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Cell Culture Approaches to Generating Brown Adipose Tissue for Autologous Transplantation


OBJECTIVE: The objective of this topic is to develop an in vitro culture approach to generating the approximately 50 grams of brown adipose tissue or brown fat from autologous cells that could be used for re-implantation and prevention or treatment of obesity. Brown fat appears to arise from a progenitor cell that preferentially differentiates into white fat. Under certain conditions these progenitor (or pre-progenitor) cells can be induced to differentiate into brown fat. Factors that have been implicated in this pathway include cold exposure, cytokines, adrenergic modulation, enzymes, growth factors and specific phosphorylation pathways. DESCRIPTION: Obesity along with its metabolic concomitant condition, diabetes are becoming increasingly prevalent in the general population as well as the military. Increasingly personnel are being rejected for these factors or need to be deferred later because of acquired obesity during service. Brown fat is a primary site of energy expenditure through thermogenesis that is mediated by the uncoupling protein-1 located in mitochondria. Brown fat is present in mammals especially in babies and during hibernation. Human adults have also been shown to have brown fat (1,2). The present project seeks proposals that will use easily accessible cells from a given individual to generate brown fat for re-implantation in that same individual. The approach would help the overweight and obese by boosting energy metabolism and thus making weight loss and maintenance feasible. Increasing brown fat in rats in amounts comparable by weight to the 50 grams of brown adipose for humans noted above resulted in the body weights being 20% lower than that of normal animals. Even on a calorie-rich diet the animals did not put on weight. (3). A number of approaches have been utilized to study brown fat. PHASE I: Conduct a detailed design and feasibility study to define a prototype source and culture system for the generation of brown adipose tissue. The source of cells should be readily available, for example in a subcutaneous fat or muscle biopsy or circulating blood (3-6). Cell culture systems should be consistent with a smooth transfer to the clinic through ethical, legal, social, and regulatory constraints. No human or animal use studies should be conducted during this phase. PHASE II: Based on the detailed design of phase I, a prototype system shall be fabricated and demonstrated during Phase II. The performance of the prototype should be quantitatively tested and characterized. The evaluation data will be used to refine the initial prototype, improve its performance and validate improvement and potential performance using militarily relevant procedures. FDA will be approached to determine requirements for clearance should a given system prove efficacious in animal experiments. The product will be a patentable system to generate brown adipose tissue. PHASE III DUAL USE APPLICATIONS: Animal studies consistent with FDA input progressing to phase I/II human studies will be performed in this phase. It is expected that this work will set the stage for a pivotal trial of this approach to obesity/overweight. REFERENCES [1] Cypress A et al. NEJM 360:1509 [2] Higuchi T, Kinuya S, Taki J et al. Annals of Nuclear Medicine 18:547 (2004). [3] Veliopoulos A, Muller-Decker K, Strzoda D et al. Science 10:1126 (2010). [4] Kajimura S et al. Nature online 10:1038 (2010) [5] Petrovic N et al. JBC on line 285:7153 (2010) [6] Haas B et al. Sci. Signal. On line 210:1126 (2009). [7] Newson SA et al. J. Endo rinology on line preprint 5 July 2010. Also see: REFERENCES:
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