AntiobesityResearch.com

A Researcher's Resource for Obesity Therapeutics 


        
 Fat Metabolism

      		
    

  



  

    
 MOLECULAR TARGETS 
     

    
    

        

            Molecule
            Obesity/IR?
            Remarks [references]
           
        
 
         
            ACC
            Various
             Increase peripheral vs decrease CNS [7,10,14,20,38,47] 
        
    
        
 
           CA
            Increase
            [19]
        

        
 
           CPT1
            various
            Decrease peripheral (CPT1b) vs increase CNS(CPT1c) [10,27] 
        

        
 
           DGAT
            Increase
            [11,23,31,33,34,39]
        

                
 
           FABP
            Increase
            [5,6,50]
        

        
 
           FAS
            Various
            Decrease peripheral vs increase CNS [10,23,26,27] 
        
 
           LCFA
            Unclear
            Decrease central (needs further study) [18,24,25]
        

        
 
           Lipase
            Increase
            [8,9,21,35] 
        
 
           MaCoA
            Various
            Increase peripheral vs decrease CNS [10,37,41]
        

                
 
           CIDEA
            Increase
            [51]
        

                        
 
           PRDM16
            Decrease
            [58,59,60]
        

            
 
           BMP7
            Decrease
            [60]
        

        
        
 
           UCP's
            Decrease
            [4,28,32,36,43,49,54]
        


    



 
 

    
              


    
        
 COMMERCIAL: LEADS --> PRODUCTS 
     

    
        

        

            Target
            Compound
            Company  [references]
           
        

        
 
         
            ACC
            CP640186
             Pfizer [7,20]
        
    
        
 
           FABP
            BMS309403
            BMS [5]
        

        
 
            FAS
            C75
             N/K [3,13]
        
    
        
 
           FAS
            Cerulenin
            N/K [13]
        

        
 
            Lipase
            Orlistat
             GSK [8,9]
        
    
        
 
           Lipase
            Cetilistat
            Alizyme&Takeda [8,21,35,63]
         

        
 
            Lipase
            GT-389255
             Peptimmune [35]
        
    
        
 
           ?????
            Palmitoleates
            Tethys Bioscience [2]
         

                
 
           DGAT
            N/K
            BMS [62]
         

        


  
       Abbreviations: FAS=fatty acid synthase; ACC=acetyl CoA carboxylase; FABP=fatty acid binding protein;
  CLA=conjugated linoleic acid; CA=carbonic anhydrase; CPT=carnitine palmitoyltransferase; DGAT=Diacylglyceroltransferase; LCFA=long chain fatty acid;
  MaCoA=malonylCoA; mTOR=mammalian target of rapamycin; UCP=uncoupling protein; N/K=not known 
 
 



    

    
              
   
    
 References
     


    

        

         
        

1. Aguiari P, Leo S,
Zavan B, Vindigni V, Rimessi A, Bianchi K, Franzin C, Cortivo R, Rossato M,
Vettor R, Abatangelo G, Pozzan T, Pinton P, Rizzuto R. High glucose induces adipogenic
differentiation of muscle-derived stem cells. Proc Natl Acad Sci U S A. 2008 Jan
29;105(4):1226-31.



2. Cao H, Gerhold K, Mayers JR,
Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to
systemic metabolism. Cell.
2008 Sep 19;134(6):933-44.



3. Dhillo WS. Appetite regulation: an overview. Thyroid. 2007
May;17(5):433-45.



4. Farmer SR. Molecular determinants of brown
adipocyte formation and function. Genes Dev. 2008 May 15;22(10):1269-75.



5. Furuhashi M,
Hotamisligil GS. Fatty acid-binding proteins: role in
metabolic diseases and potential as drug targets. Nat Rev Drug Discov. 2008 Jun;7(6):489-503.



6. Furuhashi M, Tuncman
G, Gsrgn CZ, Makowski L, Atsumi G, Vaillancourt E, Kono K, Babaev VR, Fazio S,
Linton MF, Sulsky R, Robl JA, Parker RA, Hotamisligil GS. Treatment of diabetes and
atherosclerosis by inhibiting fatty-acid-binding protein aP2. Nature. 2007 Jun 21;447(7147):959-65.



7. Harwood HJ Jr. Acetyl-CoA carboxylase inhibition for
the treatment of metabolic syndrome. Curr Opin Investig Drugs. 2004 Mar;5(3):283-9.



8. Heal DJ, Smith SL,
Fisas A, Codony X, Buschmann H. Selective 5-HT6 receptor ligands:
progress in the development of a novel pharmacological approach to the
treatment of obesity and related metabolic disorders. Pharmacol Ther. 2008 Feb;117(2):207-31.



9. Ioannides-Demos LL,
Proietto J, McNeil JJ. Pharmacotherapy for obesity. Drugs. 2005;65(10):1391-418.



10. Lane MD, Wolfgang M,
Cha SH, Dai Y. Regulation of food intake and energy
expenditure by hypothalamic malonyl-CoA. Int J Obes (Lond). 2008 Sep;32 Suppl 4:S49-54.



11. Matsuda D, Tomoda H. DGAT inhibitors for obesity. Curr Opin Investig Drugs. 2007 Oct;8(10):836-41.



12. Nedergaard J,
Bengtsson T, Cannon B. Unexpected evidence for active brown
adipose tissue in adult humans.
Am J Physiol Endocrinol Metab. 2007 Aug;293(2):E444-52.



13. Nisoli E, Carruba MO. Emerging aspects of pharmacotherapy for
obesity and metabolic syndrome.
Pharmacol Res. 2004 Nov;50(5):453-69



14. Ronnebaum SM, Joseph
JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, Sherry AD, Newgard CB. Chronic suppression of acetyl-CoA
carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose
rather than lipid metabolism.
J Biol Chem. 2008 May 23;283(21):14248-56.



15. Scherer
PE. Adipose tissue: from lipid storage compartment to
endocrine organ. Diabetes.
2006 Jun;55(6):1537-45.



16. Sharma AM, Staels B. Review: Peroxisome
proliferator-activated receptor gamma and adipose tissue--understanding
obesity-related changes in regulation of lipid and glucose metabolism. J Clin Endocrinol Metab. 2007 Feb;92(2):386-95.



17. Shi H, Strader AD,
Woods SC, Seeley RJ. The effect of fat removal on glucose
tolerance is depot specific in male and female mice. Am J Physiol Endocrinol Metab. 2007
Oct;293(4):E1012-20.



18. Silveira MB, Carraro R,
Monereo S, Tbar J. Conjugated linoleic acid (CLA) and
obesity.  Public Health Nutr. 2007
Oct;10(10A):1181-6



19. Supuran CT. Carbonic anhydrases: novel therapeutic
applications for inhibitors and activators. Nat Rev Drug Discov. 2008 Feb;7(2):168-81.



20. Tong L, Harwood HJ Jr. Acetyl-coenzyme A carboxylases:
versatile targets for drug discovery. J Cell Biochem. 2006 Dec 15;99(6):1476-88.



21. Vincent RP, le Roux
CW. New agents in development for the
management of obesity. Int J
Clin Pract. 2007 Dec;61(12):2103-12.



23. Proulx K, Cota D,
Woods SC, Seeley RJ. Fatty acid synthase inhibitors modulate
energy balance via mammalian target of rapamycin complex 1 signaling in the
central nervous system.
Diabetes. 2008 Dec;57(12):3231-8.



23. Chen HC, Farese RV
Jr. Inhibition of triglyceride synthesis as a treatment
strategy for obesity: lessons from DGAT1-deficient mice.
Arterioscler Thromb Vasc Biol. 2005;25(3):482-6




24. Li JJ, Huang CJ, Xie D. Anti-obesity effects of conjugated linoleic acid,
docosahexaenoic acid, and eicosapentaenoic acid. Mol Nutr Food Res.
2008;52(6):631-45.



25. Liu LF, Purushotham
A, Wendel AA, Belury MA. Combined effects of rosiglitazone and conjugated linoleic
acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed
mice. Am J Physiol Gastrointest Liver Physiol. 2007;292(6):G1671-82.



26. 
Lopez M and Carlos Dieguez. C75, a Fatty Acid Synthase (FAS) Inhibitor. Recent Patents on Endocrine, Metabolic & Immune
Drug Discovery 2007, 1, 53-62 53 



27. Mera P, Bentebibel A,
Lopez-Vinas et al. C75
is converted to C75-CoA in the hypothalamus, where it inhibits carnitine
palmitoyltransferase 1 and decreases food intake and body weight. Biochem
Pharmacol. 2008; 77:1084-95.



28. Ravussin E, Kozak LP.
Have we entered the brown adipose tissue renaissance?
Obes Rev. 2009;10:265-8.



29. Ronnett GV, Kleman
AM, Kim EK, Landree LE, Tu Y. Fatty acid metabolism, the central nervous system, and
feeding. Obesity (Silver Spring). 2006 5:201S-207S.



30. Ronnett GV, Kim EK,
Landree LE, Tu Y.Fatty acid metabolism as a target for obesity treatment.
Physiol Behav. 2005 May 19;85(1):25-35.



31. Tomoda H, Omura S. Potential therapeutics for obesity and atherosclerosis: inhibitors
of neutral lipid metabolism from microorganisms. Pharmacol Ther.
2007 Sep;115(3):375-89.



32. Voss-Andreae A,
Murphy JG, Ellacott KL, Stuart RC, Nillni EA, Cone RD, Fan W. Role of the central melanocortin circuitry in adaptive
thermogenesis of brown adipose tissue. Endocrinology. 2007
Apr;148(4):1550-60.



33. Zammit VA, Buckett LK,
Turnbull AV, Wure H, Proven A. Diacylglycerol acyltransferases: Potential roles as
pharmacological targets. Pharmacol Ther. 2008;118(3):295-302.



34. Zhao G, Souers AJ, Validation of diacyl glycerolacyltransferase I as a novel
target for the treatment of obesity and dyslipidemia using a potent and
selective small molecule inhibitor. J Med Chem. 2008;51(3):380-3.



35. Halford JC.Obesity drugs in clinical development. Curr Opin Investig Drugs. 2006 Apr;7(4):312-8.



36. Celi FS. Brown adipose tissue--when it pays to
be inefficient. N Engl J Med.
2009 Apr 9;360(15):1553-6.



37. Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD.
Differential effects of central fructose and glucose on hypothalamic
malonyl-CoA and food intake. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16871-5.



38. Choi CS, Savage DB,
Abu-Elheiga L, Liu ZX, Kim S, et al. Continuous fat oxidation in acetyl-CoA
carboxylase 2 knockout mice increases total energy expenditure, reduces fat
mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A. 2007 Oct
16;104(42):16480-5.



39. Choi CS, Savage DB,
Kulkarni A, Yu XX, Liu ZX, et al. Suppression of diacylglycerol
acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides
reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem. 2007 Aug 3;282(31):22678-88. 




40. Cypess AM, Lehman S,
Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A,
Kolodny GM, Kahn CR. Identification and importance of brown
adipose tissue in adult humans.
N Engl J Med. 2009 Apr 9;360(15):1509-17.



41. Lane MD, Cha SH. Effect of glucose and fructose on food
intake via malonyl-CoA signaling in the brain. Biochem Biophys Res Commun. 2009 Apr 24;382(1):1-5.
Epub 2009 Mar 3.



42. Weisberg SP, McCann
D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage
accumulation in adipose tissue.
J Clin Invest. 2003 Dec;112(12):1796-808.



43. van Marken
Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy
ND, Schrauwen P, Teule GJ. Cold-activated brown adipose tissue in
healthy men. N Engl J Med.
2009 Apr 9;360(15):1500-8.



44. Virtanen KA, Lidell
ME, Orava J, Heglind M, Westergren R, et al. Functional brown adipose tissue in
healthy adults. N Engl J Med.
2009 Apr 9;360(15):1518-25.



45. Wellen KE,
Hotamisligil GS. Obesity-induced inflammatory changes in
adipose tissue. J Clin
Invest. 2003 Dec;112(12):1785-8.



46. Wintour EM, Henry BA.
Glycerol transport: an additional
target for obesity therapy?
Trends Endocrinol Metab. 2006 Apr;17(3):77-8.



47. Wolf G. Role of fatty acids in the development
of insulin resistance and type 2 diabetes mellitus. Nutr Rev. 2008 Oct;66(10):597-600.



48. Xu H, Barnes GT, Yang
Q, Tan G, Yang D, Chou CJ,et al.Chronic inflammation in fat plays a
crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003 Dec;112(12):1821-30.



49. Enerback S. The origins of brown adipose tissue. N Engl J Med. 2009 May 7;360(19):2021-3



50. Maeda K, Cao H, Kono K, Gorgun CZ, Furuhashi M, et al. Adipocyte/macrophage fatty acid binding
proteins control integrated metabolic responses in obesity and diabetes. Cell Metab. 2005 Feb;1(2):107-19.



51. Gummesson A, Jerns
M, Svensson PA, Larsson I, Glad CA, Schle E, Gripeteg L, Sjholm K, Lystig TC,
Sjstrm L, Carlsson B, Fagerberg B, Carlsson LM. Relations of adipose tissue CIDEA gene
expression to basal metabolic rate, energy restriction, and obesity:
population-based and dietary intervention studies. J Clin Endocrinol Metab. 2007 Dec;92(12):4759-65. 



52. Inouye KE, Shi H,
Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS. Absence of CC chemokine ligand 2 does
not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes. 2007 Sep;56(9):2242-50.



53.Karamanlidis G,
Karamitri A, Docherty K, Hazlerigg DG, Lomax MA. C/EBPbeta reprograms white 3T3-L1
preadipocytes to a Brown adipocyte pattern of gene expression. J Biol Chem. 2007 Aug 24;282(34):24660-9.



54. Muraoka M, Fukushima
A, Viengchareun S, Lombs M, Kishi F, Miyauchi A, Kanematsu M, Doi J, Kajimura
J, Nakai R, Uebi T, Okamoto M, Takemori H. Involvement of SIK2/TORC2 signaling
cascade in the regulation of insulin-induced PGC-1{alpha} and UCP-1 gene
expression in brown adipocytes.
Am J Physiol Endocrinol Metab. 2009; 296: E1430-9.



55. Petrovic N, Shabalina
IG, Timmons JA, Cannon B, Nedergaard J. Thermogenically competent nonadrenergic
recruitment in brown preadipocytes by a PPARgamma agonist. Am J Physiol Endocrinol Metab. 2008
Aug;295(2):E287-96.



56. Ravussin E, Kozak LP.
Have we entered the brown adipose
tissue renaissance? Obes Rev.
2009 May;10(3):265-8.



57. Science DailyScientists Create Energy-burning Brown Fat In 
Mice. Science Daily Website, Accessed: 9-17-09



58. Seale P, Bjork B,
Yang W, Kajimura S, Chin S, Kuang S, Scim A, Devarakonda S, Conroe HM,
Erdjument-Bromage H, Tempst P, Rudnicki MA, Beier DR, Spiegelman BM. PRDM16 controls a brown fat/skeletal
muscle switch. Nature. 2008
Aug 21;454(7207):961-7. 



59. Seale P, Kajimura S,
Spiegelman BM. Transcriptional control of brown
adipocyte development and physiological function--of mice and men. Genes Dev. 2009 Apr 1;23(7):788-97. 



60. Tseng YH, Kokkotou E,
Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO,
Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein
7 in brown adipogenesis and energy expenditure. Nature. 2008 Aug 21;454(7207):1000-4.



61. Waki H, Tontonoz P. Endocrine functions of adipose tissue. Annu Rev Pathol. 2007;2:31-56.



62. Bristol Myers Sqibb Pharmaceuticals web site. In the Pipeline Accessed: 9-17-09



63. Takeda Pharmaceuticals web site. Development activities Accessed: 9-17-09