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. 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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 carnitine palmitoyltransferase-1 (CPT-1) activity, increasing fatty acid oxidation and ATP levels (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). Since enzymes of the fatty acid metabolic pathways are highly expressed in hypothalamic neurons that regulate feeding behavior (9Kim E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar), we hypothesize that C75-induced alterations in fatty acid metabolism may affect neuronal energy flux, which could signal a change in energy status, leading to changes in feeding behavior. AMPK (AMP-activated protein kinase) is activated by metabolic stresses such as nutrient starvation (10da Silva Xavier G. Leclerc I. Salt I.P. Doiron B. Hardie D.G. 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Smith K. Bloom S.R. Carling D. Small C.J. J. Biol. Chem. 2004; 279: 12005-12008Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar) that AMPK is involved with the regulation of food intake support our hypothesis. Therefore, we chose to study AMPK as a candidate metabolic sensor in the hypothalamus, which might perceive changes in energy status caused by C75. Animals—All animal experiments were done in accordance with guidelines on animal care and use established by the Johns Hopkins University School of Medicine Institutional Animal Care and Use Committee. Male BALB/c mice (7–9 weeks) were purchased from Charles River Laboratories (and housed in a controlled-light (a 12 h light/12 h on to and to and food from at the of the for to of were with the of the to to the and to a of the of the mice were housed in and for and as C75 in AICAR compound S.R. Med. Chem. 2002; 12 PubMed Scopus Google Scholar) in such that the could in a of control were done and food intake were at h h and h C75 were with of weight C75 in of h the by of AICAR the of h off and of of compound of C75 of by food intake at the were as the and the to a of hypothalamic and were in were in of to a and were for the protein by of on a and and used as a and ATP were from and by and as L.E. G. Miller J.N. C. Witters L.A. Kuhajda F.P. Ronnett G.V. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). were at on in with were with on and were for neurons were in and ATP levels were the the ATP by the were by a and and of as (9Kim E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar). with from of NPY and a the for used at the The were an and were as (9Kim E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar) with M. J. 2001; PubMed Google Scholar). were in for h at and with and in at by a In NPY from a the NPY and were as (9Kim E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar). in from a from L. A. for and used for NPY in and for and were in for and of of in and were an and were and by are as were by of by C75, the C75-induced alterations in fatty acid AMPK activation inhibition, and feeding behavior. We mice with to food intake of C75 mice had to food the C75 reduced food intake the and in a of and of C75 caused a and reduction in food intake The also a reduction in with our (4Loftus T. Jaworsky D. Frehywot G. Townsend C. Ronnett G. Lane M. Kuhajda F. Science. 2000; 288: 2379-2381Crossref PubMed Scopus (832) Google Scholar), indicate that C75 food intake via central a compound that stimulates AMPK activity, is and phosphorylated to D. E.W. J. Biol. Chem. Full Text PDF PubMed Google Scholar), which the effects of AMP on AMPK activation J.E. F. Carling D. Beri R.K. 1994; PubMed Scopus Google Scholar). We chose a to alter AMPK activity, as to a as we to to the effects of on a We the of of as its may it is D. Witters L.A. Biochem. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In to the feeding by C75, of AICAR increased food intake. of increased food intake to h and at and food intake increased to of control with the U. Filipsson K. Abbott C.R. Woods A. Smith K. Bloom S.R. Carling D. Small C.J. J. Biol. Chem. 2004; 279: 12005-12008Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar), the of AICAR increased food intake. Despite in food intake, of AICAR significant on weight weight change in to food intake L. Science. 2001; PubMed Scopus Google Scholar). that of AICAR for had on food intake weight W.W. M. J. Appl. Physiol. 2000; PubMed Scopus Google Scholar) that a reduction in and an in of a of AICAR may have an on the of peripheral such that weight change increased food intake. the of AMPK on food intake, we used compound C, which is a AMPK inhibitor G. R. Y. Y. J. M. J. T. Fujii N. N. Hirshman M.F. Goodyear L.J. J. 2001; PubMed Scopus Google Scholar, M. J.T. I. Kim J. J. Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. Cell. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). The of of compound caused a and reduction in food intake at h and of compound to a weight loss as with the of AICAR on the of compound on feeding profound at h and The of compound also had a reduction in food intake that a decreased food intake and of control h and AICAR compound may have cellular effects that the on food intake an AMPK activator and inhibitor the that AMPK is involved in feeding behavior. We the of of the C75 with the of of for C75 in experiments to the central and peripheral effects of C75 on the change in AMPK activation and to C75 and AICAR of C75 of caused a decrease in food intake and of control and food reduced to of control The of C75 on food intake and that of compound C. The of the peripheral of C75 on food intake with the of may the that can via an peripheral of that C75 and compound effects on food intake with of C75 the of The hypothalamus an role in energy and peripheral that affect food intake (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). the expression of AMPK in D. R.J. Witters L.A. J. 1999; PubMed Scopus Google Scholar, C. J. J. Mol. 2001; 17: PubMed Scopus Google Scholar), its in the is C75 FAS and stimulates CPT-1, the that the for (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). of may signal a energy in neurons of the hypothalamus, which may hypothalamic the of C75 on hypothalamic AMPK activity, we the of C75 on the level of phosphorylation of the α subunit S.A. Davison M. Woods A. Davies S.P. Beri R.K. Carling D. Hardie D.G. J. Biol. Chem. 1996; 271: 27879-27887Abstract Full Text Full Text PDF PubMed Scopus (1005) Google Scholar) of AMPK (pAMPKα) in the hypothalamus, which with its activity of C75 i.c.v., and the levels of hypothalamic pAMPKα were by The level of and as a with levels of pAMPKα in control C75 reduced the levels of pAMPKα and in the hypothalamus and at and a and seen with central of C75, of C75 of reduced the levels of pAMPKα in the hypothalamus at and h and In C75 had on pAMPKα levels in the increased pAMPKα levels at h and These demonstrated that C75 rapidly decreased AMPK activity in the hypothalamus. The decrease in hypothalamic pAMPKα levels could from the metabolic changes that as a of FAS inhibition, which energy and signal a energy balance. These also indicate that the phosphorylation of AMPK is regulated in the hypothalamus in the in response to C75. metabolic the in neurons and in the decreased food intake seen with C75 may signal an energy in leading to AMPK an to preserve energy levels the of fatty acid for C75 the of that the activity of AMPK is elevated in fasted L.A. G. B. Biochem. Biophys. 1994; PubMed Scopus Google Scholar). hypothalamic AMPK is to the level of pAMPKα of food at the of in mice change in pAMPKα levels h of food a and for h in a in the level of hypothalamic pAMPKα a and S.P. Hardie D.G. 1995; PubMed Scopus Google Scholar) in AMPK activity and in to feeding in the that the activation of hypothalamic AMPK could involved in the of food intake. We C75 could AMPK phosphorylation in the of when AMPK phosphorylation is is in a C75-induced FAS and AMPK activity, as C75 feeding even in fasted mice (4Loftus T. Jaworsky D. Frehywot G. Townsend C. Ronnett G. Lane M. Kuhajda F. Science. 2000; 288: 2379-2381Crossref PubMed Scopus (832) 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). h of C75 and the levels of hypothalamic pAMPKα were C75 reduced the level of pAMPKα with that of control and our that C75 food intake even in fasted the of C75 to the levels of pAMPKα in fasted mice the that C75 might at in by an C75 the ATP that C75 increases ATP levels in (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) and even in neurons L.E. G. Miller J.N. C. Witters L.A. Kuhajda F.P. Ronnett G.V. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar). Since an in the AMP/ATP ratio is known to activate AMPK D.G. Carling D. Eur. J. Biochem. 1997; 246: 259-273Crossref PubMed Scopus (1138) Google Scholar, 16Winder W.W. J. Appl. Physiol. 2001; 91: 1017-1028Crossref PubMed Scopus (325) Google Scholar), we that a C75-induced in hypothalamic ATP levels could contribute to a decrease in in reduced hypothalamic AMPK activity. of of hypothalamic neurons with C75 to a significant in neuronal ATP levels to and of control at and C75 caused a change in ATP levels in neurons L.E. G. Miller J.N. C. Witters L.A. Kuhajda F.P. Ronnett G.V. J. Biol. Chem. 2004; 279: Full Text Full Text PDF PubMed Scopus Google Scholar), a decrease in the ratio of AMP/ATP and of Therefore, is that an in ATP caused by C75 also to the decrease in AMPK activity in the hypothalamus. AICAR the of C75 and the of AICAR could the C75-induced decrease in food intake, we mice h the of with C75 of i.p., h by an of AICAR C75 reduced food intake at h to of control In AICAR increased food intake at h to of the of AICAR reversed the C75-induced anorexia, in food intake that to that of control mice. The of AICAR on mice of with the metabolism of AICAR D. Witters L.A. Biochem. Sci. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The of an on food intake the may the of the of C75 and the of anorexia by AICAR of AMPK activity, AICAR the decrease in the level of hypothalamic pAMPKα that with C75 treatment. mice an by an h as and and C75 and and C75 and AICAR were for the and level of pAMPKα in which increased in and that C75 and a profound decrease in pAMPKα levels. AICAR C75 reversed the C75-induced decrease in hypothalamic pAMPKα levels. have used with the that AICAR the C75-induced changes in both behavior and the status of AMPK phosphorylation a of for the effects of C75 and These indicate that AICAR both C75-induced anorexia and the C75-induced of AMPK activity. C75 pCREB, and NPY in cellular metabolism and expression D.G. Hawley S.A. 2001; PubMed Scopus Google Scholar). the changes in the phosphorylation status of AMPK in the hypothalamus the level of pAMPKα in the arcuate we for pAMPKα the arcuate nucleus pAMPKα in the arcuate nucleus of mice The of by experiments the with pAMPKα increased to of control in the arcuate nucleus of mice fasted for h pAMPKα reduced in mice to of even in the of reduced food intake These changes are with our data a and and that C75 pAMPKα levels in the arcuate We have demonstrated by that C75 decreased hypothalamic NPY expression (4Loftus T. Jaworsky D. Frehywot G. Townsend C. Ronnett G. Lane M. Kuhajda F. Science. 2000; 288: 2379-2381Crossref PubMed Scopus (832) Google Scholar, E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar). We the decreases in pAMPKα in the arcuate with changes in NPY that with C75 treatment. NPY expression in neurons the arcuate nucleus in and fasted mice with of hypothalamic (9Kim E.K. Miller I. Landree L.E. Borisy-Rudin F.F. Brown P. Tihan T. Townsend C.A. Witters L.A. Moran T.H. Kuhajda F.P. Ronnett G.V. Am. J. Physiol. 2002; 283: E867-E879Crossref PubMed Scopus (123) Google Scholar), NPY expression in the arcuate nucleus of mice to of control and in fasted mice to of control that the NPY expression fasted M. J. 2001; PubMed Google Scholar, S. J.E. A. Mol. 1997; 51: PubMed Scopus Google Scholar), suggesting that leptin NPY expression M. J. 2001; PubMed Google Scholar). the pathways involved in the of NPY that with C75 we the level of in the arcuate nucleus M. 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J. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. C. C. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar), it of to study a change in levels in as AMPK to changes in energy status to C75 AMPK may as a in the central nervous as it in peripheral such as muscle (23Minokoshi Y. Kim Y.-B. Peroni O. Fryer L.G. Muller C. Carling D. Kahn B. Nature. 2002; 415: 339-343Crossref PubMed Scopus (1670) Google Scholar, D.G. Carling D. M. Annu. Rev. Biochem. 1998; PubMed Scopus Google Scholar). have by which AMPK could AMPK may Davies S.P. Carling D. Hardie D.G. 1997; PubMed Scopus Google Scholar), may via as to the nucleus I. Hawley S.A. A. Woods A. Carling D. Hardie D.G. Biochem. J. 1998; PubMed Scopus Google Scholar) and involved in T. Biochem. 2003; PubMed Google Scholar). The of pathways to support the that the levels of fatty the fatty acid synthetic are in the of energy balance. it that of hypothalamic causes a reduction in food intake, suggesting that increased fatty as a sensor of nutrient in hypothalamic neurons S. A. R. L. Med. 2003; PubMed Scopus Google Scholar). its of FAS and of activity, C75 may alter energy with the C75 is to affect of cellular such as metabolism M.D. D.J. D. Woods S.C. Seeley R.J. Med. 2003; PubMed Scopus Google Scholar). of the of alterations in energy may hypothalamic AMPK, as demonstrated in the The of a The study that at of the of C75 is the of AMPK activity, that AMPK is a for the of and W.W. 2000; PubMed Scopus Google Scholar). AMPK may as a the effects of C75 and can even food intake in mice. The of AMPK and the FAS to in a that modulation of may as a for appetite and weight We of the FAS for of