Change in either energy intake or energy expenditure alone will meet resistance as compensatory adjustments occur, because body fat seems to be regulated homeostatically. Therefore, combined therapy targeting the multiple aspects of body weight regulation mechanism will solve this resistance. Some of the recent basic medical experiments attracting considerable attention as targets for obesity treatment in the complex mechanism of body weight regulation are as followings: intranasal leptin, peripheral cannabinoid-1 receptor inverse agonism reversing leptin resistance and hypothalamic autophagy acting on food-intake regulation; gut microorganism serving as nutritional and pharmacological targets for treating obesity and obesity-associated diseases; PRDM16, NAD-dependent deacetylase SirT1, Fibroblast growth factor 21, Retinaldehyde dehydrogenase, PGC-1α dependent myokine irisin, Pten, Thioesterase superfamily member 1, and study on exposure to cold temperature which target on energy expenditure, thermogenesis and brown adipose tissue as therapeutic means for obesity treatment. Also, the cytoplasmic domain of tissue factor (the initiator of the coagulation cascade) and protease-activated receptor 2 has received great attention as
a new therapeutic target for reducing body weight gain in obese individuals and treating obesity-associated type 2 diabetes.

Keywords: Food-intake regulation, Gut microorganism,Brown adipose tissue, Energy expenditure, Tissue factor

1. Bray GA, Tartaglia LA. Medicinal strategies in the treatment of obesity. Nature 2000;404:672-7.
   
2. Schulz C, Paulus K, J?hren O, Lehnert H. Intranasal leptin reduces appetite and induces weight loss in rats with diet-induced obesity (DIO). Endocrinology 2012;153:143-53.
   
3. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral Cannabinoid-1 Receptor Inverse Agonism Reduces Obesity by Reversing Leptin Resistance. Cell Metab 2012;16:167-79.
   
4. Experimental Drug Suppresses Appetite in Mice: Study. Drug Information Online 2012 July 26. Available from:URL: http://www.drugs.com/news/experimental-suppresses-appetite-mice-study-39486.html
5. Meng Q, Cai D. Defective hypothalamic autophagy directs the central pathogenesis of obesity via the IkappaB kinase beta (IKKbeta)/NF-kappaB pathway. J Biol Chem 2011;286:32324-32.
   
6. Delzenne NM, Neyrinck AM, B?ckhed F, Cani PD. Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol 2011;7:639-46.
   
7. Wostmann BS, Larkin C, Moriarty A, Bruckner-Kardoss E. Dietary intake, energy metabolism, excretory losses of adult male germfree Wistar rats. Lab Anim Sci 1983;33:46-50.
   
8. Cani PD, Delzenne NM. The role of the gut microbiota in energy metabolism and metabolic disease. Curr Pharm Des 2009;15:1546-58.
   
9. Cani PD, Delzenne NM. Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Curr Opin Pharmacol 2009;9:737-43.
   
10. Muccioli GG, Naslain D, B?ckhed F, Reigstad CS, Lambert DM, Delzenne NM, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol 2010;6:392.
    
11. Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 5th ed. New York: W.H. Freeman and Company; 2008. p.916-7.
12. Kiefer FW, Vernochet C, O'Brien P, Spoerl S, Brown JD, Nallamshetty S, et al. Retinaldehyde dehydrogenase 1 regulates a thermogenic program in white adipose tissue. Nat Med 2012;18:918-25.
    
13. Cypess AM, Chen YC, Sze C, Wang K, English J, Chan O, et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci USA 2012;109:10001-5.
    
14. Seale P, Bjork B, Yang W, Kajimura S, Chin S, Kuang S, et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 2008;454:961-7.
    
15. Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab 2007;6:38-54.
    
16. Kajimura S, Seale P, Tomaru T, Erdjument-Bromage H, Cooper MP, Ruas JL, et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev 2008;22:1397-409.
    
17. Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al. Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011;121:96-105.
    
18. Ohno H, Shinoda K, Spiegelman BM, Kajimura S. PPAR agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab 2012;15:395-404.
    
19. Qiang L, Wang L, Kon N, Zhao W, Lee S, Zhang Y, et al. Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Ppar . Cell 2012;150:620-32.
    
20. Turning White Fat Into Energy-Burning Brown Fat:Hope for New Obesity and Diabetes Treatments. ScienceDaily 2012 Aug 2. Available from: URL:http://www.sciencedaily.com/releases/2012/08/120802122305.htm
21. Barbera MJ, Schluter A, Pedraza N, Iglesias R, Villarroya F, Giralt M. Peroxisome proliferator-activated receptor alpha activates transcription of the brown fat uncoupling protein-1 gene. A link between regulation of the thermogenic and lipid oxidation pathways in the brown fat cell. J Biol Chem 2001;276:1486-93.
    
22. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, et al. FGF21 regulates PGC-1 and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271-81.
    
23. Bostr?m P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1- -dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463-8.
    
24. Chalhoub N, Baker SJ. PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol 2009;4:127-50.
    
25. Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 1995;141:1399-406.
    
26. Masse I, Molin L, Billaud M, Solari F. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18. Dev Biol 2005;286:91-101.
    
27. Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996;382:536-9.
    
28. Ortega-Molina A, Efeyan A, Lopez-Guadamillas E, Mu?oz-Martin M, G?mez-L?pez G, Ca?amero M, et al. Pten positively regulates brown adipose function, energy expenditure, longevity. Cell Metab 2012;15:382-94.
    
29. Li LO, Klett EL, Coleman RA. Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta 2010;1801:246-51.
    
30. Zhang Y, Li Y, Niepel MW, Kawano Y, Han S, Liu S, et al. Targeted deletion of thioesterase superfamily member 1 promotes energy expenditure and protects against obesity and insulin resistance. Proc Natl Acad Sci USA 2012;109:5417-22.
    
31. Adams SH, Chui C, Schilbach SL, Yu XX, Goddard AD, Grimaldi JC, et al. BFIT, a unique acyl-CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity. Biochem J 2001;360:135-42.
    
32. Zhang N, Lawrence DA. Tissue factor and obesity, a two-way street. Nat Med 2011;17:1343-4.
    
33. Riewald M, Ruf W. Science review: role of coagulation protease cascades in sepsis. Crit Care 2003;7:123-9.
    
34. Kassel KM, Owens AP 3rd, Rockwell CE, Sullivan BP, Wang R, Tawfik O, et al. Protease-activated receptor 1 and hematopoietic cell tissue factor are required for hepatic steatosis in mice fed a Western diet. Am J Pathol 2011;179:2278-89.
    
35. Badeanlou L, Furlan-Freguia C, Yang G, Ruf W, Samad F. Tissue factor-protease-activated receptor 2 signaling promotes diet-induced obesity and adipose inflammation. Nat Med 2011;17:1490-7.