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![Page 1: Lipid droplet (L) of a dead adipocyte macrophages (M) disrupted basal membrane (BM) cytoplasmic remnants (CR) cell debris (CD) Cinti et al, J Lipid Res.](https://reader036.fdocuments.us/reader036/viewer/2022062701/5542eb67497959361e8d2d62/html5/thumbnails/1.jpg)
lipid droplet (L) of a dead adipocyte
macrophages (M)
disrupted basal membrane (BM)
cytoplasmic remnants (CR)
cell debris (CD)
Cinti et al, J Lipid Res 2005
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Visceral and Subcutaneous Adipose Tissue Volumes AreCross-Sectionally Related to Markers of Inflammation and
Oxidative StressThe Framingham Heart Study
Pou CM et al, Circulation, 20071.250
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T. AdiposoInfiltrato dimacrofagi
SOVRACCARICOENERGETICO
InfiammazioneIpossiaApoptosiStress RE
INSUF F.
ADI
P.
LIPOTOSSICITÀSTRESS OSSIDATIVO
Adipochine
PAI-1IL-6LeptinaAdiponectinaTNF-AngiotensinogenoResistina
VisceraleVs
Sottocutaneo (sc)
VISC> SCVISC > SCSC > VISC
?VISC > SCVISC > SC
?
FFA
ADIPOCHINE
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MECCANISMI ADATTATIVI E MALADATTATIVI DELL’INSUFFICIENZA ADIPOCITARIA
• Sovraccarico− (p. es.) Ipertensione
• Riduz. di funzione− Deficit di pompa
• Conseguenze dirette− Astenia, Riduz. Attiv. fisica
• Meccanismi (mala)adattativi− RAAS, Catecolamine− Riten. Idrosalina, Tachicardia
• Danno tissutale − Dilatazione e fibrosi
• Sovraccarico− (p. es.) Calorico,Obesità
• Riduz. di funzione− Deficit di effetto tampone
• Conseguenze dirette− Lipotoss.; Insulino-res.
• Meccanismi (mala)adattativi− Insulina, Adipochine− Più Obes e Ins. Res.
• Danno tissutale − Infiammazione e ateroscl.
INSUFFICIENZACARDIACA
INSUFFICIENZAADIPOCITARIA
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INSULINO-RESISTENZALIPOTOSSICITÀ
STRESS OSSIDATIVOINFIAMMAZIONE
DIABETE
DISFUNZIONE ENDOTELIALEATEROSCLEROSIINFIAMMAZIONE
ADIPOCHINE
FFA
FFA
ADIPOCHINE
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SINDROME METABOLICAIDF CONSENSUS 2005
OBESITÀ CENTRALE M F Europidi 94 80 Asiatici 90 80 Cinesi 90 80 Giapponesi 85 90
OBESITÀ CENTRALE M F Europidi 94 80 Asiatici 90 80 Cinesi 90 80 Giapponesi 85 90
più almeno 2 tra i seguenti criteri:
• Trigliceridi: >150 mg/dl• HDL-C: <40 (M) < 50 (F) mg/dl• Pressione arteriosa: > 130 Sist.
oppure
> 85 mmHg Diast.oppure
terapia ipotensivante• Glic. a digiuno: >100 mg/dl
1° International Congress on Prediabetes and the Metabolic Syndrome, Berlin 14/4/2005
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MICRO-ALBUMINURIA
Lipolisi
Insulina
PAI-1IL-6
ResistinaTNF-α
Adiponectina
VLDLApoBPCR
GlucosioFFA
FFA
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
SmallLDL
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
SmallLDL
SmallLDL
Glucosio
SNSSNSSNS
RAS
STRESS OSSIDATIVO
DIABETE
INSULINO - RESISTENZA
NAFLD
NASH
IFG
IGT
Insulina
INSULINO-RESISTENZA
CVD
OBESITÀ ADDOMINALEINSULINO-RESISTENZA
LIPOTOSSICITÀINFIAMMAZIONE
STRESS OSSIDATIVODISFUNZIONE ENDOTELIALE
DISLIPIDEMIA
IPERTENSIONE IFGIGT
DIABETE
IPERURICEMIA
NAFLDNASH
MICROALBUMINURIA
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MICRO-ALBUMINURIA
Lipolisi
Insulina
PAI-1IL-6
ResistinaTNF-α
Adiponectina
VLDLApoBPCR
GlucosioFFA
FFA
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
SmallLDL
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
VLDLHDL
LDL
Colesterolo
Trigliceridi
CETP
Trigliceridi
CETP
Colesterolo
SmallLDL
SmallLDL
Glucosio
SNSSNSSNS
RAS
STRESS OSSIDATIVO
DIABETE
INSULINO - RESISTENZA
NAFLD
NASH
IFG
IGT
Insulina
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TERAPIA
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Terapia farmaco-
logica
Modifi-cazioni
del comporta-
mento
Attivitàfisica
Nutrizione equili-brata
Trattamento integrato
Moderata riduzione di peso (5-10%) a lungo termine
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Modificazionidel peso = -
Terapiacomportamentale
AttivitàFisica Metabolismo
Basale
TermogenesiFarmaci
Dieta
Farmaci
Modificazione dello stile di vita
Chirurgia
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Obiettivi della perdita di peso
I soggetti con Obesità e Sovrappeso che fanno parte di un programma ben articolato possono ottenere una perdita di peso pari al 10% del peso iniziale, valore che può essere mantenuto per 1 o più anni.
Evidenza di Categoria A
Linee guida NIH (NHLBI-NIDDK), 1998 - LIGIO, 1999
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Riduzione del rischio cardiovascolare già con un dimagrimento del 10-15% (Albu J. et al., Diab Rev 3:2,335-347, 1995)
Aumento di colesterolo HDL con un dimagrimento del 5-10%(Schwartz, R.S. Metabolism 36:165-171, 1987)
Miglioramento della sensibilità insulinica, del compenso glicemico, riduzione della terapia ipoglicemizzante con una diminuzione del 5-10% del peso corporeo in pz. obesi e diabetici(Wing R.R. et al., Archiv Intern Med 151:97-102, 1991)
Evidenze dei benefici della perdita di peso
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Terapia Dietetica
Le diete ipocaloriche (LCD) sono
raccomandate per la perdita di peso in
pazienti sovrappeso ed obesi.
Evidenza di Categoria A
Linee guida NIH (NHLBI-NIDDK), 1998Linee guida NIH (NHLBI-NIDDK), 1998 - LIGIO, 1999
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Le diete ipocaloriche possono ridurre il peso corporeo totale in media dell’8 percento, e possono aiutare nella riduzione del tessuto adiposo
addominale in un periodo di 6 mesi. Evidenza di Categoria A
Terapia Dietetica
Linee guida NIH (NHLBI-NIDDK), 1998 - LIGIO, 1999
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Dieta Ipocalorica (LCD)
800-1500 Kcal die
composizione modificata per ridurre i fattori di rischio cardiovascolari (colesterolo, ipertensione)
perdita di peso lenta ma progressiva
Vantaggi
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Deficit calorico
BMI > 27 e < 35: 300-500 Kcal die ~ 250 g /sett.~ 10% BW /6 mesi
BMI > 35: 500-1000 Kcal
die ~ 500-1000 g /sett.~ 10% BW /6 mesi
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La riduzione dei grassi come parte di una dieta ipocalorica è un modo pratico per ridurre le calorie. Evidenza di Categoria A
Deficit calorico
Linee guida NIH (NHLBI-NIDDK), 1998 - LIGIO, 1999
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Dieta ricca di grassi
scarso effetto termogenetico
scarso effetto sull’appetito
scarso effetto saziante
non modificapasto successivo
aumento dei depositi di grasso
bilancio energetico positivo
aumento introitocalorico
COSTO METABOLICO COSTO METABOLICO OBBLIGATORIOOBBLIGATORIO
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SPESASPESA ENERGETICAENERGETICA
METABOLISMMETABOLISMOO BASALEBASALE
EFFETTO TERMICO EFFETTO TERMICO DEL CIBODEL CIBO
ATTIVITÀ ATTIVITÀ FISICAFISICA
~60%
~30%
~10%
Componenti della spesa energetica
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Effetto termogenetico degli alimenti
proteine 20-30% EE
lipidi 0-3% EE
carboidrati 5-10% EE
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Linee guida NIH (NHLBI-NIDDK), 1998 - LIGIO, 1999
Composizione Nutrizionale per Una Dieta Ipocalorica
Fibre 20-30 g die
Calcio 1000-1500 mg die
Cloruro di sodio < 100 mmol die (~2.4 g Na o 6 g NaCl)
Carboidrati 55% o più delle calorie totali
Proteine 15% delle calorie totali
Colesterolo < 300 mg die
Acidi grassi polinsaturi 7-10% delle calorie totali
Acidi grassi monoinsaturi 10-15% delle calorie totali
Acidi grassi saturi 8-10% delle calorie totali
Grassi totali 30% delle calorie totali
Calorie 500-1000 kcal die in meno rispetto all’introito consueto
Nutrienti Apporto raccomandato
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Diete fortemente Ipocaloriche (VLCD)
500-800 Kcal die
composizione modificata per rimpiazzare i deficit proteici e vitaminici: 0.8-1.5 g prot. die
vitamine e sali minerali
perdita di peso rapida
Vantaggi
Svantagginon applicabilità a lungo termine
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Efficacia dei regimi dietetici
36 pz. obesi/diabetici:I gruppo
VLCD LCDII gruppo
LCD
8 sett.
20° sett.p<0.05
-18.6 kg
-10.1 kg
1 annop n.s.
-8.6 kg
-6.8 kg
Wing R.R. Diab Rev 1995
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Formula di Harris-Benedict per il calcolo del metabolismo basale
Maschi:
66 + (13.7 x kg + 5 x cm - 6.8 x anni)
Femmine:
665 + (9.5 x kg + 1.8 x cm - 4.7 x anni )
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Formula per il calcolo del metabolismo basale
Maschi:
900 + (10x kg)
Femmine:
700 + (7x kg)
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Physical Activity
“Late 20th century urban life is a paradise of energy conservation at the level of the individual. People never need to run, they rarely need to walk, and they can often sit.”
IJO 1996;20:S1-S8
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CALO PONDERALE
Spesa energetica totale
Massa magrafino al 30% del tot.
Controllo adipostatico (leptina)
che si oppone ai cambiamenti di peso
Indotta da regimi ipocalorici proteolisi gluconeogenesi epatica.
ESERCIZIO FISICO COME STRUMENTO PER LIMITARE LA PERDITA DI MASSA MAGRA
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DIMINUZIONE DELLA MASSA MAGRA: RIMEDI
Esercizio fisico:
• Aerobico (endurance)Aumenta la VO2 max, migliora la fitness CV. Aumenta la spesa energetica tot. (ancora controverso se aumenti spesa energ. a riposo).
• Anaerobico (potenziamento)Aumenta la forza e la massa muscolare; il migioramento globale delle funzioni muscoloscheletriche fa aumentare l’attività fisica spontanea.
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ALLENAMENTOFrequenzacardiaca
Tipo di esercizio Effetto allenante Substratoutilizzato
50-60% aerobico Perdita di peso lipidi/glicogeno
60-85% aerobico/anaerobico Cardiovascolare erespiratorio
glicogeno/lipidi
>85% anaerobico Potenza muscolare glicogeno
Frequenza cardiaca massimale = 220-età
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EFFETTO DI DIETA + ESERCIZIO FISICO
Pavlou et al. Am J Clin Nutr ,1989
- 16
- 12
- 8
- 4
0
% P
eso
- 20
(mesi) 0 12 36
+ Es. fisico
Solo dieta
TRATTAMENTO FOLLOW-UP
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STRATEGIA TERAPEUTICA
Attività fisica
Spontanea: 100 Kcal die
Volontaria: 300-400 Kcal/3-4 volte sett.(1 ora di corsa leggera = ca. 400 Kcal)
American Heart Association Dietary Guidelines (2000)
Raccomanda di svolgere regolare attività fisica (almeno 1500-2000
Kcal/sett.)
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CRONOLOGIA DEGLI INSUCCESSI FARMACOTERAPICI DELL’OBESITÀ
FarmacoData Effetto
1893
1934
1937
1967
1971
1997
Estratti tiroidei
Dinitrofenolo
Amfetamina
Pillola “arcobaleno” (digitale, diuretico)
Aminorex
Fenfluramina + FenterminaDexfenfluramina + Fentermina
Ipertiroidismo
Cataratta; neuropatia
Dipendenza
Morte
Ipertensione polm.
Valvulopatie
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Areetattili
olfattivevisive
AreagustativaprimariaArea
gustativasecondaria
Nucleodel trattosolitario
Nucleo Paraventr.
IpotalamoLaterale
Nucleo Arcuato
Sistema nervoso simpatico
5HTNADA
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FARMACI ANORESSIZZANTI
Noradrenergici (amfetamina, fentermina,
dietilpropione, mazindolo, fenilpropanolamina)
Serotoninergici (fenfluoramina, dexfenfluramina, fluoxetina)
(sibutramina)
Noradrenergici / Serotoninergici
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RECENTI/ATTUALI FARMACI ANTI-OBESITÀ
Farmaco Bersaglio Meccanismo StatusInibitori introito calorico ( anoressizzanti)
Fenfluramina Neuroni serotoninerg. reuptake/ release Ritirato
Fentermina Neuroni noradrenerg. reuptake Ritirato
FenfluraminaFentermina (Fen / Phen)
Neuroni Serot./noradr. reuptake/ release Ritirato
Dexfenfluramina Neuroni serotoninerg. reuptake/ release Ritirato
Sibutramina Neuroni serot./noradr. reuptake Approvato
Inibitori assorbimento dei grassi
Orlistat Lipasi pancreatiche assorb. grassi Approvato
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Meccanismo d’azione: inibizione del re-uptake
di noradrenalina e serotonina.
Dose: 10-15 mg/die in unica
somministrazione
SIBUTRAMINA
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SIBUTRAMINA
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FARMACI INIBENTI L’ASSORBIMENTO DEI GRASSI
Inibitori delle lipasi gastrichee pancreatiche:
Orlistat
• Deriva per idrogenazione dalla lipstatina, molecola estratta dal microrganismo Streptomyces toxyricini.• Inibisce l’assorbimento di circa il 30% dei grassi ingeriti.
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Lume intestinale
Cellula della mucosa
Linfatici
FA
MG
LipasiGastrointestinali
TG
MicelleAcidi biliariMG
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FA
MG
Lipasi + Orlistat
TG
MicelleAcidi biliariMG
Lume intestinale
Cellula della mucosa
Linfatici
30%
ORLISTAT
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RIMONABANT
Bloccante selettivo del recettore 1 degli endocannabinoidi (CB1).
Conclusa la fase III di sperimentazione.
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RIMONABANT
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NUOVE MOLECOLE IN FASE DI SPERIMENTAZIONE CLINICA
Molecola Fase Casa Farmaceutica
Axokine (CNTF) III RegeneronLeptina II Amgen
CON AZIONE SUL SNCRimonabant (CNR1 antagon.) III Sanofi-SynthelaboBupropione II GlaxoSmithKlineTopiramato III Johnson & Johnson
INIBITORI DELLE LIPASI PANCREATICHEATL-962 I Alizyme
AGONISTI 3-ADRENERGICISB-418790 (AZ-40140) II GlaxoSmithKlineLY-377604 I Eli LillyN-5984 I Nissin Kyorin Pharm.
AGONISTI DEL RECETTORE-A DELLA CCKGI-181771 II GlaxoSmithKline
AGONISTI DEL RECETTORE DELLA TIROXINAAgonisti TH-R-IBristol-Myers Squibb
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IPOTALAMONucleoArcuato
MeccanismiEffettori
TRHMCHGABAaltri
NPY-R
MC4-R
-
+
+
Ipofisi:TSHaltro
SimpaticoParasimpatico
MCH-R
MC4-R
CART-R
CortecciaIpotalamoAreeolfattorie
TRH-R
Barriera
Emato-encefalica
POMC(MSH)CART
NPYAgRP
Leptina
OB-R
OB-R
Stimolioressizzanti
Stimolianoressizzanti
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CHIRURGIA CHIRURGIA BARIATRICABARIATRICA
Altri interventi non Altri interventi non malassorbitivimalassorbitivi
GastroplasticaGastroplasticaOrizzontaleOrizzontale
GastroplasticaGastroplasticaVerticaleVerticale
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•• Suppression of ghrelin productionSuppression of ghrelin production by the excluded stomach may be another mechanism of weight loss.by the excluded stomach may be another mechanism of weight loss.
•• PoriesPories et al. reported 58%, 55%, and 49% loss of excess weight (definedet al. reported 58%, 55%, and 49% loss of excess weight (defined as the patient’s weight minus the patient’s as the patient’s weight minus the patient’s estimatedestimated "ideal" body weight) at 5, 10, and 14 years postoperatively. "ideal" body weight) at 5, 10, and 14 years postoperatively. •• A gastrojejunostomy produces a dumping syndrome if the patientA gastrojejunostomy produces a dumping syndrome if the patient ingests high-carbohydrate foods.ingests high-carbohydrate foods.•• Deficiencies of iron, calcium, thiamin, and vitamins A,Deficiencies of iron, calcium, thiamin, and vitamins A, C, D, and BC, D, and B
1212 have been observed, and long-term have been observed, and long-term
supplementationsupplementation is recommendedis recommended
Bypass gastrico Roux-en-YBypass gastrico Roux-en-Y (SRVG-RGB)(SRVG-RGB)
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