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
