Physical Remodeling & Anti-obesity

H. Y. Yang

( obesity )WHO10 () >80 cm ( ) >94cm ( )( International Diabetes Federation ) (100,00 ) 2002( trans fat ) (safe level) 200379 FDA200611 10 7 7StingChallenge 41OroChin CometHyper Tight

? ( body-mass index ) ( National Center for Chronic Disease Prevention & Health Promotion ) 18.5~ 24.9 kg/m2 < 18.5 25.0 -29.9 ( overweight ) >30 ( obese ) : =( Kg ) / (, m)2 99.79 1.905 99.79/ (1.905) 2 = 27.5 kg/m2

WHO

( )() : 1978Coleman DL( obese, ob )( diabetes, db ) ( 5 ) ob95% ( ) ( ) 1995Jeffery Friedman 1p31obLeptin ( ) leptin

(Cell 138, 976989; 2009) leptin ( ).leptin

97MillenniumLouis Tartaglia ( arcuate nucleus)ciliary neurotropic factor ( CNTF ) Amegen Inc. 9000 leptin lupin Regeneron ciliary neurotropic factor ( CNTF )Axokine -melanocyte-stimulating hormone (-MSH ) neuropeptide Y ( NPY ), agouti-related peptide ( AGRP ) ( ) ( hereditary lipodystrophies ) peroxisome proliferator activated receptor (PPAR) [Ref] Friedman JM, Halaas JL: Leptin and the regulation of body weight in mammals. Nature 395:763, 1998.

-- 2 arcuate nucleus Neuropeptide Y ( NPY ), agouti-related peptide ( AgRP ), melanin-concentrating hormone, Galanin ( ), Orexin, , 2 Cocaine- and amphetamine-regulated transcript , cholecystokinin (CCK ) , Peptide YY ( PYY3-36 NPY NPY )pancreatic polypeptide ( PP )Corticotropin-releasing hormone, -MSH (-melanocyte-stimulating hormone ) , oxyntomodulin ( OXM ) insulin, Glucagon-like peptide-1 ( GLP-1 ), Bombesin, Urocortin, Serotonin ( ) paraventricular nucleus ( PVN )dorsomedial nucleus (DMH), ventromedial nucleus (VMH), lateral hypothalamic area (LHA)perifornical area (PFA) nucleus tractus solitarii (NTS)

1. 2. 3. : Leptin, Adiponectin, Resistin : Insulin, Pancreatic polypeptide, : Peptide YY, Grrelin, Glucagon-Like Peptide-1, Oxyntomodulin, Cholecystokinin, Bombesin

1. : Neuropeptide Y, Melanocortin, Cocaine- and amphetamine-regulated transcript , 2. : Glucagon-Like Peptide-1, Neuropeptide Y, Cholecystokinin

: LeptinghrelinPYY 3-36 Ghrelin / leptin / insulin / adiponectin -MSH pro-opiomelanocortin ( POMC )/ cocaine-amphetamine related transcruipt ( CART) -melanocyte-stimulating hormone (-MSH ) neuropeptide Y ( NPY ), agouti-related peptide ( AGRP ) paraventricular nucleusventromedial hypothalamus lateral hypothalamus

melanin concentrating hormone(MCH) orexinMCH-1 CARTNPYNPY-1, 5 AgRP MC-3, 4 NPY- AgRP- -MSH paraventricular melanocortin-4 ( MC-4 ) medial paraventricular nucleus/ ventromedial hypothalamus dorsal motor nucleus tractus solitarius melanocortin-4 receptor , pro-opiomelanocortin, receptor-2; 5-HT: proconvertase-1, serotonin; the leptin leptin 5-HT2C : serotonin -1 -2: noradrenergic receptors; -MSH: melanocyte-stimulating hormone; AGRP:

agouti-related peptide; ARC:

hypothalamic arcuate nucleus; CART:

cocaine-amphetamine regulated transcript; CB-1R: cannabinoid

modifying activity of the CART neuronal tract; CRH-1R CRH-2R : corticotrophin releasing hormone 1 or 2 receptor; DMV : dorsal motor nucleus; DRN: dorsal raphe nucleus; FI : food intake; GABA: gamma-aminobutyric acid; GHSR: growth hormone secretogogue receptor; H1R: 1; H3R: 3; His: ; LC: mu-opioid receptor; MC3R: MCH receptor; NE: SNS: locus coeruleus; LH : lateral hypothalamus; R : melanocortin-3 receptor; MC4R: melanocortin-4 receptor; MCH: melanin concentrating hormone; MCHR: neuropeptide Y; NTS: nucleus of the tractus solitarius; ORX: orexin; PNS: paraventricular nucleus; Rb: long form of the leptin receptor; pro-opiomelanocortin; PVN:

norepinephrine (noradrenaline); NPY:

parasympathetic nervous system; POMC:

sympathetic nervous system; VMH: ventromedial hypothalamus; Y-1R: neuropeptide receptor-1.

ghrelin ( 1999 Kenji Kanagawa, Masayasu Kojima ( paracrine) 28 Acyl ghrelin Growth hormone secretagogue receptor 1a GHRH 2000 Llily Matthias Tschop ( appetide-stimulating ) arcuate nuclus NPY AGRP acyl ghrelin- Growth hormone secretagogue receptor 1a (GHS-R1a)- ghrelin O-acyltransferase (GOAT) Peptide YY ( PYY3-36 ) YY ( PYY3-36 ) 12

( Leptin1994 Jeffrey Friedman Zhang ob 167 CCK ) insulin ( gastric bypass ) ghrelin

cholecystokinin ( CCK ) 2 :

1.

CCAAT/ (C/EBPs G ( PPAR) (ADD1) ADD1 fatty acid synthase glycerol-3-phosphate acyltransferase PPAR acyl-CoA oxidase and carnitine palmitoyl-CoA transferase I ADD1 PPAR ADD1 PPAR mRNA ADD1 PPAR The beneficial metabolic effects of PPAR ligands. result, circulating FFA levels are diminished. Activation of PPAR- also results in changes in adipokine production, remodeling of adipose tissue, and the concurrent repartioning of lipids from lipolytic visceral fat into subcutaneous fat that contains newly generated, small insulin-sensitive adipocytes. PPAR- agonists also decrease the inflammation of adipose tissue that is induced by obesity and contributes to increased insulin resistance. As a result of these multiple adipocentric actions (pale orange), PPAR- activation improves insulin sensitivity in skeletal muscle and liver, and reduces hyperglycemia. In dyslipidemic subjects, PPAR- agonists induce lipid uptake and catabolism and the production of apolipoproteins -I and A-II, thereby diminishing circulating TG and increasing HDL-C levels (cream). In addition to their anti-dyslipidemic activities, recent in vitro and preclinical data indicate that PPAR- agonists also have direct vasoprotective effects (brown). Activation of PPAR- increases fatty acid oxidation and uncouples energy metabolism in skeletal muscle. Thus, PPAR- agonists lower triglycerides, increase HDL-C and protect against obesity in preclinical species (dark red). Dotted lines represent activities observed only in preclinical experiments and in vitro. PPAR- agonists are effective in treating Type II DM. They modulate the expression

of numerous genes in adipocytes, which results in improved insulin sensitivity, increased fatty acid uptake and decreased lipolysis. As a

( adipokines ) adiponectinTNF-resistin

PPAR, peroxisome proliferator activated receptor; TZD, thiazolidinediones; HSD, hydroxysteroid dehydrogenase; AMPK, adenosine monophosphate activated protein kinase; PTP1B, protein tyrosine phosphatase. O, obesity; I, insulin resistance; G, glucose intolerance; D, dyslipidemia; A, atherosclerosis; H, hypertension.

2.

ATP 1990 peroxisome proliferators-activated receptors ( PPAR-, - , - ) Thiazolidinedione fibrate PPAR PPAR- ( )

Glaxo SmithKline GW 501516 PPAR- 2005 1 9 HDL GW501516 Glaxo 2 3. Glaxo PPAR-delta PPAR-delta PPAR-delta PPAR-delta PPAR-delta GW501516, PPAR-delta 20 9000 ( ) Insulin receptor substrate- 1( ),- 2 ( )

: > 60 % ( BMI) X Matabolic syndrome X ( LDLHDL)

:

Dinitrophenol 1996fenfluramine dexfenfluramine aminorex 2005 (American College of Physicians ) 6orlistat, sibutramine, phentermine, diethylpropion, fluoxetine, bupropionFDA fluoxetinebupropion FDA ( Swedish Obese Subject Study, 2004 ) 212%28 %

( l ) PPA ( phenyl propanolamine) ( X ) III benzphetaminemazindol phendimetrazine IV phenterminediethylpropion, (2) 1950 60 (Amphetamines) 54 phenmetrazine ( Preludin , Boehringer-Ingelheim ) 59 65 phendimetrazine

( Bontril )( psychosis ) ( )(3) ( Serotonin agonist ) fenfluramine 1995 ( Redux, Wywth-Ayerst ) 1997 70

1997

Sibutramin ( Meridia , Abbott Reductil 2002 3 ) NE, 5-HT, DA Sibutramin ( 1998 2 2001 9 150 28 19 ) Sibutramin 10 mg 15 mg fluoxetine ( 60 mg/D 3 )sertraline NE, DA bupropion ( SR300-400 mg/D ) topiramate ( TPM ) ( phentermine)( amphetamine ) fenfluraminedexfenfluramine ( l ) (2) FDA ( Biguanide ) Metformin Metformin( 850 mg, ) + Orlistat ( 120 mg, ) Acarbose ( Lipase) RocheOrlistat ( Xenical 60 mgAlli )( lipase) 30% 65-10% ( > 12% )20029 200117% Rimonabant (Acomplia endocannabinoid CB1 Sanofi Aventis ( pleasure receptor) CB1 16 2 Acomplia 19 3.1

Acomplia 1.9 Acomplia 5- 10% adiponectin(HDL) Acomplia Sanofi-Aventis 2005 (Food and Drug Administration) Acomplia

( l) (Psyllium ) Madar(Calotropis gigantea) (3)

Madar(Calotropis gigantea)

Psyllium

1. 2. 3. ( Leptin ) pegylated ( lipodystrophy ) dihydropyridine neuropeptide Y1 antagonist : 5-HT2C lorcaserin (APD356)

4. 5. 6. 7. 8. 9.

MCH( Melanin-concentrating hormone )GW856464 Amylin pramlintide( AC137) L PYY3-36 NastechMerckI lipase Cetilistat ( ATL-962Alizyme )Xenical Naltrexone ( 50 mg/ D)+ bupropion ( 300 mg/ D)Contrave Bupropion ( 300 mg/D ) + zonisamide ( 400 mg/ D )Empatic topiramate Qnexa

10. Phentermine +

1. ( ephedrine ) ephedrine ( 20 mg) + caffeine ( 200 mg) FDA < 10 mg ( ) 2. 3. 4. 5. -3 L-796568 -3 Bromocriptine ( ergocet ) 1.6-2.4 mg/D, Ecopipam D1 D5 Axokine leptin

: 1997 3-4 30 ( ) 2000 / 3 30 80% { (220- ) x 0.8 50 136 } )

1. 2. 3. chromium picolinate -Hydroxy--methylbutyrate leucine 4. ( conjugated linoleic acid ) C18:2C 9, 10C11, 12. trans-10 cis-12 isomer 5. 6. (Garcinia cambogia ) hydroxycitric acid ATP-citrate lyase

7.

(Hoodia gordonii ) steroidal glycoside ATP

8.

(Citrus aurantium )phenylephrine QTinterval

9.

Triphala guggul Amorphophallus konjac Glucomannan ( mannose )

10. ()Chitosan ( acetylated chitin )

Gugul( Commiphora mukul ) Guar gumsterol guggulsterone Gugulipid Cyamopsis tetragonolobus Medohar ( mannosegalactose) Royal Slim

Amorphophallus konjac Cyamopsis tetragonolobus ( Stiftung Warentest ) 2003 2 20 14 ( wenig geeignet) CM3 ReductilDrenolAcloss ExtraAcloss VitaminFormolineBoxogetten SXenicalStrobbyJogun KapselnRedaxaBiofax Fucus 2000 Vencipon N Dragees( mit Einschrankung geeignet) CM3 AlginatGrapefruit SpezialMatricurBioNorm Sattungs-KapselnDecorpa Recatol Algin Lemon AmfepramonDexfenfluraminFenfluraminMefenorex Norpseudoephedrin(Cathin) 2001 6 Antidiapositum X-112 S Mirapront N Regenon Rondimen Vita-Schlanktropfen SchuckPonderaxIsomerideCafilon Fasupond Phenylpropanolamin(PPA) Boxogetten SFugoa NRecatol Mono PPA Reductil Xenical ReductilXenical PPA 30

1. Statins : HMG-CoA reductase ( LDL, HDL) pleiotropic Atorvastatin, Simvastatin ( Zocor ), Pravastatin , Fluvastatin, Rosuvastatin, Lovastatin, Pitavastatin Statin Combination Therapies : Lovastatin/Nicotinic Acid, Atorvastatin/Amlodipine Simvastatin/Ezetimibe ( Vytorin ): 20048Merck Schering Ploughsimvastatin (Zocor, Merck ) ezetimibe( Zetia, Schering Plough) Atorvastatin ( Lipitor, Pfizer)+ cholesteryl ester transfer protein (CETP)Torcetrapib :

AtorvastatinTorcetrapib 2. 3. 4. 5. Fibrates : PPAR Fenofibrate, Bezafibrate, Gemfibrozil Cholesterol Absorption Inhibitors : Ezetimibe Nicotinic Acid Derivatives Bile Acid Sequestrants : Niacin : Colesevelam , Cholestyramine

A. 1. 2. : Cholesteryl Ester Transfer Protein Inhibitors : Blocks cholesterol ester transfer from HDL to LDL and VLDL, raises HDL-C and lowers LDL-C cholesterol. CP529,414, (Torcetrapib, Pfizer ) JTT-705, CETi-1 Apo A-1 : Mimic HDL-C anti-atherogenic properties Up regulate multiple genes (ABCA1, ABCG1, ABCG5, ABCG8, CETP, Apo A-IV, Apo-E) that Liver X receptor (LXR) :

raise HDL-C and promote reverse cholesterol transport. Anti-atherogenic in mice models. Also upregulates genes (SREBP1c, FAS) that increase hepatic TG synthesis. Reverse Lipid Transport Pathway Activators : ETC-1001, ESP-15228, ESP-24232 Vascular Protectants : AGI-1067 Acyl-CoA Cholesterol Acyltransferase Inhibitors : Eflucimibe , Pactimibe, Avasimbe

B.

: Peroxisome Proliferator Activated Receptor( PPAR ) : , HDL-C, Tesaglitazar, Ragaglitazar ( Novo Nordisk ), GW-501516

1. PPAR/ : PPAR PPAR

2. PPAR : ABCA1 , HDL-C . Microsomal Triglyceride Transfer Protein Inhibitors : Implitapide, CP-346086 Squalene Synthase Inhibitors : TAK-475 Lipoprotein Lipase Activators : Ibrolipim Lipoprotein(a) Antagonists : Gemcabene Bile Acid Reabsorption Inhibitors : BARI-1453, S-8921

PIPELINE

Brand Vytorin

Generic ezetimibe/simvastatin ETC-216 JTT-705

Company Merck/Schering-Plough Pfizer Pfizer Japan Tobacco Merck Bristol-Myers Squibb Manufacturer Bristol-Myers Squibb

Proposed Use Cholesterol lowering CETP inhibitor HDL infusion CETP inhibitor OTC OTC Patent Expiration April 20, 2006

Availability 2004 2006 2007 2007 Unknown Unknown

Lipitor/torcetrapib atorvastatin/torcetrapib

Mevacor OTC Pravachol OTC Brand Pravachol

lovastatin pravastatin Generic pravastatin

PATENT EXPIRATIONS

Zocor

simvastatin

Merck

June 23, 2006

1. 2. 3. Evans RM, Barish GD & Wang Y-X. PPARs and the complex journey to obesity. Nature Medicine 10: 1-7, 04

Berger J & Moller DE. The mechanisms of action of PPARs. Annu. Rev. Med 53 : 409435, 2002. Friedman JM & Halaas JL. Leptin and the regulation of body weight in mammals. Nature 395: 763-770, 98