Current Biology,
Год журнала:
2021,
Номер
31(17), С. 3797 - 3809.e5
Опубликована: Июль 16, 2021
While
energy
balance
is
critical
to
survival,
many
factors
influence
food
intake
beyond
caloric
need
or
"hunger."
Despite
this,
some
neurons
that
drive
feeding
in
mice
are
routinely
referred
as
"hunger
neurons,"
whereas
others
not.
To
understand
how
specific
hypothalamic
circuits
control
interoceptive
hunger,
we
trained
discriminate
fasted
from
sated
periods.
We
then
manipulated
three
neuronal
populations
with
well-known
effects
on
while
performed
this
task.
activation
of
ARCAGRP
caused
report
being
food-restricted,
LHVGAT
neuron
LHVGLUT2
inhibition
did
In
contrast,
attenuated
natural
Each
population
evoked
distinct
consumption
and
reward.
After
satiety-
sickness-induced
devaluation,
drove
calorie-specific
feeding,
calorie-indiscriminate
intake.
Our
data
support
a
role
for
homeostatic
implicate
them
driving
hunger-like
internal
state
directs
behavior
toward
sources.
Moreover,
manipulations
LH
not
evoke
mice,
suggesting
they
may
govern
more
related
reward,
compulsion,
generalized
than
balance,
but
also
these
can
be
powerful
negative
appetite
modulators
mice.
This
study
highlights
the
complexity
regulation
used
framework
characterize
other
affect
hunger
identify
potential
therapeutic
targets
eating
disorders.
Semaglutide,
a
glucagon-like
peptide
1
(GLP-1)
analog,
induces
weight
loss,
lowers
glucose
levels,
and
reduces
cardiovascular
risk
in
patients
with
diabetes.
Mechanistic
preclinical
studies
suggest
loss
is
mediated
through
GLP-1
receptors
(GLP-1Rs)
the
brain.
The
findings
presented
here
show
that
semaglutide
modulated
food
preference,
reduced
intake,
caused
without
decreasing
energy
expenditure.
Semaglutide
directly
accessed
brainstem,
septal
nucleus,
hypothalamus
but
did
not
cross
blood-brain
barrier;
it
interacted
brain
circumventricular
organs
several
select
sites
adjacent
to
ventricles.
induced
central
c-Fos
activation
10
areas,
including
hindbrain
areas
targeted
by
semaglutide,
secondary
direct
GLP-1R
interaction,
such
as
lateral
parabrachial
nucleus.
Automated
analysis
of
access,
activity,
distribution,
connectivity
revealed
may
involve
meal
termination
controlled
neurons
Transcriptomic
microdissected
from
semaglutide-treated
rats
showed
upregulation
prolactin-releasing
hormone
tyrosine
hydroxylase
area
postrema.
We
body
interaction
diverse
populations
indirectly
affecting
activity
neural
pathways
involved
reward,
Molecular Metabolism,
Год журнала:
2021,
Номер
48, С. 101206 - 101206
Опубликована: Март 7, 2021
Over
the
past
20
years,
insights
from
human
and
mouse
genetics
have
illuminated
central
role
of
brain
leptin-melanocortin
pathway
in
controlling
mammalian
food
intake,
with
genetic
disruption
resulting
extreme
obesity,
more
subtle
polymorphic
variations
influencing
population
distribution
body
weight.
At
end
2020,
U.S.
Food
Drug
Administration
(FDA)
approved
setmelanotide,
a
melanocortin
4
receptor
agonist,
for
use
individuals
severe
obesity
due
to
either
pro-opiomelanocortin
(POMC),
proprotein
convertase
subtilisin/kexin
type
1
(PCSK1),
or
leptin
(LEPR)
deficiency.
Herein,
we
chart
pathway's
history,
explore
its
pharmacology,
genetics,
physiology,
describe
how
neuropeptidergic
circuit
became
an
important
druggable
target.
Unravelling
subset
has
revealed
importance
appetitive
control;
coupling
this
studying
molecular
pharmacology
compounds
that
bind
receptors
brought
new
drug
market.
This
process
provides
discovery
template
complex
disorders,
which
setmelanotide
took
25
years
transform
single
gene
into
drug.
Endocrine Reviews,
Год журнала:
2021,
Номер
43(2), С. 314 - 328
Опубликована: Сен. 7, 2021
Abstract
The
central
nervous
system
(CNS)
receives
information
from
afferent
neurons,
circulating
hormones,
and
absorbed
nutrients
integrates
this
to
orchestrate
the
actions
of
neuroendocrine
autonomic
systems
in
maintaining
systemic
metabolic
homeostasis.
Particularly
arcuate
nucleus
hypothalamus
(ARC)
is
pivotal
importance
for
primary
sensing
adiposity
signals,
such
as
leptin
insulin,
nutrients,
glucose.
Importantly,
energy
state–sensing
neurons
ARC
not
only
regulate
feeding
but
at
same
time
control
multiple
physiological
functions,
glucose
homeostasis,
blood
pressure,
innate
immune
responses.
These
findings
have
defined
them
master
regulators,
which
adapt
integrative
physiology
state
organism.
disruption
fine-tuned
leads
an
imbalance
between
intake
expenditure
well
deregulation
peripheral
metabolism.
Improving
our
understanding
cellular,
molecular,
functional
basis
regulatory
principle
CNS
could
set
stage
developing
novel
therapeutic
strategies
treatment
obesity
syndrome.
In
review,
we
summarize
insights
with
a
particular
emphasis
on
neurocircuitries
regulating
food
homeostasis
factors
that
inform
brain
organismal
status.
The
role
of
serotonin
in
food
intake
has
been
studied
for
decades.
Food
is
mainly
regulated
by
two
brain
circuitries:
(i)
the
homeostatic
circuitry,
which
matches
energy
to
expenditure,
and
(ii)
hedonic
involved
rewarding
motivational
aspects
consumption.
In
serotonergic
signaling
contributes
integration
metabolic
signals
that
convey
body's
status
facilitates
ability
suppress
when
needs
have
met.
may
reduce
reward-related,
contrast,
peripherally
acting
promotes
absorption
storage.
Disturbed
associated
with
obesity,
emphasizing
importance
understand
intake.
However,
unraveling
serotonin-mediated
regulation
complex,
as
effects
different
regions
depend
on
regional
expression
receptor
subtypes
downstream
via
connections
other
regions.
We
therefore
provide
an
overview
regulatory
systems
Furthermore,
we
discuss
disturbances
obesity
its
potential
therapeutic
implications.
Physiological Reviews,
Год журнала:
2021,
Номер
102(2), С. 689 - 813
Опубликована: Сен. 6, 2021
During
the
past
30
yr,
investigating
physiology
of
eating
behaviors
has
generated
a
truly
vast
literature.
This
is
fueled
in
part
by
dramatic
increase
obesity
and
its
comorbidities
that
coincided
with
an
ever
increasing
sophistication
genetically
based
manipulations.
These
techniques
have
produced
results
remarkable
degree
cell
specificity,
particularly
at
signaling
level,
played
lead
role
advancing
field.
However,
putting
these
findings
into
brain-wide
context
connects
physiological
signals
neurons
to
behavior
somatic
requires
thorough
consideration
neuronal
connections:
field
also
seen
extraordinary
technological
revolution.
Our
goal
present
comprehensive
balanced
assessment
how
associated
energy
homeostasis
interact
many
brain
levels
control
behaviors.
A
major
theme
engage
sets
interacting
neural
networks
throughout
are
defined
specific
connections.
We
begin
discussing
some
fundamental
concepts,
including
ones
still
engender
vigorous
debate,
provide
necessary
frameworks
for
understanding
controls
meal
initiation
termination.
include
key
word
definitions,
ATP
availability
as
pivotal
regulated
variable
homeostasis,
neuropeptide
signaling,
homeostatic
hedonic
eating,
structure.
Within
this
context,
we
discuss
network
models
regions
endbrain
(or
telencephalon),
hypothalamus,
hindbrain,
medulla,
vagus
nerve,
spinal
cord
work
together
gastrointestinal
tract
enable
complex
motor
events
permit
animals
eat
diverse
situations.
