Role of neuronal energy status in the regulation of adenosine 5'-monophosphate-activated protein kinase, orexigenic neuropeptides expression, and feeding behavior.
Nutrient sensing in the hypothalamus is tightly related to food intake regulation. However, the mechanisms by which the nutrient-sensing cells of the brain translate this signal of energy need into feeding behavior via regulation of neuropeptide expression are not known. To address this issue, we investigated two neuronal cell lines expressing agouti-related protein (AgRP), ex vivo hypothalamic tissues, and in vivo whole animals. Maintaining cells in a low cellular ATP concentration generated by low glucose, 2-deoxyglucose (2-DG), ATP synthesis inhibitor, and 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside increased phosphorylation of AMP-activated protein kinase (AMPK) and increased AgRP expression, whereas maintaining cells in high ATP status by high glucose and pyruvate supplementation in 2-DG-treated cells decreased phosphorylation of AMPK and decreased AgRP expression. Overexpression of a dominant-inhibitory mutant of AMPK significantly decreased low-glucose- or 2-DG-induced AgRP expression. Furthermore, ex vivo hypothalamus culture in high glucose concentrations decreased both expression and phosphorylation of AMPK and expression of both AgRP and neuropeptide Y, whereas pyruvate supplementation suppressed a 2-DG-induced AgRP expression. Finally, our in vivo studies clearly show that central administration of pyruvate dramatically delayed 2-DG-induced food intake. These data indicate that modulation of ATP levels in neuronal cells triggers a cascade of events via AMPK that modulate feeding behavior to restore energy status of cells.
Lee
Kichoon
K
Department of Animal Sciences, The Ohio State University, Columbus, Ohio 43210, USA. lee.2626@osu.edu
Li
Bing
B
Xi
Xiaochun
X
Suh
Yeunsu
Y
Martin
Roy J
RJ
D055372:AMP-Activated Protein Kinases; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors; D054369:Agouti-Related Protein; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001066:Appetite / Q000502:physiology*; D045744:Cell Line, Tumor; D003847:Deoxyglucose / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000502:physiology*; D005247:Feeding Behavior / Q000502:physiology*; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology; D046509:Tissue Culture Techniques
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007004:Hypoglycemic Agents; D036341:Intercellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009478:Neuropeptide Y; D009479:Neuropeptides; D011506:Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D005947:Glucose