Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system.
Diabetes. 2008-09-05; 57(12): 3231-3238
DOI: 10.2337/db07-1690
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1. Diabetes. 2008 Dec;57(12):3231-8. doi: 10.2337/db07-1690. Epub 2008 Sep 5.
Fatty acid synthase inhibitors modulate energy balance via mammalian target of
rapamycin complex 1 signaling in the central nervous system.
Proulx K(1), Cota D, Woods SC, Seeley RJ.
Author information:
(1)Department of Psychiatry, University of Cincinnati, Genome Research Institute,
Cincinnati, OH, USA.
OBJECTIVE: Evidence links the hypothalamic fatty acid synthase (FAS) pathway to
the regulation of food intake and body weight. This includes pharmacological
inhibitors that potently reduce feeding and body weight. The mammalian target of
rapamycin (mTOR) is an intracellular fuel sensor whose activity in the
hypothalamus is also linked to the regulation of energy balance. The purpose of
these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1)
signaling is involved in mediating the effects of FAS inhibitors.
RESEARCH DESIGN AND METHODS: We measured the hypothalamic phosphorylation of two
downstream targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6),
after administration of the FAS inhibitors C75 and cerulenin in rats. We
evaluated food intake in response to FAS inhibitors in rats pretreated with the
mTOR inhibitor rapamycin and in mice lacking functional S6K1 (S6K1(-/-)). Food
intake and phosphorylation of S6K1 and S6 were also determined after C75
injection in rats maintained on a ketogenic diet.
RESULTS: C75 and cerulenin increased phosphorylation of S6K1 and S6, and their
anorexic action was reduced in rapamycin-treated rats and in S6K1(-/-) mice.
Consistent with our previous findings, C75 was ineffective at reducing caloric
intake in ketotic rats. Under ketosis, C75 was also less efficient at stimulating
mTORC1 signaling.
CONCLUSIONS: These findings collectively indicate an important interaction
between the FAS and mTORC1 pathways in the central nervous system for regulating
energy balance, possibly via modulation of neuronal glucose utilization.
DOI: 10.2337/db07-1690
PMCID: PMC2584128
PMID: 18776140 [Indexed for MEDLINE]