title: A peptidomimetic targeting white fat causes weight loss and improved insulin resistance in obese monkeys.
abstract: Obesity, defined as body mass index greater than 30, is a leading cause of morbidity and mortality and a financial burden worldwide. Despite significant efforts in the past decade, very few drugs have been successfully developed for the treatment of obese patients. Biological differences between rodents and primates are a major hurdle for translation of anti-obesity strategies either discovered or developed in rodents into effective human therapeutics. Here, we evaluate the ligand-directed peptidomimetic CKGGRAKDC-GG-(D)(KLAKLAK)(2) (henceforth termed adipotide) in obese Old World monkeys. Treatment with adipotide induced targeted apoptosis within blood vessels of white adipose tissue and resulted in rapid weight loss and improved insulin resistance in obese monkeys. Magnetic resonance imaging and dual-energy x-ray absorptiometry confirmed a marked reduction in white adipose tissue. At experimentally determined optimal doses, monkeys from three different species displayed predictable and reversible changes in renal proximal tubule function. Together, these data in primates establish adipotide as a prototype in a new class of candidate drugs that may be useful for treating obesity in humans.
authors.affiliation: David H. Koch Center, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kirstin F
authors.initials: KF
authors.lastname: Barnhart
authors.forename: Dawn R
authors.initials: DR
authors.lastname: Christianson
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Hanley
authors.forename: Wouter H P
authors.initials: WH
authors.lastname: Driessen
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Bernacky
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Baze
authors.forename: Sijin
authors.initials: S
authors.lastname: Wen
authors.forename: Mei
authors.initials: M
authors.lastname: Tian
authors.forename: Jingfei
authors.initials: J
authors.lastname: Ma
authors.forename: Mikhail G
authors.initials: MG
authors.lastname: Kolonin
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Saha
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: James F
authors.initials: JF
authors.lastname: Hulvat
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D015502:Absorptiometry, Photon; D052436:Adipose Tissue, White / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D000886:Anthropometry; D002520:Cercopithecidae; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005247:Feeding Behavior; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D008969:Molecular Sequence Data; D009765:Obesity / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D015431:Weight Loss / Q000187:drug effects*
chemical_list: D057786:Peptidomimetics
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18637-42
references.pmid: 22049339
references.citation: J Nutr. 2008 Feb;138(2):397-402
references.pmid: 18203910
references.citation: J Lipid Res. 1995 Mar;36(3):451-61
references.pmid: 7775857
references.citation: Cancer Res. 2004 Jan 15;64(2):435-9
references.pmid: 14744752
references.citation: Nat Med. 2004 Jun;10(6):581-2
references.pmid: 15170200
references.citation: Science. 2008 Oct 24;322(5901):583-6
references.pmid: 18801968
references.citation: Am J Physiol Renal Physiol. 2007 Jul;293(1):F382-90
references.pmid: 17429029
references.citation: Lancet. 1992 Nov 28;340(8831):1326-9
references.pmid: 1360044
references.citation: J Med Chem. 2009 May 28;52(10):3293-9
references.pmid: 19397319
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2182-7
references.pmid: 19168626
references.citation: Obes Rev. 2011 Feb;12(2):131-41
references.pmid: 20122135
references.citation: Int J Obes Relat Metab Disord. 1993 Jan;17(1):53-61
references.pmid: 8383642
references.citation: Nat Rev Drug Discov. 2006 Nov;5(11):919-31
references.pmid: 17080028
references.citation: J Soc Gynecol Investig. 1995 Sep-Oct;2(5):708-15
references.pmid: 9420879
references.citation: Metabolism. 1994 Jul;43(7):847-54
references.pmid: 8028507
references.citation: Obesity (Silver Spring). 2009 Aug;17(8):1499-505
references.pmid: 19325546
references.citation: Cardiovasc Diabetol. 2009 Apr 23;8:22
references.pmid: 19389241
references.citation: Diabetes. 2010 Apr;59(4):907-15
references.pmid: 20103704
references.citation: FASEB J. 2007 Oct;21(12):3272-8
references.pmid: 17513561
references.citation: Curr Opin Clin Nutr Metab Care. 2007 Mar;10(2):142-8
references.pmid: 17285001
references.citation: J Biol Chem. 2008 Oct 24;283(43):29447-60
references.pmid: 18718906
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R257-65
references.pmid: 12069952
references.citation: Diabetologia. 2005 Nov;48(11):2203-5
references.pmid: 16193286
references.citation: Nat Med. 1999 Sep;5(9):1032-8
references.pmid: 10470080
references.citation: J Gerontol A Biol Sci Med Sci. 2005 Dec;60(12):1518-24
references.pmid: 16424283
references.citation: Nat Med. 2002 Feb;8(2):121-7
references.pmid: 11821895
references.citation: Pharm Res. 2011 Aug;28(8):1792-818
references.pmid: 21181547
references.citation: Lancet. 2010 Aug 14;376(9740):517-23
references.pmid: 20709233
references.citation: Diabetes Care. 2002 Mar;25(3):517-23
references.pmid: 11874940
references.citation: Cancer Cell. 2004 Sep;6(3):275-84
references.pmid: 15380518
references.citation: JAMA. 2009 Feb 4;301(5):533-5
references.pmid: 19190318
references.citation: Nature. 2010 Dec 16;468(7326):878
references.pmid: 21164452
references.citation: Curr Treat Options Cardiovasc Med. 2010 Aug;12(4):381-95
references.pmid: 20842561
references.citation: Ther Adv Cardiovasc Dis. 2009 Feb;3(1):75-90
references.pmid: 19144669
references.citation: Nat Rev Endocrinol. 2010 May;6(5):255-69
references.pmid: 20234354
references.citation: N Engl J Med. 2008 May 1;358(18):1941-50
references.pmid: 18450605
references.citation: J Control Release. 2010 Oct 15;147(2):261-8
references.pmid: 20647023
references.citation: Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10730-5
references.pmid: 12149466
references.citation: Lancet. 2009 Mar 28;373(9669):1083-96
references.pmid: 19299006
references.citation: Nat Med. 2004 Jun;10(6):625-32
references.pmid: 15133506
references.citation: Cancer Res. 2009 Jun 15;69(12):5259-66
references.pmid: 19491274