AMPK-Dependent Mechanisms but Not Hypothalamic Lipid Signaling Mediates GH-Secretory Responses to GHRH and Ghrelin

GH (growth hormone) secretion/action is modulated by alterations in energy homeostasis, such as malnutrition and obesity. Recent data have uncovered the mechanism by which hypothalamic neurons sense nutrient bioavailability, with a relevant contribution of AMPK (AMP-activated protein kinase) and mTOR (mammalian Target of Rapamycin), as sensors of cellular energy status. However, whether central AMPK-mediated lipid signaling and mTOR participate in the regulation of pituitary GH secretion remains unexplored. We provide herein evidence for the involvement of hypothalamic AMPK signaling, but not hypothalamic lipid metabolism or CPT-1 (carnitine palmitoyltransferase I) activity, in the regulation of GH stimulatory responses to the two major elicitors of GH release in vivo, namely GHRH (growth hormone–releasing hormone) and ghrelin. This effect appeared to be GH-specific, as blocking of hypothalamic AMPK failed to influence GnRH (gonadotropin-releasing hormone)-induced LH (luteinizing hormone) secretion. Additionally, central mTOR inactivation did not alter GH responses to GHRH or ghrelin, nor this blockade affected LH responses to GnRH in vivo. In sum, we document here for the first time the indispensable and specific role of preserved central AMPK, but not mTOR, signaling, through a non-canonical lipid signaling pathway, for proper GH responses to GHRH and ghrelin in vivo.

[1]  B. Rotblat,et al.  How does mTOR sense glucose starvation? AMPK is the usual suspect , 2020, Cell Death Discovery.

[2]  N. Casals,et al.  Sensing of nutrients by CPT1C regulates late endosome/lysosome anterograde transport and axon growth , 2019, eLife.

[3]  Q. Lei,et al.  Metabolite sensing and signaling in cell metabolism , 2018, Signal Transduction and Targeted Therapy.

[4]  N. Casals,et al.  CPT1C in the ventromedial nucleus of the hypothalamus is necessary for brown fat thermogenesis activation in obesity , 2018, Molecular metabolism.

[5]  Baile Wang,et al.  Hypothalamic AMPK as a Mediator of Hormonal Regulation of Energy Balance , 2018, International journal of molecular sciences.

[6]  M. Poutanen,et al.  Metabolic regulation of female puberty via hypothalamic AMPK–kisspeptin signaling , 2018, Proceedings of the National Academy of Sciences.

[7]  C. Slawson,et al.  Real Talk: The Inter-play Between the mTOR, AMPK, and Hexosamine Biosynthetic Pathways in Cell Signaling , 2018, Front. Endocrinol..

[8]  N. Casals,et al.  CPT1C promotes human mesenchymal stem cells survival under glucose deprivation through the modulation of autophagy , 2018, Scientific Reports.

[9]  A. Ribes,et al.  Ghrelin Causes a Decline in GABA Release by Reducing Fatty Acid Oxidation in Cortex , 2018, Molecular Neurobiology.

[10]  M. Avendano,et al.  Disentangling puberty: novel neuroendocrine pathways and mechanisms for the control of mammalian puberty , 2017, Human reproduction update.

[11]  F. Villarroya,et al.  Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance , 2017, Cell metabolism.

[12]  M. Tena-Sempere,et al.  Hypothalamic AMPK: a canonical regulator of whole-body energy balance , 2016, Nature Reviews Endocrinology.

[13]  Eun-Kyoung Kim,et al.  Hypothalamic AMPK-induced autophagy increases food intake by regulating NPY and POMC expression , 2016, Autophagy.

[14]  A. Herbison Control of puberty onset and fertility by gonadotropin-releasing hormone neurons , 2016, Nature Reviews Endocrinology.

[15]  F. Liu,et al.  Hypothalamic roles of mTOR complex I: integration of nutrient and hormone signals to regulate energy homeostasis. , 2016, American journal of physiology. Endocrinology and metabolism.

[16]  Min-Seon Kim,et al.  Leptin signalling pathways in hypothalamic neurons , 2016, Cellular and Molecular Life Sciences.

[17]  D. Cocchi,et al.  Role of AMP‐Activated Protein Kinase Activators in Antiproliferative Multi‐Drug Pituitary Tumour Therapies: Effects of Combined Treatments with Compounds Affecting the mTOR‐p70S6 Kinase Axis in Cultured Pituitary Tumour Cells , 2015, Journal of neuroendocrinology.

[18]  D. Cota,et al.  Influence of mTOR in energy and metabolic homeostasis , 2014, Molecular and Cellular Endocrinology.

[19]  A. Kalsbeek,et al.  Estradiol Regulates Brown Adipose Tissue Thermogenesis via Hypothalamic AMPK , 2014, Cell metabolism.

[20]  G. Lopaschuk,et al.  Hypothalamic malonyl-CoA and the control of food intake , 2013, Physiology & Behavior.

[21]  N. Casals,et al.  Hypothalamic Ceramide Levels Regulated by CPT1C Mediate the Orexigenic Effect of Ghrelin , 2013, Diabetes.

[22]  M. J. Vazquez,et al.  Hypothalamic mTOR Signaling Mediates the Orexigenic Action of Ghrelin , 2012, PloS one.

[23]  Tao Xi,et al.  Beclin 1-mediated autophagy in hepatocellular carcinoma cells: implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling. , 2012, Cellular signalling.

[24]  M. Tena-Sempere,et al.  Kisspeptins and reproduction: physiological roles and regulatory mechanisms. , 2012, Physiological reviews.

[25]  F. Villarroya,et al.  BMP8B Increases Brown Adipose Tissue Thermogenesis through Both Central and Peripheral Actions , 2012, Cell.

[26]  Christian Appenzeller‐Herzog,et al.  Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling. , 2012, Trends in cell biology.

[27]  A. Bartke Pleiotropic effects of growth hormone signaling in aging , 2011, Trends in Endocrinology & Metabolism.

[28]  M. J. Vazquez,et al.  The Central Sirtuin 1/p53 Pathway Is Essential for the Orexigenic Action of Ghrelin , 2011, Diabetes.

[29]  M. Tena-Sempere,et al.  Energy balance and puberty onset: emerging role of central mTOR signaling , 2010, Trends in Endocrinology & Metabolism.

[30]  M. J. Vazquez,et al.  Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  Jun-ping Wen,et al.  Globular adiponectin regulates energy homeostasis through AMP-activated protein kinase–acetyl-CoA carboxylase (AMPK/ACC) pathway in the hypothalamus , 2010, Molecular and Cellular Biochemistry.

[32]  S. Sangiao-Alvarellos,et al.  Influence of Ghrelin and Growth Hormone Deficiency on AMP‐Activated Protein Kinase and Hypothalamic Lipid Metabolism , 2010, Journal of neuroendocrinology.

[33]  F. Gaytán,et al.  The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. , 2009, Endocrinology.

[34]  I. Shimon,et al.  Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro. , 2009, Endocrine-related cancer.

[35]  Tamas L. Horvath,et al.  UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals , 2008, Nature.

[36]  Ricardo Lage,et al.  Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. , 2008, Cell metabolism.

[37]  Kohjiro Ueki,et al.  Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. , 2007, Cell metabolism.

[38]  C. Proud,et al.  The rapid activation of protein synthesis by growth hormone requires signaling through mTOR. , 2007, American journal of physiology. Endocrinology and metabolism.

[39]  George Thomas,et al.  Hypothalamic mTOR Signaling Regulates Food Intake , 2006, Science.

[40]  E. Ghigo,et al.  Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children , 2006, Clinical endocrinology.

[41]  D. Hardie,et al.  Cannabinoids and Ghrelin Have Both Central and Peripheral Metabolic and Cardiac Effects via AMP-activated Protein Kinase* , 2005, Journal of Biological Chemistry.

[42]  F. Casanueva,et al.  Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. , 2003, Endocrinology.

[43]  F. Casanueva,et al.  Effects of glucose, free fatty acids or arginine load on the GH‐releasing activity of ghrelin in humans , 2002, Clinical endocrinology.

[44]  F. Casanueva,et al.  Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats. , 2000, European journal of endocrinology.

[45]  F. Casanueva,et al.  Neuroendocrine Regulation and Actions of Leptin , 1999, Frontiers in Neuroendocrinology.

[46]  F. Casanueva,et al.  Influence of metabolic substrates and obesity on growth hormone secretion , 1995, Trends in Endocrinology & Metabolism.

[47]  P. Plotsky,et al.  Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. , 1985, Science.

[48]  H. Kawano,et al.  Immunohistochemical studies of intrahypothalamic somatostatin-containing neurons in rat , 1982, Brain Research.

[49]  J. B. Martin,et al.  Evidence for an endogenous ultradian rhythm governing growth hormone secretion in the rat. , 1976, Endocrinology.

[50]  E. Ghigo,et al.  Ghrelin: from somatotrope secretion to new perspectives in the regulation of peripheral metabolic functions. , 2006, Frontiers of hormone research.