).

  8. 8.

    , & A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217–222 (1987).

  9. 9.

    , & Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by the adenylate energy charge. J. Biol. Chem. 255, 2308–2314 (1980).

  10. 10.

    , , & Activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by adenosine 5′-monophosphate. Biochem. Biophys. Res. Commun. 132, 497–504 (1985).

  11. 11.

    , & The AMP-activated protein kinase — a multisubstrate regulator of lipid metabolism. Trends Biochem. Sci. 14, 20–23 (1989).

  12. 12.

    , , , & Central AMPK contributes to sleep homeostasis in mice. Neuropharmacology 57, 369–374 (2009).

  13. 13.

    & Beyond energy homeostasis: the expanding role of AMP-activated protein kinase in regulating metabolism. Cell Metab. 21, 799–804 (2015).

  14. 14.

    AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels. Annu. Rev. Nutr. 34, 31–55 (2014).

  15. 15.

    et al. AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nat. Cell Biol. 17, 1304–1316 (2015).

  16. 16.

    et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007).

  17. 17.

    et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233 (2011).

  18. 18.

    & Predominant α2/β2/γ3 AMPK activation during exercise in human skeletal muscle. J. Physiol. 577, 1021–1032 (2006).

  19. 19.

    et al. Different expression of the catalytic alpha subunits of the AMP activated protein kinase — an immunohistochemical study in human tissue. Histol. Histopathol. 26, 589–596 (2011).

  20. 20.

    et al. Chemoproteomic analysis of intertissue and interspecies isoform diversity of AMP-activated protein kinase (AMPK). J. Biol. Chem. 288, 35904–35912 (2013).

  21. 21.

    , , , & Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem. J. 346, 659–669 (2000).

  22. 22.

    et al. Molecular cloning, genomic organization, and mapping of PRKAG2, a heart abundant gamma2 subunit of 5′-AMP-activated protein kinase, to human chromosome 7q36. Genomics 70, 258–263 (2000).

  23. 23.

    et al. AMPKα modulation in cancer progression: multilayer integrative analysis of the whole transcriptome in Asian gastric cancer. Cancer Res. 72, 2512–2521. (2012).

  24. 24.

    , , & AMP-activated protein kinase α 2 isoform suppression in primary breast cancer alters ampk growth control and apoptotic signaling. Genes Cancer 4, 3–14 (2013).

  25. 25.

    , et al. Hypoxia, AMPK activation and uterine artery vasoreactivity. J. Physiol. 594, 1357–1369 (2016).

  26. 26.

    et al. Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J. Neurochem. 72, 1707–1716 (1999).

  27. 27.

    , , & AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation. J. Mol. Neurosci. 17, 45–58 (2001).

  28. 28.

    et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

  29. 29.

    et al. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J. Biol. Chem. 279, 19970–19976 (2004).

  30. 30.

    et al. AMPK β1 deletion reduces appetite, preventing obesity and hepatic insulin resistance. J. Biol. Chem. 285, 115–122 (2010).

  31. 31.

    , , & AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 18, 556–566 (2013).

  32. 32.

    et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

  33. 33.

    The LKB1–AMPK pathway — friend or foe in cancer? Cancer Cell 23, 131–132 (2013).

  34. 34.

    et al. Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

  35. 35.

    et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl Acad. Sci. USA 101, 3329–3335 (2004).

  36. 36.

    , & LKB1-dependent signaling pathways. Annu. Rev. Biochem. 75, 137–163 (2006).

  37. 37.

    , , , & Structure of the LKB1–STRAD–MO25 complex reveals an allosteric mechanism of kinase activation. Science 326, 1707–1711 (2009).

  38. 38.

    et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).

  39. 39.

    et al. The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J. Biol. Chem. 280, 29060–29066 (2005).

  40. 40.

    et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005).

  41. 41.

    et al. AMPK is a direct adenylate charge-regulated protein kinase. Science 332, 1433–1435 (2011).

  42. 42.

    , & Differential regulation by AMP and ADP of AMPK complexes containing different γ subunit isoforms. Biochem. J. 473, 189–199 (2016).

  43. 43.

    , , & 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C α and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421–425 (1995).

  44. 44.

    , , , & Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139–148 (2007).

  45. 45.

    et al. Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. J. Biol. Chem. 281, 5335–5340 (2006).

  46. 46.

    et al. Regulation of AMP-activated protein kinase by multisite phosphorylation in response to agents that elevate cellular cAMP. J. Biol. Chem. 281, 36662–36672 (2006).

  47. 47.

    et al. PKA phosphorylates and inactivates AMPKα to promote efficient lipolysis. EMBO J. 29, 469–481 (2010).

  48. 48.

    et al. p70S6 kinase phosphorylates AMPK on serine 491 to mediate leptin's effect on food intake. Cell Metab. 16, 104–112 (2012).

  49. 49.

    et al. Phosphorylation by Akt within the ST loop of AMPK-α1 down-regulates its activation in tumour cells. Biochem. J. 459, 275–287 (2014).

  50. 50.

    et al. Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J. 27, 1537–1548 (2008).

  51. 51.

    , , & AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

  52. 52.

    et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

  53. 53.

    , , & AMPK, insulin resistance, and the metabolic syndrome. J. Clin. Invest. 123, 2764–2772 (2013).

  54. 54.

    et al. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351, 275–281 (2016).

  55. 55.

    , , & AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005).

  56. 56.

    , & Monitoring energy balance: metabolites of fatty acid synthesis as hypothalamic sensors. Annu. Rev. Biochem. 74, 515–534 (2005).

  57. 57.

    , & Hypothalamic fatty acid metabolism: a housekeeping pathway that regulates food intake. Bioessays 29, 248–261 (2007).

  58. 58.

    , , & AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol. Med. 14, 539–549 (2008).

  59. 59.

    , , , & Regulation of brown fat by AMP-activated protein kinase. Trends Mol. Med. 21, 571–579 (2015).

  60. 60.

    et al. Hypothalamic AMP-activated protein kinase as a mediator of whole body energy balance. Rev. Endocr. Metab. Disord. 12, 127–140 (2011).

  61. 61.

    & Recent insights into the role of hypothalamic AMPK signaling cascade upon metabolic control. Front. Neurosci. 6, 185 (2012).

  62. 62.

    et al. Activation of AMP-activated protein kinase within the ventromedial hypothalamus amplifies counterregulatory hormone responses in rats with defective counterregulation. Diabetes 55, 1755–1760 (2006).

  63. 63.

    et al. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons. J. Clin. Invest. 117, 2325–2336 (2007).

  64. 64.

    et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 7, 389–399 (2008).

  65. 65.

    et al. Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat. Med. 16, 1001–1008 (2010).

  66. 66.

    et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).

  67. 67.

    et al. Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-α2 subunit. Diabetes 53, 2242–2249 (2004).

  68. 68.

    , , & Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003 (2011).

  69. 69.

    et al. Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice. Diabetes 60, 735–745 (2011).

  70. 70.

    et al. BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149, 871–885 (2012).

  71. 71.

    et al. Nicotine induces negative energy balance through hypothalamic AMP-activated protein kinase. Diabetes 61, 807–817 (2012).

  72. 72.

    et al. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20, 41–53 (2014).

  73. 73.

    et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014).

  74. 74.

    et al. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc. Natl Acad. Sci. USA 104, 19285–19290 (2007).

  75. 75.

    et al. Anti-obesity effects of α-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat. Med. 10, 727–733 (2004).

  76. 76.

    et al. Diet-induced obesity alters AMP kinase activity in hypothalamus and skeletal muscle. J. Biol. Chem. 281, 18933–18941 (2006).

  77. 77.

    & Differential effects of exercise and dietary docosahexaenoic acid on molecular systems associated with control of allostasis in the hypothalamus and hippocampus. Neuroscience 168, 130–137 (2010).

  78. 78.

    et al. Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling. J. Endocrinol. 198, 157–168 (2008).

  79. 79.

    & Central lactate metabolism suppresses food intake via the hypothalamic AMP kinase/malonyl-CoA signaling pathway. Biochem. Biophys. Res. Commun. 386, 212–216 (2009).

  80. 80.

    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 57, 594–605 (2008).

  81. 81.

    , , & Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc. Natl Acad. Sci. USA 100, 12624–12629 (2003).

  82. 82.

    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 55, 1327–1336 (2006).

  83. 83.

    et al. Thiamine deficiency induces anorexia by inhibiting hypothalamic AMPK. Neuroscience 267, 102–113 (2014).

  84. 84.

    et al. Leptin activates hypothalamic acetyl-CoA carboxylase to inhibit food intake. Proc. Natl Acad. Sci. USA 104, 17358–17363 (2007).

  85. 85.

    et al. Enhanced hypothalamic AMP-activated protein kinase activity contributes to hyperphagia in diabetic rats. Diabetes 54, 63–68 (2005).

  86. 86.

    et al. Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistance. Mol. Metab. 4, 961–970 (2015).

  87. 87.

    , , , & Acute effects of glucagon-like peptide-1 on hypothalamic neuropeptide and AMP activated kinase expression in fasted rats. Endocr. J. 55, 867–874 (2008).

  88. 88.

    , & Coinjection of CCK and leptin reduces food intake via increased CART/TRH and reduced AMPK phosphorylation in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 306, E1284–E1291 (2014).

  89. 89.

    et al. Ciliary neurotrophic factor suppresses hypothalamic AMP-kinase signaling in leptin-resistant obese mice. Endocrinology 147, 3906–3914 (2006).

  90. 90.

    et al. Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes 59, 2772–2780 (2010).

  91. 91.

    et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 6, 55–68 (2007).

  92. 92.

    , , , & Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase–acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus. Mol. Cell. Biochem. 344, 109–115 (2010).

  93. 93.

    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 149, 4544–4553 (2008).

  94. 94.

    et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE 3, e1797 (2008).

  95. 95.

    et al. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals. Nature 454, 846–851 (2008).

  96. 96.

    et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 24, 2670–2679 (2010).

  97. 97.

    et al. Central resistin regulates hypothalamic and peripheral lipid metabolism in a nutritional-dependent fashion. Endocrinology 149, 4534–4543 (2008).

  98. 98.

    et al. Nicotine improves obesity and hepatic steatosis and ER stress in diet-induced obese male rats. Endocrinology 155, 1679–1689 (2014).

  99. 99.

    et al. Olanzapine depot formulation in rat: a step forward in modelling antipsychotic-induced metabolic adverse effects. Int. J. Neuropsychopharmacol. 17, 91–104 (2014).

  100. 100.

    , , , & Olanzapine-activated AMPK signaling in the dorsal vagal complex is attenuated by histamine H1 receptor agonist in female rats. Endocrinology 155, 4895–4904 (2014).

  101. 101.

    , & Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).

  102. 102.

    et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 7, 377–388 (2008).

  103. 103.

    et al. The central Sirtuin 1/p53 pathway is essential for the orexigenic action of ghrelin. Diabetes 60, 1177–1185 (2011).

  104. 104.

    et al. Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of ghrelin. Diabetes 62, 2329–2337 (2013).

  105. 105.

    , & Brain lipid sensing and the neural control of energy balance. Mol. Cell. Endocrinol. 418, 3–8 (2015).

  106. 106.

    , , , & Differential effects of central ghrelin on fatty acid metabolism in hypothalamic ventral medial and arcuate nuclei. Physiol. Behav. 118, 165–170 (2013).

  107. 107.

    et al. AMP-activated protein kinase is physiologically regulated by inositol polyphosphate multikinase. Proc. Natl Acad. Sci. USA 109, 616–620 (2012).

  108. 108.

    , , & Convergence of IPMK and LKB1–AMPK signaling pathways on metformin action. Mol. Endocrinol. 28, 1186–1193 (2014).

  109. 109.

    et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 10, 366–378 (2009).

  110. 110.

    et al. Profound obesity secondary to hyperphagia in mice lacking kinase suppressor of ras 2. Obesity (Silver Spring) 19, 1010–1018 (2011).

  111. 111.

    et al. PAS kinase is a nutrient and energy sensor in hypothalamic areas required for the normal function of AMPK and mTOR/S6K1. Mol. Neurobiol. 50, 314–326 (2014).

  112. 112.

    , , & Dorsal hindbrain 5′-adenosine monophosphate-activated protein kinase as an intracellular mediator of energy balance. Endocrinology 150, 2175–2182 (2009).

  113. 113.

    et al. Endogenous leptin signaling in the caudal nucleus tractus solitarius and area postrema is required for energy balance regulation. Cell Metab. 11, 77–83 (2010).

  114. 114.

    et al. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab. 13, 320–330 (2011).

  115. 115.

    , , , & Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat. Neuroscience 314, 35–46 (2016).

  116. 116.

    & Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).

  117. 117.

    , & Central eural regulation of brown adipose tissue thermogenesis and energy expenditure. Cell Metab. 19, 741–756 (2014).

  118. 118.

    et al. The brain and brown fat. Ann. Med. 47, 150–168 (2015).

  119. 119.

    , , & Activation of brown adipose tissue thermogenesis by the ventromedial hypothalamus. Nature 289, 401–402 (1981).

  120. 120.

    et al. The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity. J. Clin. Invest. 111, 91–98 (2003).

  121. 121.

    et al. Neuronal protein tyrosine phosphatase 1B deficiency results in inhibition of hypothalamic AMPK and isoform-specific activation of AMPK in peripheral tissues. Mol. Cell. Biol. 29, 4563–4573 (2009).

  122. 122.

    , & The role of estrogens in control of energy balance and glucose homeostasis. Endocr. Rev. 34, 309–338 (2013).

  123. 123.

    et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).

  124. 124.

    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 156, 947–960 (2015).

  125. 125.

    , & The role of AMP-activated protein kinase in the androgenic potentiation of cannabinoid-induced changes in energy homeostasis. Am. J. Physiol. Endocrinol. Metab. 308, E482–E495 (2015).

  126. 126.

    et al. New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454, 1000–1004 (2008).

  127. 127.

    et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).

  128. 128.

    et al. Interscapular brown adipose tissue metabolic reprogramming during cold acclimation: interplay of HIF-1α and AMPKα. Biochim. Biophys. Acta 1810, 1252–1261 (2011).

  129. 129.

    et al. Desnutrin/ATGL is regulated by AMPK and is required for a brown adipose phenotype. Cell Metab. 13, 739–748 (2011).

  130. 130.

    , , , & β-adrenoceptors, but not α-adrenoceptors, stimulate AMP-activated protein kinase in brown adipocytes independently of uncoupling protein-1. Diabetologia 48, 2386–2395 (2005).

  131. 131.

    , , , & Upregulation of AMPK during cold exposure occurs via distinct mechanisms in brown and white adipose tissue of the mouse. J. Physiol. 580, 677–684 (2007).

  132. 132.

    et al. Adrenergic regulation of AMP-activated protein kinase in brown adipose tissue in vivo. J. Biol. Chem. 286, 8798–8809 (2011).

  133. 133.

    , & Adenosine 5′-monophosphate-activated protein kinase-mammalian target of rapamycin cross talk regulates brown adipocyte differentiation. Endocrinology 151, 980–992 (2010).

  134. 134.

    et al. MicroRNA-455 regulates brown adipogenesis via a novel HIF1an–AMPK–PGC1α signaling network. EMBO Rep. 16, 1378–1393 (2015).

  135. 135.

    et al. ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure. eLife 4, e08428 (2015).

  136. 136.

    et al. Cold tolerance, cold-induced hyperphagia, and nonshivering thermogenesis are normal in α1-AMPK−/− mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 301, R473–R483 (2011).

  137. 137.

    & Leptin and the central nervous system control of glucose metabolism. Physiol. Rev. 91, 389–411 (2011).

  138. 138.

    & Leptin revisited: its mechanism of action and potential for treating diabetes. Nat. Rev. Drug Discov. 11, 692–708 (2012).

  139. 139.

    , , , & Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus. Diabetes 50, 2673–2681 (2001).

  140. 140.

    , , & Role of hypothalamic adenosine 5′-monophosphate-activated protein kinase in the impaired counterregulatory response induced by repetitive neuroglucopenia. Endocrinology 148, 1367–1375 (2007).

  141. 141.

    et al. Hypothalamic AMP-activated protein kinase mediates counter-regulatory responses to hypoglycaemia in rats. Diabetologia 48, 2170–2178 (2005).

  142. 142.

    , , , & AMP-activated protein kinase and nitric oxide regulate the glucose sensitivity of ventromedial hypothalamic glucose-inhibited neurons. Am. J. Physiol. Cell Physiol. 297, C750–C758 (2009).

  143. 143.

    , , , & Role of neuronal energy status in the regulation of adenosine 5′-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior. Endocrinology 146, 3–10 (2005).

  144. 144.

    et al. Key role for AMP-activated protein kinase in the ventromedial hypothalamus in regulating counterregulatory hormone responses to acute hypoglycemia. Diabetes 57, 444–450 (2008).

  145. 145.

    et al. Glucose, insulin, and leptin signaling pathways modulate nitric oxide synthesis in glucose-inhibited neurons in the ventromedial hypothalamus. Am. J. Physiol. Regul. Integr. Comp. Physiol. 292, R1418–R1428 (2007).

  146. 146.

    et al. Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes 59, 2435–2443 (2010).

  147. 147.

    , , & Hypothalamic nutrient sensing activates a forebrain–hindbrain neuronal circuit to regulate glucose production in vivo. Diabetes 60, 107–113 (2011).

  148. 148.

    , , & Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PLoS ONE 8, e56660 (2013).

  149. 149.

    et al. Leptin receptor signaling in the hypothalamus regulates hepatic autonomic nerve activity via phosphatidylinositol 3-kinase and AMP-activated protein kinase. J. Neurosci. 35, 474–484 (2015).

  150. 150.

    et al. Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels. Endocrinology 153, 3633–3645 (2012).

  151. 151.

    , & Glucoreceptors controlling feeding and blood glucose: location in the hindbrain. Science 213, 451–452 (1981).

  152. 152.

    , & Participation of hindbrain AMP-activated protein kinase in glucoprivic feeding. Diabetes 60, 436–442 (2011).

  153. 153.

    et al. The selectivity of protein kinase inhibitors: a further update. Biochem. J. 408, 297–315 (2007).

  154. 154.

    et al. Hypoglycemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab. 19, 527–538 (2014).

  155. 155.

    , , , & Metformin: from mechanisms of action to therapies. Cell Metab. 20, 953–966 (2014).

  156. 156.

    & Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem. J. 471, 307–322 (2015).

  157. 157.

    & Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 49, 434–441 (2006).

  158. 158.

    , , & Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 54, 339–349 (2011).

  159. 159.

    et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256–260 (2013).

  160. 160.

    et al. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice. Diabetes 63, 880–891 (2014).

  161. 161.

    et al. Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat. Med. 19, 1649–1654 (2013).

  162. 162.

    , & Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000).

  163. 163.

    et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, 2355–2369 (2010).

  164. 164.

    et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542–546 (2014).

  165. 165.

    et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63, 727–735 (2014).

  166. 166.

    et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528, 262–266 (2015).

  167. 167.

    et al. Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase. Nature 415, 339–343 (2002).

  168. 168.

    & Neuronal regulation of energy homeostasis: beyond the hypothalamus and feeding. Cell Metab. 22, 962–970 (2015).

  169. 169.

    et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat. Med. 18, 1847–1856 (2012).

  170. 170.

    , & Comparative distribution of estrogen receptor-α and -β mRNA in the rat central nervous system. J. Comp. Neurol. 388, 507–525 (1997).

  171. 171.

    et al. Glucose regulates hypothalamic long-chain fatty acid metabolism via AMP-activated kinase (AMPK) in neurons and astrocytes. J. Biol. Chem. 288, 37216–37229 (2013).

  172. 172.

    & Unraveling the brain regulation of appetite: lessons from genetics. Nat. Neurosci. 15, 1343–1349 (2012).

  173. 173.

    , , & Energy balance regulation by thyroid hormones at central level. Trends Mol. Med. 19, 418–427 (2013).

  174. 174.

    , & Neural control of energy balance: translating circuits to therapies. Cell 161, 133–145 (2015).

  175. 175.

    Cognitive and autonomic determinants of energy homeostasis in obesity. Nat. Rev. Endocrinol. 11, 489–501 (2015).

  176. 176.

    & Estrogens and the control of energy homeostasis: a brain perspective. Trends Endocrinol. Metab. 26, 411–421 (2015).

  177. 177.

    , & Unexpected evidence for active brown adipose tissue in adult humans. Am. J. Physiol. Endocrinol. Metab. 293, E444–E452 (2007).

Download references

Acknowledgements

The authors would like to acknowledge funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 281854: the ObERStress project (awarded to M.L.). Xunta de Galicia awarded to M.L. (2015-CP079) and R.N. (2015-CP080 and PIE13/00024), Ministry of Economy and Competitiveness (MINECO) Instituto de Salud Carlos III (PI12/01814 and PIE13/00024 awarded to M.L.), MINECO co-funded by the FEDER Program of EU (awarded to M.L. (SAF2015-71026-R); R.N. (BFU2015-70664-R); M.T.S. (BFU2014-2502157581-P); and C.D. (BFU2014-55871-P)). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of Instituto de Salud Carlos III, Spain.

Author information

Affiliations

  1. Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain

    • Miguel López
    • , Rubén Nogueiras
    •  & Carlos Diéguez
  2. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain

    • Miguel López
    • , Rubén Nogueiras
    • , Manuel Tena-Sempere
    •  & Carlos Diéguez
  3. Department of Cell Biology, Physiology and Immunology, University of Córdoba; Instituto Maimónides de Investigación Biomédica (IMIBIC)/Hospital Reina Sofía, 14004 Córdoba, Spain

    • Manuel Tena-Sempere
  4. FiDiPro Program, Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland

    • Manuel Tena-Sempere

Authors

  1. Search for Miguel López in:

  2. Search for Rubén Nogueiras in:

  3. Search for Manuel Tena-Sempere in:

  4. Search for Carlos Diéguez in:

Contributions

M.L. researched data for the article and wrote the manuscript. All authors made substantial contributions to discussion of the content and reviewed/edited the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Miguel López.