Controllo dell

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Modello temporaneo (molto) semplificato dei
circuiti del SNC implicati nellanoressia e nella
cachessia del portatore di tumore
Recettore per la melanocortina, MCR
-
Leptina e insulina
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Neuropeptidi anorexigenici CRH
Lipolisi
Controllo dellappetito
norepinefrina, dopamina, serotonina
Termogenesi ? e metabolismo basale ?
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Modello temporaneo (molto) semplificato dei
circuiti del SNC implicati nellanoressia e nella
cachessia del portatore di tumore
-
Recettore per la melanocortina, MCR
-
Leptina e insulina
-


Neuropeptidi anorexigenici CRH
Lipolisi
norepinefrina, dopamina, serotonina
Anoressia
Termogenesi ? e metabolismo basale ?
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Regulation of NPY production in the hypothalamic
arcuate nucleus. Glucocorticoids stimulate
hypothalamic production of neuropeptide Y (NPY),
leading to increased food intake and reduced
energy expenditure. Leptin, which is produced by
adipose tissue, blocks NPY production, as does
insulin, which is produced by the pancreas, and
increased NPY decreases leptin and insulin
production.
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Digiuno post-prandiale (5-6 h)
GLUCOSIO
catecolamine
insulina
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Digiuno prolungato (1-7 giorni)
Proteine
GLUCOSIO
Aminoacidi
CORPI CHETONICI

glucagone
ACIDI GRASSI
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Digiuno protratto
N ureico nelle urine ? (da 12 a 2 g/24 h)
GLUCOSIO
Tessuti
Aminoacidi
CORPI CHETONICI

glucagone
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Controllo dellossidazione degli acidi grassi

insulina glucagone
Chetogenesi
in absence of oxalacetate
Keton bodies
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CARATTERISTICHE ENDOCRINO-METABOLICHE DEL
SOGGETTO DIGIUNANTE E DEL PORTATORE DI TUMORE
Nel soggetto digiunante

• Aumento della lipolisi
• Blocco della sintesi de novo degli acidi grassi
• Inibizione della lipogenesi
• Inibizione della lipasi lipoproteica
  (iperlipemia)
• Aumento della proteolisi muscolare
• Aumento dellazoto ureico nelle urine
• Riduzione della sintesi proteica nei muscoli
  scheletrici
• Aumento della sintesi epatica delle proteine
  della fase acuta
• Aumento della gluconeogenesi dagli aminoacidi,
  dal glicerolo, dallacido lattico (prodotto dal
  tumore e dai tessuti dellospite)
• Resistenza allinsulina
• Iperinsulinemia
• Intolleranza al glucosio
• Aumento del metabolismo basale
• Insulinemia fortemente aumentata
• Cortisolo nel siero aumentato

(digiuno prolungato)

• Riduzione del metabolismo basale
• Insulinemia ridotta
• Cortisolo nel siero non modificato

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Tumore
(TNFa)
ACIDI GRASSI TRIGLICERIDI
(TNFa)
Tumore
Effetto del tumore sulla sintesi e
sullutilizzazione degli acidi grassi dopo il
pasto
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N ureico nelle urine ? ? ?
Sintesi proteica ? PROTEINE
Corpi chetonici
PIF
TNFa
Aminoacidi
Aminoacidi
TNF
Corpi chetonici
Sintesi delle proteine della fase acuta
Caratteristiche metaboliche del portatore di
tumore
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Breve storia della scoperta del ruolo delle
citochine infiammatorie nella cachessia
neoplastica

• Cerami e coll. negli anni 70 osservano in
  conigli affetti da tripanosomiasi una notevole
  riduzione della massa corporea proteica e
  lipidica associata a una marcata iperlipidemia
  come risultato di una ridotta attività
  lipoprotein- lipasica
• Kawakami e Cerami nel 1981 dimostrano che il
  trattamento con endotossine batteriche induce
  nel topo la comparsa di un fattore serico capace
  di sopprimere lattività lipoprotein-lipasica
• Beutler e Cerami nel 1985 dimostrano che il
  fattore inibitorio dellattività
  lipoprotein- lipasica corrisponde a una molecola
  polipeptidica, di origine macrofagica, a
  struttura ben definita che viene denominata
  cachettina
• Beutler e Cerami nel 1986 dimostrano che la
  sequenza aminoacidica della cachettina è omologa
  a quella del fattore di necrosi tumorale (TNF)
• Successivamente lanalisi genetica ha confermato
  che la cachettina e il TNF sono molecole
  identiche.

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Catabolic mediators in cancer. Both tumor-derived
and humoural (cytokines) factors are involved in
mediating anorexia and metabolic changes,
characteristic of the cachectic state.
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ATP
INSULINA GLUCAGONE_--_
ESOCHINASI
GLUCAGONE
GLUCOSIO 6-FOSFATASI
GLUCOCHINASI
ADP
ATP
GLUCAGONE
INSULINA GLUCAGONE_--_
FRUTTOSIO 1,6-DIFOSFATASI
FOSFOFRUTTOCHINASI
ADP
ADP
ADP
GLICEROCHINASI
ATP
ATP
GLICEROLO
INSULINA GLUCAGONE_--_
ADP
PIRUVATO CHINASI
ATP
LATTATO
GDP
FOSFOENOLPIRUVATO CARBOSSICHINASI
GLUCAGONE
GTP
ATP
PIRUVATO CARBOSSILASI
ADP
PROPIONATO
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MF
Cori cycle with sources of gluconeogenic
substrates. Tumours produce factors such as
lipid-mobilizing factor (LMF), which induces
breakdown of adipose tissue into fatty acids, and
proteolysis-inducing factor (PIF), which induces
protein degradation (amino acids) in skeletal
muscle. Tumour necrosis factor (TNF)-a also
contributes to these processes. These are
important gluconeogenic substrates that can be
used in acute-phase protein (APP) synthesis by
the liver. Tumours convert glucose to lactate,
which is transferred to the liver, where it is
converted back into glucose. This cycle uses a
large amount of energy, and might contribute to
cachexia.
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Synthesis and degradation of proteins in skeletal
muscle. Protein levels in muscle are determined
by the amount of dietary intake of protein and
levels of protein synthesis. Decreases in plasma
insulin concentrations or insulin sensitivity of
skeletal muscle can activate three main
proteolytic pathways that underlie protein
catabolism in skeletal muscle. These are the
lysosomal system, which proteolyses extracellular
proteins and cell-surface receptors the
cytosolic calcium-activated system, which
involves calpains I and II and is involved in
tissue injury, necrosis and autolysis, and the
ATP-ubiquitin-dependent proteolytic pathway. This
proteolysis leads to hepatic production of
acute-phase protein (APP), which can limit the
availability of certain amino acids for protein
synthesis in skeletal muscle. Protein deamination
also leads to nitrogen excretion, producing a
negative nitrogen balance, and glucose
production, which increases muscle activity.
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Ubiquitin-proteasome pathway Ubiquitin (Ub)
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The UbiquitinProteasome Pathway of Proteolysis.
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Indicazioni sulla partecipazione del sistema
ubiquitinico nella proteolisi dei muscoli
scheletrici nella cachessia neoplastica

• Aumento dellmRNA dellubiquitina del muscolo
  retto-addominale di portatore di cancro gastrico
• Aumento delle subunità alfa e beta del proteosoma
  nei muscoli del portatore di tumore
• Aumentata espressione dellenzima E2 che coniuga
  lubiquitina alle proteine
• Aumentata espressione dellenzima E3 legante la
  proteina

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Muscle breakdown. Signaling pathways that
regulate protein homeostasis in skeletal muscle.
Cytokines such as TNF-a together with IFN-g
activate the transcription factor NF-kB. This
leads to decreased expression of MyoD, a
transcription factor that may be important for
replenishing wasted muscle. Activated NF-kB also
acts as a repressor of proteasome subunit
expression and hence suppresses protein
degradation, an activity that is antagonized by
glucocorticoids. (The proteasome is a
multisubunit complex involved in the breakdown of
ubiquitinated proteins.) Tumor factors such as
PIF increase production of proteasome subunits
through the intermediary 15-HETE. It is not known
whether this is a direct or indirect effect
(dashed arrows). Eicosapentaenoic acid (EPA)
inhibits 15-HETE production in response to PIF
and prevents muscle wasting in cancer patients.
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Interactions between pro-inflammatory cytokines
and PIF
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The Importance of Myosin in Cachexia. Soluble
factors released from tumors or immune effector
cells and implicated in cachexia can lead to a
specific decrease in the levels of the myosin
heavy chain, a muscle contractile protein. The
data provide support for the existence of two
pathways. In Panel A, the combination of tumor
necrosis factor a (TNF-a) and interferon- g
(IFN-g) results in the suppression of the nuclear
transcription factor MyoD and, hence, a decrease
in the transcription of the myosin heavy chain a
deficit in the cellular pool of myosin heavy
chain results in cachexia. Cytokines such as
interleukin-6 increase the production of
ubiquitin and E3 ubiquitin ligase proteins. In
Panel B, stimulation of the ubiquitin
ligasedependent proteasome pathway leads to
increased and preferential ubiquination of the
myosin heavy chain, causing the dissociation of
myosin from the contractile apparatus and its
subsequent degradation into peptides by the
proteasomes. The loss of functional contractile
units, probably combined with the selective loss
of other specific proteins, leads to muscle
atrophy and wasting.
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Proton transport by UCP1 across the inner
mitochondrial membrane Normally, proton transport
across the inner mitochondrial membrane is
coupled to phosphorylation of ADP to generate
ATP. An increase in membrane proton permeability
that is not coupled to an energy-consuming system
constitutes a proton leak. This leak decreases
the coupling of respiration to ADP
phosphorylation, and increases substrate
oxidation and the dissipation of oxidation energy
as heat. This process protects against
hypothermia and regulates energy balance. Both
animal and plant mitochondria contain a group of
mitochondrial carrier proteins known as the
uncoupling proteins (UCP). UCP1 is highly
expressed by brown adipose tissue (BAT) the
main site for thermogenesis. The inner membrane
of BAT mitochondria have a high permeability to
protons, due to the abundance of UCP1, so ATP
production is uncoupled, leading to heat
production. Two mechanisms have been proposed by
which UCP1 is able to transport protons. a In
the first model, UCP1 transports protons (H) and
fatty acids (RCOO-). The fatty acid provides a
free carboxyl group that makes proton transport
possible. The proton is then liberated from the
fatty acid after it has crossed the membrane. b
In the second model, the protonated form of the
fatty acid diffuses freely across the membrane,
and UCP1 transports the anionic form of the fatty
acid (RCOO-) back across to the other side.
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