Jaemin Lee, Ph.D. Department of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST)

Transcription

1 Jaemin Lee, Ph.D. Department of New Biology Daegu Gyeongbuk Institute of Science and Technology (DGIST)

2 No Actual or Potential Conflict of Interest

3

4 1985 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

5 1986 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

6 1987 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

7 1988 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

8 1989 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

9 1990 No Data <10% 10%-14% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

10 1991 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

11 1992 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

12 1993 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

13 1994 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

14 1995 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

15 1996 No Data <10% 10%-14% 15%-19% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

16 1997 No Data <10% 10%-14% 15%-19% 20%-24% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

17 1998 No Data <10% 10%-14% 15%-19% 20%-24% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

18 1999 No Data <10% 10%-14% 15%-19% 20%-24% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

19 2000 No Data <10% 10%-14% 15%-19% 20%-24% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

20 2001 No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

21 2002 No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

22 2003 No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

23 2004 No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% (*BMI 30, or ~ 30 lbs. overweight for 5 4 person)

24 2005 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

25 2006 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

26 2007 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

27 2008 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

28 2009 (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

29 2010 In the US, 69% of adult population are overweight and 36% are obese (2010) (*BMI 30, or ~ 30 lbs. overweight for 5 4 person) No Data <10% 10%-14% 15%-19% 20%-24% 25%-29% 30%

30 - Worldwide obesity has increased more than double since In 2014, 18% of adults are obese (600 million) and 39% are overweight. WHO, Business Insider

31 KSSO In Korea, 31.8% of adults obese (BMI 25) and 53.9% overweight (BMI 23) (2013)

32 Diabetes (T2DM) Cancer Hypertension Overweight Obesity Infertility Cardiovascular Diseases Dyslipidemia Modified from Maric-Bilkan (2013), Bonora and Targher (2012) and WHO (2014)

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34 Healthy Food intake Energy expenditure Modified from Friedman Nat Med

35 Obese/ Leptin resistant Food intake Energy expenditure Modified from Friedman Nat Med

36 Zhang et al. Trends in Pharmacological Sciences (2015)

37 Morris and Rui. American Journal of Physiology - Endocrinology and Metabolism (2009)

38 Obesity, T2DM ER Stress Unfolded proteins

39 ER Stress Unfolded Protein Response (UPR)

40 Unfolded Protein ATF-6 Normal Protein Folding Perk Folded Protein BAX GRP78 Ire-1 BAK Ire-1 ATF-6 Perk BAX BAK ER To Golgi or Final Destination

41 Unfolded Protein ATF-6 ER Stress Perk Unfolded Protein BAX Ire-1 BAK GRP78 ATF-6 ERAD Perk P P P P P P BAX P P P Ire-1 BAK Proteosome-mediated degradation Migration to golgi Proteolytic cleavage by SP1 and SP2 eif2b eif2 eif2 5` 5` XBP-1(unspliced) 3` 3` XBP-1(spliced) NF- B activation TRAF2 ASK1 Active transcription factor (NH 2 terminal) ATF-4 translation Global Translation XBP-1(s) JNK activation ERSE-UPRE XBP-1 Chaperones UPRE-ERSE Chaperones ERAD components ER proliferation Increased ER folding capacity Increased ER folding capacity

42 Hypothalamus Ozcan et al Cell Metabolism

43 Veh 4-PBA Hypothalamus Leptin Leptin Ozcan et al Cell Metabolism Chemical chaperone (4-PBA) treatment restores leptin sensitivity

44 Pharmacological ways - CNS-acting drugs effective, many side effects Phentermine, Lorcaserin (available), many others are withdrawn - Peripherally acting drug Orlistat only drug for long-term treatment, less effective Surgical ways - Bariatric surgeries (so far the most effective, but very intrusive) There is no leptin sensitizing agent as therapeutics

45 Connectivity Map (CMAP) - Gene expression profiles from chemical treatment Lamb et al Science - Providing a list of chemicals with similar or reverse gene expression pattern with query

46 PBA WT Liver Gene Expression PBA ob/ob Liver Gene Expression Overexpressed XBP1s ob/ob Liver Gene Expression Lean and Obese Hypothalamic Gene Expression PBA and TUDCA induced Hypothalamic Gene Expression Selection of top and bottom genes Selection of top and bottom genes CMAP CMAP Liver Absolute Product Score Hypothalamic Absolute Product Score Candidate Selection Candidate Selection Liu, Lee et al Cell

47 COOH Thunder god vine ( 미역줄나무 / 뇌공등 / 雷公藤 ) O H HO Celastrol

48 Food Intake (g/mouse) 50 Diet-induced obese mice 2.5 Body Weight (g) Vehicle Celastrol *** *** Days 0 Vehicle Celastrol Liu, Lee et al Cell Celastrol reduces body weight and food intake of diet-induced obese mice

49 Lean Mass (g) NS Fat (%) *** 0 Vehicle Celastrol 0 Vehicle Celastrol Liu, Lee et al Cell Celastrol reduces only fat, not lean mass

50 Body Weight (g) Vehicle Celastrol Food Intake (g/mouse) NS Days 0 Vehicle Celastrol Liu, Lee et al Cell Celastrol has no effect on body weight and food intake of leptin sensitive lean mice

51 db/db mice ob/ob mice 55 Vehicle Celastrol 55 Body Weight (g) Body Weight (g) Vehicle Celastrol Days Days 24 Liu, Lee et al Cell Celastrol does not reduce body weight in leptin signaling deficient mice (db/db and ob/ob)

52 Vehicle Celastrol Leptin pstat3 Tyr705 Stat3 Actin Liu, Lee et al Cell

53 p-stat3 staining on the hypothalamic samples DMH DMH DMH 3V 3V Veh + Sal Veh+Lep DMH DMH 3V 3V Cel + Sal Cel + Lep TCN in DMH (%) TFI in DMH (%) Veh + Sal Veh + Sal *** ** Veh + Lep Veh + Lep *** *** ** Cel + Sal Cel + Sal * Cel + Lep Cel + Lep Lee et al Nat. Med.

54 p-stat3 staining on the hypothalamic samples VMH VMH VMH Veh + Sal Veh + Lep VMH VMH Cel + Sal Cel + Lep TFI in VMH (%) TCN in VMH (%) Veh + Sal Veh + Sal * Veh + Lep Veh + Lep *** * ** Cel + Sal Cel + Sal Cel + Lep Cel + Lep Lee et al Nat. Med.

55 p-stat3 staining on the hypothalamic samples ARC Veh + Sal Cel + Sal ARC ARC 3V 3V 3V 3V ARC ARC Veh + Lep Cel + Lep TCN in ARC (%) TFI in ARC (%) 250 ** Veh + Sal Veh + Sal ** * Veh + Lep Veh + Lep * Cel + Sal Cel + Sal Cel + Lep Cel + Lep Lee et al Nat. Med.

56 Vehicle Celastrol p-perk PERK Liu, Lee et al Cell Celastrol reduces ER stress in the hypothalamus of obese mice

57 Liver Vehicle Celastrol Lean/ Chow Obese/ HFD Liu, Lee et al Cell Celastrol ameliorates obesity-associated metabolic disorders

58 CMAP Celastrol microarray data Signature selection Connectivity map Enrichment score Hypothalamus gene expression Absolute enrichment score Celastrol Withaferin A O OH O ,000 1,500 Individual drugs H H H H H O O OH Lee et al Nat. Med. In vivo trials

59 Absolute enrichment score Celastrol Withaferin A O OH O ,000 1,500 Individual drugs H H H H H O Lee et al Nat. Med. O OH

60 Body weight (g) Vehicle Withaferin A *** Time (d) Food intake (g) Vehicle *** Withaferin A Lee et al Nat. Med.

61 Lean mass (g) Fat (%) *** 0 Vehicle Withaferin A 0 Vehicle Withaferin A Lee et al Nat. Med.

62 Body weight (g) Vehicle Withaferin A n.s. Food intake (g) Time (d) Vehicle Withaferin A Lee et al Nat. Med.

63 50 db/db mice 60 ob/ob mice Body weight (g) Vehicle Withaferin A Time (d) n.s. Body weight (g) Vehicle Withaferin A Time (d) n.s. Lee et al Nat. Med.

64 *** 2.0 Vehicle Withaferin A p-perk PERK p-perk Thr980 /PERK Vehicle Withaferin A Lee et al Nat. Med.

65 Reversing leptin resistance by reducing hypothalamic ER stress can be promising therapeutics Celastrol and Withaferin A are strong leptin sensitizer and reverse leptin resistance in obese mice CMAP is a powerful tool to discover new drugs

66 Lee and Ozcan JBC

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