Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin.

Current evidence suggests that hypothalamic fatty acid metabolism may play a role in regulating food intake; however, confirmation that it is a physiologically relevant regulatory system of feeding is still incomplete. Here, we use pharmacological and genetic approaches to demonstrate that the physiological orexigenic response to ghrelin involves specific inhibition of fatty acid biosynthesis induced by AMP-activated protein kinase (AMPK) resulting in decreased hypothalamic levels of malonyl-CoA and increased carnitine palmitoyltransferase 1 (CPT1) activity. In addition, we also demonstrate that fasting downregulates fatty acid synthase (FAS) in a region-specific manner and that this effect is mediated by an AMPK and ghrelin-dependent mechanisms. Thus, decreasing AMPK activity in the ventromedial nucleus of the hypothalamus (VMH) is sufficient to inhibit ghrelin's effects on FAS expression and feeding. Overall, our results indicate that modulation of hypothalamic fatty acid metabolism specifically in the VMH in response to ghrelin is a physiological mechanism that controls feeding.

[1]  B. Wisse,et al.  A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. , 2001, Diabetes.

[2]  M. Lane,et al.  Control of energy homeostasis: role of enzymes and intermediates of fatty acid metabolism in the central nervous system. , 2006, Annual review of nutrition.

[3]  Y. Minokoshi,et al.  Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. , 2008, Biochemical and biophysical research communications.

[4]  M. Schwartz,et al.  Elevated plasma ghrelin levels in Prader–Willi syndrome , 2002, Nature Medicine.

[5]  J. Flier.  Obesity Wars Molecular Progress Confronts an Expanding Epidemic , 2004, Cell.

[6]  S. Bloom,et al.  The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. , 2000, Endocrinology.

[7]  M. Prentki,et al.  Activation of Malonyl-CoA Decarboxylase in Rat Skeletal Muscle by Contraction and the AMP-activated Protein Kinase Activator 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside* , 2000, The Journal of Biological Chemistry.

[8]  B. Lowell,et al.  Mice lacking ghrelin receptors resist the development of diet-induced obesity. , 2005, The Journal of clinical investigation.

[9]  Roberto Conti,et al.  Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production , 2003, Nature Medicine.

[10]  M. W. Schwartz,et al.  Central nervous system control of food intake and body weight , 2006, Nature.

[11]  Margaret S. Wu,et al.  Role of AMP-activated protein kinase in mechanism of metformin action. , 2001, The Journal of clinical investigation.

[12]  S. Woods,et al.  Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. , 2006, Endocrinology.

[13]  M. Lane,et al.  Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[14]  S. O’Rahilly,et al.  Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids. , 2005, Diabetes.

[15]  A. Edelman,et al.  Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. , 2005, Cell metabolism.

[16]  P. Cohen,et al.  The selectivity of protein kinase inhibitors: a further update. , 2007, The Biochemical journal.

[17]  F. Casanueva,et al.  The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright © 2001 by The Endocrine Society Cellular Localization of Orexin Receptors in , 2000 .

[18]  F. Casanueva,et al.  Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus. , 2000, Biochemical and biophysical research communications.

[19]  D. Carling,et al.  AMP-activated Protein Kinase Plays a Role in the Control of Food Intake* , 2004, Journal of Biological Chemistry.

[20]  B. Lowell,et al.  Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. , 2007, Cell metabolism.

[21]  D. Cummings,et al.  Emerging therapeutic strategies for obesity. , 2006, Endocrine reviews.

[22]  L. Seoane,et al.  Orexin‐A regulates growth hormone‐releasing hormone mRNA content in a nucleus‐specific manner and somatostatin mRNA content in a growth hormone‐dependent fashion in the rat hypothalamus , 2004, The European journal of neuroscience.

[23]  D. Carling,et al.  Characterization of the Role of AMP-Activated Protein Kinase in the Regulation of Glucose-Activated Gene Expression Using Constitutively Active and Dominant Negative Forms of the Kinase , 2000, Molecular and Cellular Biology.

[24]  M. Sleeman,et al.  Absence of ghrelin protects against early-onset obesity. , 2005, The Journal of clinical investigation.

[25]  Roy G. Smith.  Development of growth hormone secretagogues. , 2005, Endocrine reviews.

[26]  M. Lane,et al.  Hypothalamic malonyl-CoA as a mediator of feeding behavior , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[27]  L. Seoane,et al.  A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat , 2004, Diabetologia.

[28]  T. Shimokawa,et al.  The brain-specific carnitine palmitoyltransferase-1c regulates energy homeostasis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[29]  L. Rossetti,et al.  Molecular disruption of hypothalamic nutrient sensing induces obesity , 2006, Nature Neuroscience.

[30]  L. Bieber,et al.  A rapid spectrophotometric assay for carnitine palmitoyltransferase. , 1972, Analytical biochemistry.

[31]  T. Horvath,et al.  A Novel Growth Hormone Secretagogue-1a Receptor Antagonist That Blocks Ghrelin-Induced Growth Hormone Secretion but Induces Increased Body Weight Gain , 2005, Neuroendocrinology.

[32]  J. Goldberg.  How does an axon grow? , 2003, Genes & development.

[33]  C. Lelliott,et al.  Tamoxifen-Induced Anorexia Is Associated With Fatty Acid Synthase Inhibition in the Ventromedial Nucleus of the Hypothalamus and Accumulation of Malonyl-CoA , 2006, Diabetes.

[34]  J. Goldstein,et al.  The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor , 1997, Cell.

[35]  A. G. Roseberry,et al.  Rapid Rewiring of Arcuate Nucleus Feeding Circuits by Leptin , 2004, Science.

[36]  T. Horvath,et al.  Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats. , 2004, Endocrinology.

[37]  M. Tschöp,et al.  Ghrelin induces adiposity in rodents , 2000, Nature.

[38]  L. Seoane,et al.  Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood , 2007, International Journal of Obesity.

[39]  D. Vicent,et al.  Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. , 1998, Diabetes.

[40]  L. Seoane,et al.  Neuropeptide Y, but Not Agouti-Related Peptide or Melanin-Concentrating Hormone, Is a Target Peptide for Orexin-A Feeding Actions in the Rat Hypothalamus , 2002, Neuroendocrinology.

[41]  C. Lelliott,et al.  Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[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]  L. Seoane,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 , 2001, Neuroscience Letters.

[44]  D. Hardie,et al.  AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. , 2005, Cell metabolism.

[45]  M. Birnbaum,et al.  AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus , 2004, Nature.

[46]  R. Heath,et al.  Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. , 2005, Cell metabolism.

[47]  M. Lane,et al.  Brain fatty acid synthase activates PPARα to maintain energy homeostasis , 2007 .

[48]  J. Brüning,et al.  Central insulin action in energy and glucose homeostasis. , 2006, The Journal of clinical investigation.

[49]  G. Ronnett,et al.  C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[50]  P. Pfluger,et al.  Ghrelin action in the brain controls adipocyte metabolism. , 2006, The Journal of clinical investigation.

[51]  C. Townsend,et al.  Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. , 2000, Science.

[52]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[53]  D. Cota,et al.  The emerging role of the endocannabinoid system in endocrine regulation and energy balance. , 2006, Endocrine reviews.

[54]  L. Seoane,et al.  Hypothalamic levels of NPY, MCH, and prepro‐orexin mRNA during pregnancy and lactation in the rat: role of prolactin , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[55]  S. O’Rahilly,et al.  Orexin Expression is Regulated by α‐Melanocyte‐Stimulating Hormone , 2007, Journal of neuroendocrinology.

[56]  A. Pocai,et al.  Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. , 2006, The Journal of clinical investigation.