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(12) United States Patent (10) Patent No.: US 9,682,093 B2 Singh (45) Date of Patent: Jun

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(12) United States Patent (10) Patent No.: US 9,682,093 B2 Singh (45) Date of Patent: Jun USOO9682093B2 (12) United States Patent (10) Patent No.: US 9,682,093 B2 Singh (45) Date of Patent: Jun. 20, 2017 (54) COMPOSITIONS AND METHODS FOR OTHER PUBLICATIONS TREATING OR PREVENTING METABOLC SYNDROME DISORDERS Schneider et al. Resveratrol Inhibits Intestinal Tumorigenesis and Modulates Host-Defense-Related Gene Expression in an Animal (71) Applicant: CHARLES R. DREW UNIVERSITY Model of Human Familial Adenomatous Polyposis. Nutrition and OF MEDICINE AND SCIENCE, Los Cancer, 39(1), 102-107, 2001.* Angeles, CA (US) Glossary of medical education terms, Institute of International Medical Education. http://www.iime.org/glossary.htm Accessed in (72) Inventor: Rajan Singh, Los Angeles, CA (US) Mar. 2013. (73) Assignee: Charles R. Drew University of Grundy et al. Diagnosis and Management of the Metabolic Syn Medicine and Science, Los Angeles, drome an American Heart Association/National Heart, Lung, and CA (US) Blood Institute Scientific Statement. Circulation 112:2735-2752, 2005.* (*) Notice: Subject to any disclaimer, the term of this Nakatani et al. Follistatin-derived peptide expression in muscle patent is extended or adjusted under 35 decreases adipose tissue mass and prevents hepatic steatosis. Am J Physiol Endocrinol Metab 300: E543-E553, 2011. First published U.S.C. 154(b) by 0 days. Jan. 4, 2011.* Iezzi et al. Deacetylase Inhibitors Increase Muscle Cell Size by (21) Appl. No.: 14/389,374 Promoting Myoblast Recruitment and Fusion through Induction of Follistatin. Developmental Cell, vol. 6, 673-684, May 2004.* (22) PCT Filed: Apr. 1, 2013 Pfitzner et al. PioglitaZone: an antidiabetic drug with cardiovascu lar therapeutic effects. Expert Rev. Cardiovasc. Ther. 4(4), 445-459 (86). PCT No.: PCT/US2O13/034.855 (2006).* Guo et al. Overexpression of Mouse Follistatin Causes Reproduc S 371 (c)(1), tive Defects in Transgenic Mice. Molecular Endocrinology 12: (2) Date: Sep. 29, 2014 96-106, 1998.* Szkudelska, K., et al., Resveratrol, Obesity and Diabetes, Eur, J. (87) PCT Pub. No.: WO2013/149258 Pharmacol., 2010, 635: 1-8. Jeong, G-S, et al., Butein from Rhus verniciflua Protects Pancreatic PCT Pub. Date: Oct. 3, 2013 Beta Cells Against Cytokine-Induced Toxicity Mediated by Inhibi tion of Nitric Oxide Formation, Biol. Pharm. Bull., 2011, 34(1): 97 (65) Prior Publication Data 102. US 2016/O12089.0 A1 May 5, 2016 Hwank, J-T. et al., Genistein, EGCG, and Capsaicin Inhibit Adipocyte Differentiation Process Via Activating AMP-Activated Protein Kinase, Biochem. Biophys. Res. Comm., 2005, 338:694 Related U.S. Application Data 699. Prasath, G.S., et al., Modulatory Effects of Fisetin, a Bioflavonoid, (60) Provisional application No. 61/618,603, filed on Mar. on Hyperglycemia by Attenuating the Key Enzymes of Carbohy 30, 2012. drate Metabolism in Hepatic and Renal Tissues in Streptozotocin Induced Diabetic Rats, Eur, J. Pharmacol., 2011, 668(3):492-496. (51) Int. Cl. Venkatesan, B., et al., Resveratrol Inhibits PDGF Receptor A6 IK3I/7034 (2006.01) Mitogenic Signaling in Mesangial Cells: Role of PTP1B, FASEB J. A6 IK 45/06 (2006.01) A6 IK 3/47 (2006.01) 2008, 22(10):3469-3482. Brown, M.L., et al., Follistatin and Follistatin Like-3 Differentially A6 IK3I/05 (2006.01) Regulate Adiposity and Glucose Homeostasis, Obesity, 2011, A6 IK3I/352 (2006.01) 19(10): 1940-1949. A 6LX 3L/095 (2006.01) A6 IK 3L/2 (2006.01) * cited by examiner (52) U.S. Cl. Primary Examiner — Clinton Brooks CPC .......... A6 IK3I/7034 (2013.01); A61 K3I/05 Assistant Examiner — Yih-Horng Shiao (2013.01); A61 K3I/095 (2013.01); A61 K (74) Attorney, Agent, or Firm — Pillsbury Winthrop Shaw 3 1/12 (2013.01); A61K 31/352 (2013.01); Pittman LLP A61K 31/417 (2013.01); A61K 45/06 (2013.01) (57) ABSTRACT (58) Field of Classification Search The invention provides methods, compositions, uses of CPC ... A61K 31/7034; A61K 31/05; A61K 31/352: compositions, assays and kits for modulating brown adipose A61K 31/417; A61K 45/06 tissue (BAT) in animals and patients with obesity, insulin USPC ................................... 514/385, 456, 35, 733 resistance and perturbed glucose homeostasis are disclosed. See application file for complete search history. Accordingly, methods, compositions, uses of compositions, (56) References Cited and kits are useful for the amelioration of pathological conditions characterized by storage of excess energy, insulin FOREIGN PATENT DOCUMENTS resistance and related metabolic syndromes often associated with obesity. WO 2006O136O2 A1 2, 2006 WO 2013 OO1270 A1 1, 2013 13 Claims, 31 Drawing Sheets U.S. Patent Jun. 20, 2017 Sheet 1 of 31 US 9,682,093 B2 Fst (+) male inite Fst (e-) female nice Day 13 pre gnant mice Sacrifice mice and collect embryos Genotyping and electropharesis separation of PCR amplicons. Fst Fst wild type e Mouse embryonic fibro blast MEF) primary cu iture Brown fat differentiation cocktail and Treatment with full -length Fst protein Gene and protein expression Cellular bioenergetics F.G. U.S. Patent Jun. 20, 2017 Sheet 2 of 31 US 9,682,093 B2 is gette expresign 88alysis is hi aas K3 grinary cuisite FG. 2A Fst it OFst k. FIG. 2B FIG. 2C U.S. Patent Jun. 20, 2017 Sheet 3 of 31 US 9,682,093 B2 FG 3 U.S. Patent Jun. 20, 2017 Sheet 4 of 31 US 9,682,093 B2 & U.S. Patent Jun. 20, 2017 Sheet S of 31 US 9,682,093 B2 st Fist KO 40X UCP F.G. 5 U.S. Patent Jun. 20, 2017 Sheet 6 of 31 US 9,682,093 B2 FG, 6 U.S. Patent Jun. 20, 2017 Sheet 7 of 31 US 9,682,093 B2 UcP1 Ko F.G. 7 PGC-1a. T KC FG, 8 U.S. Patent Jun. 20, 2017 Sheet 8 of 31 US 9,682,093 B2 Oligomycin FCCP RotenoreMyxothiazole. | U.S. Patent Jun. 20, 2017 Sheet 9 of 31 US 9,682,093 B2 FIG. O U.S. Patent Jun. 20, 2017 Sheet 10 of 31 US 9,682,093 B2 FG. A Fst 8. FIG B 1.2 5 0.8 i 9 0.4 is: 0.0 Fst WT Fst KO FIG C Fst WT Fst KO U.S. Patent Jun. 20, 2017 Sheet 11 of 31 US 9,682,093 B2 FG. D .2 OFst WT 1.0 IFst KO 0.3 0.6 e 0.4 re 0.2 0.0 AP2 PPARy PRDM16 UCP1 PGC-1a FIG. E Fst W & Fst KO 1.2 Fst WT .0 IFst KO 0.8 0.6 0.4 0.2 0. Fst WT FSt KO U.S. Patent US 9,682,093 B2 Fs Fst KO AA Arrrrist |- (8.5ugiri) Fst W FSO rst W st KO PGC-8 cidea s kye Fst W Fst Fst W Fst FG. 2A U.S. Patent Jun. 20, 2017 Sheet 13 of 31 US 9,682,093 B2 F.G. 2B rfst (8.5gins press cip SC 8-actis FG. 2C Rys c PCscr k a 3.5 s: cal s Artist is a s (Q.5ugiti S 4.08 : 0.7 0.5e . g 8. 92 a . est rst. s Esk st st K. U.S. Patent US 9,682,093 B2 &&&&&&&&&&&&&&&& FG, 2) U.S. Patent Jun. 20, 2017 Sheet 15 of 31 US 9,682,093 B2 F.G. 3A 1 . .9 to Fst W 0.8 Fst Ko ,7 s as e 4. s .3 ke se 2 s s: . k se . * s s s * s F.G. 13B GM BATM Fst W. Fst KO FSW Fst KO Adipoc pAMPK AMPK Mup GAPDH U.S. Patent Jun. 20, 2017 Sheet 16 of 31 US 9,682,093 B2 six ###283 FIG. 4A U.S. Patent Jun. 20, 2017 Sheet 17 of 31 US 9,682,093 B2 s st W st F.G. 4B U.S. Patent Jun. 20, 2017 Sheet 18 of 31 US 9,682,093 B2 F.G. 14C 2. Fst W Fs. Ko F.G. 4) U.S. Patent Jun. 20, 2017 Sheet 19 Of 31 US 9,682,093 B2 Oligomycin & : r axia t Respiration 8: 33. : &: & &: & *::: 333. *::33 E88E trix: FG 5A U.S. Patent Jun. 20, 2017 Sheet 20 of 31 US 9,682,093 B2 Ofigomycin FCC) Rotenone!Myxothiazole & E8 asa & Respiration As rower axina Respiration 338 33 3 83 &: 88 & & &: & 3:33 *:::: '833 FIG. 5B U.S. Patent Jun. 20, 2017 Sheet 21 of 31 US 9,682,093 B2 A Gastroc Fs Fst WT Fst-Tg CP1 UCP2 CP3 PROV16 PGC-O, APK pAMPK f3-actin F.G. 6A U.S. Patent Jun. 20, 2017 Sheet 22 of 31 US 9,682,093 B2 A Gastroc Fst-W C: UCP F.G. 6B U.S. Patent Jun. 20, 2017 Sheet 23 of 31 US 9,682,093 B2 CP UCP2 UCP3 PRDM16 PGC-10, AMPK pAMPK 3-actin FIG. 6C U.S. Patent Jun. 20, 2017 Sheet 24 of 31 US 9,682,093 B2 2.5 Fst WT 2.0 1.5 10 Os 0.0 FIG. 6D U.S. Patent Jun. 20, 2017 Sheet 25 Of 31 US 9,682,093 B2 FIG. 7A 120 s E 100 E 80 t g 60 : 40 20 0 Fst WT Fst-Tg FIG. 7B BA Fst WT Fst-Tig UCP UCP2 UCP3 PROM16 PGC-10 AdipoC AWPK pAMPK 3-actin U.S. Patent Jun. 20, 2017 Sheet 26 of 31 US 9,682,093 B2 FG. 7C 3 OFst W ; e OFst-Tg 5. 2 X g 1 s & Epi SC BA FIG. 7) Fs 3-acti U.S. Patent Jun. 20, 2017 Sheet 27 Of 31 US 9,682,093 B2 FG. 8A FG. 8B *, pso,01 FskW Fst-g A.
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