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A followup on the previous http://tinyurl.com/y2mhu8
message, is the below
description of how there may be a reason for our being
hungry or not being
hungry.

News and Views
Nature Medicine - 12, 1248 - 1249 (2006)
Keeping the fat off with nesfatin
Martin G Myers

A newly described neuropeptide, nesfatin-1, acts in the
brain to suppress
appetite.

Some of the components of brain circuits that control
feeding have come to
light over the last several years, including an extensive
list of hormones
and compounds that decrease feeding when injected into the
brain. Yet only a
subset of these substances are physiologically relevant and
can lend insight
into the brain processes that control appetite-moreover,
precious few
mediate meaningful long-term changes in body weight. Our
understanding of
how brain circuitry controls appetite remains sparse1, 2, 3.

In a recent issue of Nature, Oh-I et al. define a
physiologic role in the
suppression of appetite for a novel brain-expressed peptide,
nesfatin-1,
which is derived from the previously described protein
nucleobindin-2
(NUCB2, a.k.a. NEFA) (refs. 4,5 and Fig. 1). Although
lengthier studies will
be necessary, modulation of nesfatin-1 levels in the brain
alters feeding
and body weight for over one week without apparent loss of
efficacy.

Figure 1. Regulation and function of nesfatin in the control
of feeding.

Nesfatin is a prohormone that is cleaved by prohormone
convertases to an
NH2-terminal nesfatin-1 peptide and to nesfatin-2/3. Whereas
nesfatin-2/3
have no effect on feeding, nesfatin-1 suppresses eating in a
manner that
requires functional melanocortin receptors (MC3/4R).
Although there are no
data to confirm the actual site of nesfatin-mediated
satiety, the
nutritional regulation of nesfatin is restricted to the
paraventricular
nucleus of the hypothalamus (PVN), where its expression is
suppressed by
fasting and enhanced by the action of melanocortins (a
signal of satiety).
The PVN is also a major site of MC3/4R receptor expression
and action in the
suppression of feeding.

The investigators discovered that the secreted protein NUCB2
is expressed in
areas of the hypothalamus that are prominently involved in
appetite
regulation, prompting them to examine a potential role for
this molecule in
feeding. Indeed, the authors showed that injection of NUCB2
directly into
the brain of rats promotes anorexia (decreased appetite)-and
that the
injection of antibodies to NUCB2 (anti-NUCB2) to neutralize
endogenous NUCB2
in the rat central nervous system (CNS) potently stimulates
feeding. These
observations implicate NUCB2 in the neuronal pathways that
suppress
appetite.

Whereas the injection of many peptides into the brain may
nonspecifically
decrease appetite by making the animal feel sick, the
authors show that this
is not the case for NUCB2. Indeed, fasting suppressed NUCB2
expression
specifically in a region of the hypothalamus known to have
an important role
in anorexia-the paraventricular nucleus (PVN). The PVN
compiles a variety of
inputs that regulate feeding to generate an integrated
signal of hunger or
satiety that is then passed on to other regions of the
brain. One of the
major pathways that modulates the appetite-regulating
function of the PVN is
the melanocortin system, in which melanocortin peptides (such
as -melanocyte-stimulating hormone, -MSH) derived from the
arcuate nucleus
of the hypothalamus activate the melanocortin-3 and
melanocortin-4 receptors
(MC3/4R) in the PVN to promote anorexia in response to meals
and sufficient
body energy stores1, 2, 6. Melanocortin action increases the
expression of
NUCB2 in the PVN. Thus, not only does NUCB2 mediate
anorexia, but its
expression in the PVN is regulated in a manner that is
consistent with a
role in the physiologic regulation of appetite.

The authors also note that NUCB2 contains multiple potential
sites for
processing by prohormone convertases proteases that
specifically cleave
secreted precursor proteins into smaller active peptides7.
Indeed, NUCB2 is
coexpressed with multiple prohormone convertases in the
hypothalamus.
Moreover, the action of prohormone convertase on NUCB2
releases an
NH2-terminal fragment-nesfatin-1-that is present in the CNS,
is regulated by
fasting in the PVN, and possesses all of the anorectic
activity of NUCB2.

Neither the COOH-terminal NUCB2 fragments (nesfatin-2/3) nor
a mutant NUCB2
precursor that is resistant to prohormone
convertase-dependent processing
retains any effect on feeding-suggesting that nesfatin-1
must be cleaved
from intact NUCB2 in order to suppress feeding. Thus,
nesfatin-1 is a novel
peptide product of NUCB2, and it is this peptide that
mediates the anorexic
action of NUCB2 in the CNS.

Unfortunately, there are few clues detailing the mechanism
of nesfatin-1
action. NUCB2 was initially defined as a potential leucine
zipper- and 'EF
hand'-containing protein of unknown function that is
expressed in
lymphoblastic cells5. Subsequent experiments have defined
the ability of the
EF hands to complex calcium and have suggested a role for
the leucine zipper
motifs in complex formation with heterologous proteins8, 9,
10. The protein
is localized within the endoplasmic reticulum (ER) and Golgi
and is secreted
from cultured cells8, 11. Recent studies have also suggested
that the EF
hand and leucine zipper region may be involved in complex
formation with
tumor necrosis factor receptor-1 (TNFR1) and other proteins
within the
secretory pathway and on the cell surface8. All of these
attributes of NUCB2
are mediated by motifs found within nesfatin-2/3, however4.
Thus, prior
knowledge regarding NUCB2 sheds little light on the
mechanism of nesfatin-1
action.

What we do know is that the action of nesfatin-1 is blocked
by MC3/4R
antagonists and that nesfatin-1 itself does not directly
activate
melanocortin receptor-dependent signaling in cultured
cells4. If we are to
assume that nesfatin-1 produced within the PVN (where its
expression is
regulated by feeding and by melanocortin action) mediates
its anorexic
actions, one way of synthesizing these results is that
nesfatin-1 could be
expressed in melanocortin-responsive PVN neurons. In these
neurons,
nesfatin-1 could act locally to potentiate the action of
melanocortins on
MC3/4R signaling. Alternatively, nesfatin-1 could act
trans-synaptically in
a manner that requires coordinate output by other
melanocortin-dependent
signals. Clearly, other possibilities exist as well.

Certainly, we cannot rule out the possibility that the
anorectic action of
nesfatin-1 is mediated by some area or areas other than the
PVN. NUCB2 is
also expressed in the arcuate nucleus and the lateral
hypothalamic area-both
regions of the brain that modulate feeding1, 2. Going
forward, it will be
crucial to understand the site and mechanism of action for
the anorectic
signal mediated by nesfatin-1. Identifying a receptor or
nonclassical
binding partner for nesfatin-1 will be an important first
step in this
journey.