AntiobesityResearch.com

A Researcher's Resource for Obesity Therapeutics 


        
 Kinases & Phosphatases

      		
    

  



  

    
 MOLECULAR TARGETS 
     

    
    

        

            Molecule
            Obesity/IR?
            Remarks [references]
           
        
 
         
            AMPK
            Various
             Decrease peripheral vs Increase CNS [2,4,5,7-14,31] 
        
    
        
 
           PTP1B
            Increase
            [1,19-24]
            
        
 
         PI3K
            Mostly decrease
             [6,21,25-27] 
        
    
        
 
           mTOR
            Variable
            Oversimplified: Increase peripheral vs decrease CNS [15-18,29,30,33] 
        

    

    


 

    
              


    
        
 COMMERCIAL: LEADS --> PRODUCTS 
     

    
        

        

            Target
            Compound
            Company  [references]
           
        

        
 
         
            AMPK
            AICAR
             N/K [2]
        
    
        
 
           AMPK
            Metformin
             Various [5]
        

        
 
            AMPK
            A-768662
             N/K [9]
        
    
        
 
           PTP1B
            MSI-1463
             Genaera [1]
        
 
           PTP1B
            ISIS288267
             ISIS [23]
        

        
 
           PTP1B
            ISIS288291
             ISIS [23]
        

    


       

       Abbreviations: AMP-PK=AMP activated protein kinase; mTOR=mammalian target of rapamycin; PI3K=phosphatidylinositol 3-kinase;
PTP=protein tyrosine phosphatase; N/K=not known



    

            
              
  
    
 References
     





    

        

         
        

  



 1. Genaera. Phase 1 Data for Trodusquemine (MSI-1436). Accessed online 10-6-09



2. Hardie DG. AMP-activated protein kinase as a drug
target. Annu Rev Pharmacol
Toxicol. 2007;47:185-210.




3. Henry BA, Clarke IJ. Adipose tissue hormones and the
regulation of food intake. J
Neuroendocrinol. 2008 Jun;20(6):842-9.



4. Kola B, Boscaro M,
Rutter GA, Grossman AB, Korbonits M. Expanding role of AMPK in
endocrinology. Trends
Endocrinol Metab. 2006 Jul;17(5):205-1.



5. Viollet B, Foretz M,
Guigas B, Horman S, Dentin R, Bertrand L, Hue L, Andreelli F. Activation of AMP-activated protein
kinase in the liver: a new strategy for the management of metabolic hepatic
disorders. J Physiol. 2006
Jul 1;574(Pt 1):41-53.



6. Wisse BE, Kim F,
Schwartz MW. Physiology. An integrative view of
obesity. Science. 2007 Nov
9;318(5852):928-9



7. Hardie DG. AMPK: a key regulator of energy balance
in the single cell and the whole organism. Int J Obes (Lond). 2008;32 S4:S7-12.



8. Hutchinson DS,
Summers RJ, Bengtsson T. Regulation of AMP-activated protein
kinase activity by G-protein coupled receptors: potential utility in treatment
of diabetes and heart disease.
Pharmacol Ther. 2008 Sep;119(3):291-310.



9. Cool B, Zinker B,
Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R,
Zhao G, Marsh K, Kym P, Jung P, Camp HS, Frevert E. Identification and characterization of
a small molecule AMPK activator that treats key components of type 2 diabetes
and the metabolic syndrome. Cell
Metab. 2006 Jun;3(6):403-16.



10. Cant— C,
Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ,
Puigserver P, Auwerx J. AMPK regulates energy expenditure by
modulating NAD+ metabolism and SIRT1 activity. Nature. 2009 Apr 23;458(7241):1056-60.




11. Fulco M, Sartorelli
V. Comparing and contrasting the roles of
AMPK and SIRT1 in metabolic tissues. Cell Cycle. 2008 Dec;7(23):3669-79.



12. Kim WS, Lee YS, Cha
SH, Jeong HW, Choe SS, Lee MR, Oh GT, Park HS, Lee KU, Lane MD, Kim JB. Berberine
improves lipid dysregulation in obesity by controlling central and peripheral
AMPK activity. Am J
Physiol Endocrinol Metab. 2009 Apr;296(4):E812-9. Epub 2009 Jan 27.



13. Lage R, DiŽguez C,
Vidal-Puig A, L—pez M. AMPK: a metabolic gauge regulating
whole-body energy homeostasis. Trends Mol Med. 2008
Dec;14(12):539-49.



14. Viollet B, Mounier R,
Leclerc J, Yazigi A, Foretz M, Andreelli F. Targeting AMP-activated protein kinase
as a novel therapeutic approach for the treatment of metabolic disorders. Diabetes Metab. 2007 Dec;33(6):395-402.




15. Xue B, Kahn BB. AMPK integrates nutrient and hormonal
signals to regulate food intake and energy balance through effects in the
hypothalamus and peripheral tissues. J Physiol. 2006 Jul 1;574(Pt 1):73-83.



16. Cota D, Matter EK,
Woods SC, Seeley RJ The role of hypothalamic mammalian
target of rapamycin complex 1 signaling in diet-induced obesity. J Neurosci. 2008 Jul 9;28(28):7202-8.



17. Mori H, Inoki K,
MŮnzberg H, Opland D, Faouzi M, Villanueva EC, et al. Critical role for hypothalamic mTOR
activity in energy balance. Cell
Metab. 2009 Apr;9(4):362-74



18. 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.



19. Clapham JC, Arch JR. Thermogenic and metabolic antiobesity
drugs: rationale and opportunities. Diabetes Obes Metab. 2007 May;9(3):259-75.



20. Dhillo WS. Appetite regulation: an overview. Thyroid. 2007.


21. Lorenzo M, Fern‡ndez-Veledo
S, Vila-Bedmar R, Garcia-Guerra L, De Alvaro C, Nieto-Vazquez I. Insulin resistance
induced by tumor necrosis factor-alpha in myocytes and brown adipocytes.
J Anim Sci. 2008 Apr;86(14 Suppl):E94-104.



22. Nieto-Vazquez I, Fern‡ndez-Veledo
S, de Alvaro C, Rondinone CM, Valverde AM, Lorenzo M. Protein-tyrosine phosphatase
1B-deficient myocytes show increased insulin sensitivity and protection against
tumor necrosis factor-alpha-induced insulin resistance. Diabetes. 2007 Feb;56(2):404-13.



23. Pandey SK, Yu XX,
Watts LM, Michael MD, Sloop KW, Rivard AR, Leedom TA, Manchem VP, Samadzadeh L,
McKay RA, Monia BP, Bhanot S. Reduction of low molecular weight
protein-tyrosine phosphatase expression improves hyperglycemia and insulin
sensitivity in obese mice. J
Biol Chem. 2007 May 11;282(19):14291-9.



24. Salmeen A, Andersen
JN, Myers MP, Meng TC, Hinks JA, Tonks NK, Barford D. Redox regulation of protein tyrosine
phosphatase 1B involves a sulphenyl-amide intermediate. Nature. 2003 Jun 12;423(6941):769-73.



25. Hill JW, Williams KW,
Ye C, Luo J, Balthasar N, Coppari R, Cowley MA, Cantley LC, Lowell BB, Elmquist
JK. Acute effects of leptin require PI3K
signaling in hypothalamic proopiomelanocortin neurons in mice. J Clin Invest. 2008 May;118(5):1796-805.



26. Schwartz
MW, Porte D Jr. Diabetes, obesity, and the brain.
Science. 2005 Jan 21;307(5708):375-9.



27. Xu AW, Kaelin CB,
Takeda K, Akira S, Schwartz MW, Barsh GS. PI3K integrates the action of insulin
and leptin on hypothalamic neurons. J Clin Invest. 2005 Apr;115(4):951-8.



28. Narkar VA, Downes M,
Yu RT, Embler E, Wang YX, Banayo E, Mihaylova MM, Nelson MC, Zou Y, Juguilon H,
Kang H, Shaw RJ, Evans RM. AMPK and PPARdelta agonists are exercise mimetics. Cell. 2008 Aug 8;134(3):405-15.




29. Cota D, Proulx K,
Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ. Hypothalamic mTOR signaling regulates
food intake. Science. 2006
May 12;312(5775):927-30. 



30. Cota D. Mammalian target of rapamycin complex 1
(mTORC1) signaling in energy balance and obesity. Physiol Behav. 2009 Jul 14;97(5):520-4.



31. Ropelle ER, Pauli JR,
Fernandes MF, Rocco SA, Marin RM, Morari J, Souza KK, Dias MM, Gomes-Marcondes
MC, Gontijo JA, Franchini KG, Velloso LA, Saad MJ, Carvalheira JB. A central role for neuronal
AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) in
high-protein diet-induced weight loss. Diabetes. 2008 Mar;57(3):594-605. 




32. Ropelle ER, Pauli JR,
Prada P, Cintra DE, Rocha GZ, Moraes JC, Frederico MJ, da Luz G, Pinho RA,
Carvalheira JB, Velloso LA, Saad MA, De Souza CT. Inhibition of hypothalamic Foxo1
expression reduced food intake in diet-induced obesity rats. J Physiol. 2009 May 15;587(Pt 10):2341-51.



33. Woods SC, Seeley RJ,
Cota D. Regulation of food intake through
hypothalamic signaling networks involving mTOR. Annu Rev Nutr. 2008;28:295-311.