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• W2023353432 abstract "Expanding adipose tissue in obesity requires a great deal of angiogenesis to support increasing volumes of tissue. A growing body of evidence indicates that inhibiting these blood vessels can result in substantial weight loss, and now this has been demonstrated in nonhuman primates. Expanding adipose tissue in obesity requires a great deal of angiogenesis to support increasing volumes of tissue. A growing body of evidence indicates that inhibiting these blood vessels can result in substantial weight loss, and now this has been demonstrated in nonhuman primates. Extremely skeptical. That is the best description of my response to publications indicating that either diet-induced or genetic forms of obesity could be reversed by giving inhibitors to blood vessel formation. The first of these reports came from Maria Rupnick and Judah Folkman, who used agents that inhibit tumor growth and found profound weight loss in mice (Rupnick et al., 2002Rupnick M.A. Panigrahy D. Zhang C.Y. Dallabrida S.M. Lowell B.B. Langer R. Folkman M.J. Proc. Natl. Acad. Sci. USA. 2002; 99: 10730-10735Crossref PubMed Scopus (634) Google Scholar). The next of these reports used a more sophisticated approach in an attempt to direct the inhibition of the blood vessels specifically to adipose tissue. In an effort led by Wadih Arap and Renata Pasqulini, they used a technology called phage display that had been designed to identify the signatures of tumor-associated blood vessels that might be different than other blood vessels. However, they determined that many tissues, including adipose tissue, had unique properties. They were able to identify short peptide sequences that would selectively bind to the vasculature of white adipose tissue, but not other tissues they examined. As cancer researchers, they took the next logical step. They used this peptide and attached a poison pill that would produce apoptosis in the targeted blood vessels (Kolonin et al., 2004Kolonin M.G. Saha P.K. Chan L. Pasqualini R. Arap W. Nat. Med. 2004; 10: 625-632Crossref PubMed Scopus (428) Google Scholar). This targeted approach also led to rapid and substantial weight loss in mice. In their most recent manuscript published in Science Translational Medicine, this group has extended these results to obese nonhuman primates, showing substantial weight and body fat loss after 28 days of treatment with this peptide (Barnhart et al., 2011Barnhart K.F. Christianson D.R. Hanley P.W. Driessen W.H. Bernacky B.J. Baze W.B. Wen S. Tian M. Ma J. Kolonin M.G. Saha P.K. Do K.A. Hulvat J.F. Gelovani J.G. Chan L. Arap W. Pasqualini R. Sci. Transl. Med. 2011; 3 (108ra112)Crossref PubMed Scopus (62) Google Scholar). The reason for my skepticism toward this approach centered on the assumption that, whether untargeted or targeted, reducing adipose tissue blood vessels would impair adipose tissue function. While obesity is a scourge to be fought and is the direct result of expanding adipose tissue, the truth is that healthy adipose tissue serves an important function to protect the rest of the body from nutrients that, when stored in other tissues such as muscle and liver, cause metabolic dysfunction. The most obvious example of this comes from humans or mice who fail to make sufficient adipocytes. While leaner, such individuals nevertheless have severe metabolic problems, including liver steatosis, hyperlipidemia, and severe insulin resistance (Huang-Doran and Savage, 2011Huang-Doran I. Savage D.B. Pediatr. Endocrinol. Rev. 2011; 8: 190-199PubMed Google Scholar). Thus, it seemed likely that such an approach that compromised adipose tissue function could result in leaner individuals who were more at risk for metabolic disease. Ultimately, the data in mice and nonhuman primates simply do not support my assumption. In nonhuman primates, weight loss is accompanied by reduced insulin resistance (Barnhart et al., 2011Barnhart K.F. Christianson D.R. Hanley P.W. Driessen W.H. Bernacky B.J. Baze W.B. Wen S. Tian M. Ma J. Kolonin M.G. Saha P.K. Do K.A. Hulvat J.F. Gelovani J.G. Chan L. Arap W. Pasqualini R. Sci. Transl. Med. 2011; 3 (108ra112)Crossref PubMed Scopus (62) Google Scholar). In mice, our own work has demonstrated that treatment with this peptide results in rapid weight loss that is primarily due to reduced intake, and it is accompanied by metabolic improvements (Kim et al., 2010Kim D.H. Woods S.C. Seeley R.J. Diabetes. 2010; 59: 907-915Crossref PubMed Scopus (44) Google Scholar). The important point here is that the response to targeting the adipose tissue vasculature is the exact opposite of what is observed when adipocytes are not present or are pushed into apoptosis. While removal of adipocytes is associated with increased intake and decreased insulin sensitivity (Pajvani et al., 2005Pajvani U.B. Trujillo M.E. Combs T.P. Iyengar P. Jelicks L. Roth K.A. Kitsis R.N. Scherer P.E. Nat. Med. 2005; 11: 797-803Crossref PubMed Scopus (213) Google Scholar), removal of the supporting vasculature results in decreased intake and increased insulin sensitivity (Kim et al., 2010Kim D.H. Woods S.C. Seeley R.J. Diabetes. 2010; 59: 907-915Crossref PubMed Scopus (44) Google Scholar). The conclusion to be drawn is that adipocytes are an important source of signals to both the brain and other tissues and that the removal of those signals is deleterious. Targeting the adipose tissue vasculature results in changes in adipocyte communication that promote weight loss and improved metabolic regulation. This work has opened up an entirely unappreciated aspect of adipose tissue biology that explores the intimate relationship between adipocytes and their supporting vasculature. More importantly, understanding and manipulating this relationship has important therapeutic implications, given the potent effects of this particular peptide. A crucial question is whether this approach borrowed from cancer treatment is going to be sufficiently safe to be used in the growing number of individuals suffering under the burden of obesity and its comorbid conditions. After all, treating cancer is considerably different from treating a chronic condition such as obesity. Cancer patients are often under a short-term threat, while obesity is a much longer-term threat to an individual's health. As a consequence, the risk-benefit analysis is considerably different. For example, the specificity of the targeting is less of a concern in cancer as compared to obesity treatment. Imagine a peptide with 90% targeting selectivity to the tumor. Given that the plan would be to treat the cancer patient for weeks or months, as long as the tumor is being undermined faster than normal tissue, and that normal tissue can recover once treatment is terminated, it can be a viable therapy. For the obese patient who is likely to be taking such a treatment for the better part of his or her life, would 90% targeting selectivity be sufficient to avoid adverse effects on other tissues? Ninety-five percent? Ninety-nine percent? This is a complex question that will need to be answered before we know whether this approach will become therapy. The important new insights driven by the work with these targeted peptides are an important advance in an environment where few effective treatment strategies short of bariatric surgery are available to help obese patients. It is clear that more creative strategies from a wider range of disciplines are needed. To that end, further understanding of how adipose tissue signaling is altered by various aspects of its milieu, including the supporting blood vessels, macrophages, and its extracellular matrix, is necessary if we are to bring more therapies to the large unmet medical need presented by increasing rates of obesity." @default.
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• W2023353432 title "Treating Obesity Like a Tumor" @default.
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