C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism.
C75, a synthetic inhibitor of fatty acid synthase (FAS), is hypothesized to alter the metabolism of neurons in the hypothalamus that regulate feeding behavior to contribute to the decreased food intake and profound weight loss seen with C75 treatment. In the present study, we characterize the suitability of primary cultures of cortical neurons for studies designed to investigate the consequences of C75 treatment and the alteration of fatty acid metabolism in neurons. We demonstrate that in primary cortical neurons, C75 inhibits FAS activity and stimulates carnitine palmitoyltransferase-1 (CPT-1), consistent with its effects in peripheral tissues. C75 alters neuronal ATP levels and AMP-activated protein kinase (AMPK) activity. Neuronal ATP levels are affected in a biphasic manner with C75 treatment, decreasing initially, followed by a prolonged increase above control levels. Cerulenin, a FAS inhibitor, causes a similar biphasic change in ATP levels, although levels do not exceed control. C75 and cerulenin modulate AMPK phosphorylation and activity. TOFA, an inhibitor of acetyl-CoA carboxylase, increases ATP levels, but does not affect AMPK activity. Several downstream pathways are affected by C75 treatment, including glucose metabolism and acetyl-CoA carboxylase (ACC) phosphorylation. These data demonstrate that C75 modulates the levels of energy intermediates, thus, affecting the energy sensor AMPK. Similar effects in hypothalamic neurons could form the basis for the effects of C75 on feeding behavior.
Landree
Leslie E
LE
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Hanlon
Andrea L
AL
Strong
David W
DW
Rumbaugh
Gavin
G
Miller
Ian M
IM
Thupari
Jagan N
JN
Connolly
Erin C
EC
Huganir
Richard L
RL
Richardson
Christine
C
Witters
Lee A
LA
Kuhajda
Francis P
FP
Ronnett
Gabriele V
GV
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004594:Electrophysiology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D005227:Fatty Acids; D009097:Multienzyme Complexes; D000255:Adenosine Triphosphate; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; D015107:4-Butyrolactone