title: Brain fatty acid synthase activates PPARalpha to maintain energy homeostasis.
abstract: Central nervous system control of energy balance affects susceptibility to obesity and diabetes, but how fatty acids, malonyl-CoA, and other metabolites act at this site to alter metabolism is poorly understood. Pharmacological inhibition of fatty acid synthase (FAS), rate limiting for de novo lipogenesis, decreases appetite independently of leptin but also promotes weight loss through activities unrelated to FAS inhibition. Here we report that the conditional genetic inactivation of FAS in pancreatic beta cells and hypothalamus produced lean, hypophagic mice with increased physical activity and impaired hypothalamic PPARalpha signaling. Administration of a PPARalpha agonist into the hypothalamus increased PPARalpha target genes and normalized food intake. Inactivation of beta cell FAS enzyme activity had no effect on islet function in culture or in vivo. These results suggest a critical role for brain FAS in the regulation of not only feeding, but also physical activity, effects that appear to be mediated through the provision of ligands generated by FAS to PPARalpha. Thus, 2 diametrically opposed proteins, FAS (induced by feeding) and PPARalpha (induced by starvation), unexpectedly form an integrative sensory module in the central nervous system to orchestrate energy balance.
authors: Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors: Manu V
authors: MV
authors: Chakravarthy
authors: Yimin
authors: Y
authors: Zhu
authors: Miguel
authors: M
authors: López
authors: Li
authors: L
authors: Yin
authors: David F
authors: DF
authors: Wozniak
authors: Trey
authors: T
authors: Coleman
authors: Zhiyuan
authors: Z
authors: Hu
authors: Michael
authors: M
authors: Wolfgang
authors: Antonio
authors: A
authors: Vidal-Puig
authors: M Daniel
authors: MD
authors: Lane
authors: Clay F
authors: CF
authors: Semenkovich
mesh_terms: D000818:Animals; D001070:Appetitive Behavior; D001835:Body Weight; D002454:Cell Differentiation; D004789:Enzyme Activation; D064429:Fatty Acid Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006728:Hormones / Q000097:blood; D007027:Hypothalamic Diseases / Q000201:enzymology / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D006728:Hormones; D047493:PPAR alpha; D064429:Fatty Acid Synthases
references: J Lipid Res. 1992 Jan;33(1):31-9
references: 1552231
references: Science. 2000 Jun 30;288(5475):2379-81
references: 10875926
references: N Engl J Med. 2000 Dec 21;343(25):1888-9
references: 11117983
references: Diabetes Obes Metab. 1999 Sep;1(5):281-4
references: 11225639
references: J Clin Invest. 2001 Apr;107(8):1025-34
references: 11306606
references: J Clin Invest. 2001 Dec;108(11):1631-8
references: 11733558
references: Diabetes. 2002 Feb;51(2):271-5
references: 11812732
references: Prog Neuropsychopharmacol Biol Psychiatry. 2002 Jan;26(1):119-22
references: 11853101
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3240-5
references: 11867747
references: Mol Cell Biol. 2002 Jul;22(14):5027-35
references: 12077332
references: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11848-53
references: 12195019
references: Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E867-79
references: 12376313
references: Nat Med. 2003 May;9(5):483-5
references: 12724740
references: Proc Natl Acad Sci U S A. 2003 May 27;100(11):6358-63
references: 12738878
references: Nat Med. 2003 Jun;9(6):756-61
references: 12754501
references: Nature. 2003 Sep 4;425(6953):90-3
references: 12955147
references: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12624-9
references: 14532332
references: Nat Rev Neurosci. 2003 Nov;4(11):901-9
references: 14595401
references: Neuroscience. 2004;123(1):131-45
references: 14667448
references: J Biol Chem. 1993 Apr 5;268(10):6961-70
references: 8463228
references: J Biol Chem. 1995 Dec 8;270(49):29323-9
references: 7493965
references: Diabetes. 1996 Feb;45(2):190-8
references: 8549864
references: Cancer Res. 1996 Feb 15;56(4):745-51
references: 8631008
references: Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3789-94
references: 9108056
references: Prog Lipid Res. 1997 Mar;36(1):43-53
references: 9373620
references: J Biol Chem. 1999 Jan 1;274(1):305-15
references: 9867845
references: Nature. 1998 Dec 17;396(6712):670-4
references: 9872314
references: Eur J Biochem. 1999 Mar;260(2):505-11
references: 10095788
references: Neurobiol Dis. 2004 Dec;17(3):403-14
references: 15571976
references: Diabetes. 2005 Feb;54(2):462-71
references: 15677504
references: J Biol Chem. 2005 Mar 11;280(10):9023-9
references: 15637076
references: J Clin Invest. 2005 Apr;115(4):940-50
references: 15841180
references: J Clin Invest. 2005 May;115(5):1298-305
references: 15864349
references: Cell Metab. 2005 May;1(5):309-22
references: 16054078
references: Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14557-62
references: 16203972
references: N Engl J Med. 2005 Nov 17;353(20):2121-34
references: 16291982
references: J Biol Chem. 2005 Dec 2;280(48):39681-3
references: 16219771
references: J Biol Chem. 2006 Feb 3;281(5):2649-53
references: 16326700
references: J Clin Invest. 2006 Apr;116(4):1081-91
references: 16528412
references: Am J Physiol Heart Circ Physiol. 2006 May;290(5):H1798-807
references: 16339839
references: Diabetes. 2006 May;55(5):1327-36
references: 16644689
references: N Engl J Med. 2006 Aug 24;355(8):763-78
references: 16926275
references: Nature. 2006 Sep 21;443(7109):289-95
references: 16988703
references: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15410-5
references: 17030788
references: Int J Obes (Lond). 2007 Aug;31(8):1240-7
references: 17342077
references: Genesis. 2000 Feb;26(2):139-42
references: 10686610
references: Mol Cell Biol. 2004 Jan;24(1):258-69
references: 14673160
references: Biochem J. 2004 Mar 15;378(Pt 3):983-90
references: 14641110
references: Diabetes. 2004 Jul;53(7):1915-9
references: 15220220
references: J Clin Invest. 2004 Oct;114(7):908-16
references: 15467829
references: J Biol Chem. 1977 Aug 10;252(15):5483-7
references: 18465
references: Nature. 1979 Nov 29;282(5738):503-5
references: 116135