cron-web.org

[A1CR]

The role of http://en.wikipedia.org/wiki/Melanocortin in
energy is evident
in its inclusion of the adrenalin-affecting
http://en.wikipedia.org/wiki/ACTH among its members. Thus,
the http://en.wikipedia.org/wiki/Melanocortin_receptor is a
protein whose
mutation has an apparent role in overeating conditions.
Would it be possible to alter this system in those CRONies
who may be thus predisposed, which may counter the effects
of CR? The paper below suggests that using drugs to alter
our genetic predisposition to counter CR may lead to
unwanted side effects. The text that may bear on this
thesis is excerpted after the Medline citation and abstract.
It was observed that
http://en.wikipedia.org/wiki/Melanocortin stated that
http://en.wikipedia.org/wiki/Bremelanotide is a drug used to
counter a main side effect that may occur when the
melanocortin receptor use as a drug target. My opinion is
the reliance of CR mimics, drugs or hormones, when CR can be
utilized successfully, is fraught with dangers.

Adan RA, Tiesjema B, Hillebrand JJ, la Fleur SE, Kas MJ, de
Krom M.
The MC4 receptor and control of appetite.
Br J Pharmacol. 2006 Oct 16; [Epub ahead of print]
PMID: 17043670

Mutations in the human melanocortin (MC)4 receptor have been
associated with
obesity, which underscores the relevance of this receptor as
a drug target
to treat obesity. Infusion of MC4R agonists decreases food
intake, whereas
inhibition of MC receptor activity by infusion of an MC
receptor antagonist
or with the inverse agonist AgRP results in increased food
intake. This
review addresses the role of the MC system in different
aspects of feeding
behaviour. MC4R activity affects meal size and meal choice,
but not meal
frequency, and the type of diet affects the efficacy of MC4R
agonists to
reduce food intake. The central sites involved in the
different aspects of
feeding behaviour that are affected by MC4R signalling are
being unravelled.
The paraventricular nucleus plays an important role in food
intake per se,
whereas MC signalling in the lateral hypothalamus is
associated with the
response to a high fat diet. MC4R signalling in the
brainstem has been shown
to affect meal size. Further genetic, behavioural and
brain-region specific
studies need to clarify how the MC4R agonists affect feeding
behaviour in
order to determine which obese individuals would benefit
most from treatment
with these drugs. Application of MCR agonists in humans has
already revealed
side effects, such as penile erections, which may complicate
introduction of
these drugs in the treatment of obesity.

... The MC4 receptor is an attractive candidate drug target
to treat
obesity, as it not only affects several aspects of feeding
behaviour as
discussed in this review, but activation of the MC system
also increases
insulin sensitivity and energy expenditure, part of which
effect is
independent of food intake (Banno et al., 2004; Heijboer et
al., 2005).
Several pharmaceutical industries are active in the
development of MC4
receptor-specific drugs (Tian et al., 2005; Bakshi et al.,
2006; Nicholson
et al., 2006). It has proven difficult to design selective
MC4 receptor
agonists, in particular those that completely lack affinity
for the MC3
receptor (Holder and Haskell-Luevano, 2004; Todorovic and
Haskell-Luevano,
2005). However, mixed MC3/4 agonism might provide a
therapeutic advantage,
as reduced MC3 receptor activity (as in MC3-/- mice) has
been associated
with increased adipogenesis. Early rodent and human studies
revealed some
side effects of MC receptor agonists. Administration of MC4
receptor
agonists is associated with penile erections as well as
flushing, which has
resulted in a new application area for these drugs: erectile
dysfunction
(Van der Ploeg et al., 2002; Diamond et al., 2004; Wessells
et al., 2005).
Preclinical studies have identified roles of the MC system
in blood pressure
regulation (MC receptor agonists have a depressor effect
most probably via
the NTS in brainstem) (Versteeg et al., 1998), in the
inflammatory responses
(where agonists limit thermogenic responses to pyrogens)
(Catania et al.,
2004) and in pain processing (where antagonists suppress
pain sensation)
(Vrinten et al., 2001). With the development of MC4 receptor
agonists in the
treatment of obesity, it should be carefully monitored
whether these other
MC effects provide unwanted side effects.