C75, a Fatty Acid Synthase Inhibitor, Reduces Food Intake via Hypothalamic AMP-activated Protein Kinase

Abstract

Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK α subunit (pAMPKα) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKα levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKα levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKα and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus. Energy homeostasis and feeding are regulated by the central nervous system. C75, a fatty acid synthase (FAS) inhibitor, causes weight loss and anorexia, implying a novel central nervous system pathway(s) for sensing energy balance. AMP-activated protein kinase (AMPK), a sensor of peripheral energy balance, is phosphorylated and activated when energy sources are low. Here, we identify a role for hypothalamic AMPK in the regulation of feeding behavior and in mediating the anorexic effects of C75. 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), an activator of AMPK, increased food intake, whereas compound C, an inhibitor of AMPK, decreased food intake. C75 rapidly reduced the level of the phosphorylated AMPK α subunit (pAMPKα) in the hypothalamus, even in fasted mice that had elevated hypothalamic pAMPKα levels. Furthermore, AICAR reversed both the C75-induced anorexia and the decrease in hypothalamic pAMPKα levels. C75 elevated hypothalamic neuronal ATP levels, which may contribute to the mechanism by which C75 decreased AMPK activity. C75 reduced the levels of pAMPKα and phosphorylated cAMP response element-binding protein (pCREB) in the arcuate nucleus neurons of the hypothalamus, suggesting a mechanism for the reduction in NPY expression seen with C75 treatment. These data indicate that modulation of FAS activity in the hypothalamus can alter energy perception via AMPK, which functions as a physiological energy sensor in the hypothalamus. Despite significant advances in the understanding of appetite and satiety at molecular levels (1Wilding J.P. Diabet. Med. 2002; 19: 619-627Crossref PubMed Scopus (145) Google Scholar, 2Schwartz M. Woods S. Porte D.J. Seeley R. Baskin D. Nature. 2000; 404: 661-671Crossref PubMed Scopus (4865) Google Scholar, 3Woods S.C. Schwartz M.W. Baskin D.G. Seeley R.J. Annu. Rev. Psychol. 2000; 51: 255-277Crossref PubMed Scopus (270) Google Scholar), practical therapies for weight loss remain elusive. We and others (4Loftus T. Jaworsky D. Frehywot G. Townsend C. Ronnett G. Lane M. Kuhajda F. Science. 2000; 288: 2379-2381Crossref PubMed Scopus (832) Google Scholar, 5Clegg D.J. Wortman M.D. Benoit S.C. McOsker C.C. Seeley R.J. Diabetes. 2002; 51: 3196-3201Crossref PubMed Scopus (80) Google Scholar, 6Kumar M.V. Shimokawa T. Nagy T.R. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 1921-1925Crossref PubMed Scopus (112) Google Scholar, 7Shimokawa T. Kumar M.V. Lane M.D. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 66-71Crossref PubMed Scopus (171) Google Scholar, 8Thupari J.N. Landree L.E. Ronnett G.V. Kuhajda F.P. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 9498-9502Crossref PubMed Scopus (215) Google Scholar) have demonstrated that C75, a synthetic fatty acid synthase (FAS) 1The abbreviations used are: FAS, fatty acid synthase; CPT-1, carnitine palmitoyltransferase-1; AMPK, AMP-activated protein kinase; i.c.v., intracerebroventricular; i.p., intraperitoneal; FITC, fluorescein isothiocyanate; CREB, cAMP response element-binding protein; pCREB, phosphorylated CREB. 1The abbreviations used are: FAS, fatty acid synthase; CPT-1, carnitine palmitoyltransferase-1; AMPK, AMP-activated protein kinase; i.c.v., intracerebroventricular; i.p., intraperitoneal; FITC, fluorescein isothiocyanate; CREB, cAMP response element-binding protein; pCREB, phosphorylated CREB. inhibitor, caused profound weight loss and anorexia in lean, diet-induced obese (DIO) and genetically obese (ob/ob) mice. In addition to FAS inhibition, C75 also stimulates carni