Abstract
Sleep
deficiency
is
associated
with
obesity,
but
the
mechanisms
underlying
this
connection
remain
unclear.
Here,
we
identify
a
sleep-inducible
hypothalamic
protein
hormone
in
humans
and
mice
that
suppresses
obesity.
This
cleaved
from
reticulocalbin-2
(RCN2),
name
it
Raptin.
Raptin
release
timed
by
circuit
vasopressin-expressing
neurons
suprachiasmatic
nucleus
to
RCN2-positive
paraventricular
nucleus.
levels
peak
during
sleep,
which
blunted
sleep
deficiency.
binds
glutamate
metabotropic
receptor
3
(GRM3)
of
hypothalamus
stomach
inhibit
appetite
gastric
emptying,
respectively.
Raptin-GRM3
signaling
mediates
anorexigenic
effects
via
PI3K-AKT
signaling.
Of
note,
verify
connections
between
deficiencies
sleeping
state,
impaired
release,
obesity
patients
Moreover,
carrying
an
RCN2
nonsense
variant
present
night
eating
syndrome
These
data
define
unique
food
intake
prevents
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Авг. 28, 2022
Abstract
Obesity
is
a
complex,
chronic
disease
and
global
public
health
challenge.
Characterized
by
excessive
fat
accumulation
in
the
body,
obesity
sharply
increases
risk
of
several
diseases,
such
as
type
2
diabetes,
cardiovascular
disease,
nonalcoholic
fatty
liver
linked
to
lower
life
expectancy.
Although
lifestyle
intervention
(diet
exercise)
has
remarkable
effects
on
weight
management,
achieving
long-term
success
at
loss
extremely
challenging,
prevalence
continues
rise
worldwide.
Over
past
decades,
pathophysiology
been
extensively
investigated,
an
increasing
number
signal
transduction
pathways
have
implicated
obesity,
making
it
possible
fight
more
effective
precise
way.
In
this
review,
we
summarize
recent
advances
pathogenesis
from
both
experimental
clinical
studies,
focusing
signaling
their
roles
regulation
food
intake,
glucose
homeostasis,
adipogenesis,
thermogenesis,
inflammation.
We
also
discuss
current
anti-obesity
drugs,
well
compounds
trials,
that
target
these
signals.
The
evolving
knowledge
may
shed
light
future
direction
research,
move
into
new
era
precision
medicine.
Cell Metabolism,
Год журнала:
2022,
Номер
34(9), С. 1234 - 1247.e9
Опубликована: Авг. 18, 2022
With
an
increasing
prevalence
of
obesity,
there
is
a
need
for
new
therapies
to
improve
body
weight
management
and
metabolic
health.
Multireceptor
agonists
in
development
may
provide
approaches
fulfill
this
unmet
medical
need.
LY3437943
novel
triple
agonist
peptide
at
the
glucagon
receptor
(GCGR),
glucose-dependent
insulinotropic
polypeptide
(GIPR),
glucagon-like
peptide-1
(GLP-1R).
In
vitro,
shows
balanced
GCGR
GLP-1R
activity
but
more
GIPR
activity.
obese
mice,
administration
decreased
improved
glycemic
control.
Body
loss
was
augmented
by
addition
GCGR-mediated
increases
energy
expenditure
GIPR-
GLP-1R-driven
calorie
intake
reduction.
phase
1
single
ascending
dose
study,
showed
safety
tolerability
profile
similar
other
incretins.
Its
pharmacokinetic
supported
once-weekly
dosing,
reduction
persisted
up
day
43
after
dose.
These
findings
warrant
further
clinical
assessment
LY3437943.
Pharmacological Research,
Год журнала:
2022,
Номер
186, С. 106550 - 106550
Опубликована: Ноя. 11, 2022
Chronic,
excessive
neuroinflammation
is
a
key
feature
of
neurodegenerative
diseases
such
as
Alzheimer's
disease
(AD)
and
Parkinson's
(PD).
However,
neuroinflammatory
pathways
have
yet
to
be
effectively
targeted
in
clinical
treatments
for
diseases.
Interestingly,
increased
inflammation
risk
been
associated
with
type
2
diabetes
mellitus
(T2DM)
insulin
resistance
(IR),
suggesting
that
mitigate
T2DM
pathology
may
successful
treating
well.
Glucagon-like
peptide-1
(GLP-1)
an
incretin
hormone
promotes
healthy
signaling,
regulates
blood
sugar
levels,
suppresses
appetite.
Consequently,
numerous
GLP-1
receptor
(GLP-1R)
stimulating
drugs
developed
approved
by
the
US
Food
Drug
Administration
(FDA)
related
global
regulatory
authorities
treatment
T2DM.
Furthermore,
GLP-1R
anti-inflammatory,
neurotrophic,
neuroprotective
properties
disorder
preclinical
models,
hence
hold
promise
repurposing
In
this
review,
we
discuss
pathways,
intersections
between
neuroinflammation,
brain
IR,
diseases,
focus
on
AD
PD.
We
additionally
overview
current
FDA-approved
agents
development,
including
unimolecular
single,
dual,
triple
agonists,
highlight
those
trials
treatment.
propose
already-approved
agonists
safe,
efficacious,
cost-effective
strategy
ameliorating
PD
quelling
neuroinflammation.
Molecular Metabolism,
Год журнала:
2022,
Номер
63, С. 101533 - 101533
Опубликована: Июль 7, 2022
Pharmacological
strategies
that
engage
multiple
mechanisms-of-action
have
demonstrated
synergistic
benefits
for
metabolic
disease
in
preclinical
models.
One
approach,
concurrent
activation
of
the
glucagon-like
peptide-1
(GLP-1),
glucose-dependent
insulinotropic
peptide
(GIP),
and
glucagon
(Gcg)
receptors
(i.e.
triagonism),
combines
anorectic
activities
GLP-1
GIP
with
energy
expenditure
effect
glucagon.
While
efficacy
triagonism
models
is
known,
relative
contribution
GcgR
remains
unassessed.
This
work
aims
to
addresses
central
question.Herein,
we
detail
design
unimolecular
triagonists
an
empirically
optimized
receptor
potency
ratio.
These
employ
a
protraction
strategy
permitting
once-weekly
human
dosing.
Additionally,
assess
effects
these
peptides
on
weight-reduction,
food
intake,
glucose
control,
established
DIO
mouse
model
compared
clinically
relevant
GLP-1R
agonists
(e.g.
semaglutide)
dual
GLP-1R/GIPR
tirzepatide).Optimized
normalize
body
weight
mice
enhance
manner
superior
mono-agonists
co-agonists.These
pre-clinical
data
suggest
poly-pharmacology
as
effective
means
target
mechanisms
contributing
obesity
further
implicate
differentiating
factor
between
incretin
mono-
or
dual-agonists
triagonists.
Nature Metabolism,
Год журнала:
2024,
Номер
6(2), С. 290 - 303
Опубликована: Фев. 5, 2024
Abstract
Obesity
is
a
major
public
health
crisis.
Multi-specific
peptides
have
emerged
as
promising
therapeutic
strategies
for
clinical
weight
loss.
Glucagon-like
peptide-1
(GLP-1)
and
glucose-dependent
insulinotropic
polypeptide
(GIP)
are
endogenous
incretins
that
regulate
through
their
receptors
(R).
AMG
133
(maridebart
cafraglutide)
bispecific
molecule
engineered
by
conjugating
fully
human
monoclonal
anti-human
GIPR
antagonist
antibody
to
two
GLP-1
analogue
agonist
using
amino
acid
linkers.
Here,
we
confirm
the
GLP-1R
activities
in
cell-based
systems
report
ability
of
reduce
body
improve
metabolic
markers
male
obese
mice
cynomolgus
monkeys.
In
phase
1,
randomized,
double-blind,
placebo-controlled
study
participants
with
obesity
(
NCT04478708
),
had
an
acceptable
safety
tolerability
profile
along
pronounced
dose-dependent
multiple
ascending
dose
cohorts,
loss
was
maintained
up
150
days
after
last
dose.
These
findings
support
continued
evaluation
133.
