bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 13, 2024
Abstract
The
dual
glucagon/glucagon-like
peptide
1
receptor
(GCGR/GLP1R)
agonists
have
superior
efficacy
in
promoting
weight
loss
and
metabolic
improvements
obesity
dysfunction-associated
steatohepatitis
(MASH)
than
current
available
mono-agonists.
However,
the
mechanisms
underlying
these
benefits
are
not
fully
understood.
While
effects
on
appetite
regulation
glucose
control
through
GLP1R
agonism
well
established,
role
of
GCGR
changes
is
less
defined.
Using
a
GCGR/GLP1R
agonist
BI
456908
selective
semaglutide,
we
could
show
that
achieved
by
engaging
hepatic
without
adversely
affecting
control.
Furthermore,
demonstrate
critical
for
facilitating
plasma
liver
lipid
clearance
stimulated
agonist.
Overall,
findings
highlight
crucial
contributions
to
combined
GCGR/GL1R
activation.
Aging
involves
seemingly
paradoxical
changes
in
energy
metabolism.
Molecular
damage
accumulation
increases
cellular
expenditure,
yet
whole-body
expenditure
is
stable
or
decreases
with
age.
We
resolve
this
apparent
contradiction
by
positioning
the
brain
as
mediator
and
broker
economy
of
within
organism.
As
somatic
tissues
accumulate
over
time,
costly
intracellular
stress
responses
are
activated,
causing
aging/senescent
cells
to
secrete
cytokines
that
convey
increased
demand
(hypermetabolism)
brain.
To
conserve
face
a
shrinking
budget,
deploys
conservation
responses,
which
suppress
low
priority
processes,
producing
fatigue,
physical
inactivity,
blunted
sensory
capacities,
immune
alterations,
endocrine
“deficits”.
term
cascade
Brain-body
Energy
Conservation
(BEC)
model
aging.
The
BEC
outlines
i)
energetic
cost
aging,
ii)
how
perception
senescence-associated
hypermetabolism
may
drive
manifestations
iii)
principles
underlying
modifiability
aging
trajectories
stressors
geroscience
interventions.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: June 29, 2024
DNA
methylation
is
a
widely
studied
epigenetic
mark,
affecting
gene
expression
and
cellular
function
at
multiple
levels.
in
the
mammalian
genome
occurs
primarily
cytosine-phosphate-guanine
(CpG)
dinucleotides,
patterning
of
landscape
(i.e.,
presence
or
absence
CpG
given
genomic
location)
exhibits
generally
bimodal
distribution.
Although
much
known
about
enzymatic
writers
erasers
methylation,
it
not
fully
understood
how
these
enzymes,
along
with
genetic,
chromatin,
regulatory
factors,
control
wide
landscape.
In
this
study,
analyzed
annotated
Islands
(CGIs)
independent
CpGs
as
their
proximity
to
other
substrates.
Analysis
aided
by
computationally
efficient
stochastic
mathematical
model
dynamics,
enabling
parameterization
from
data.
We
find
that
switch-like
dependence
on
local
density.
The
threshold
steepness
switch
modified
cell
lines
which
key
enzymes
are
knocked
out.
Modeling
further
elucidates
parameters,
including
catalytic
rates
lengthscales
inter-CpG
interaction,
tune
properties
switch.
Together,
results
support
competition
between
opposing
TET1-3
demethylating
methyltransferases
(DNMT3A/B)
an
ultrasensitive
switch,
analogous
protein
phosphorylation
(termed
‘zero-order
ultra-sensitivity’)
proposed
Goldbeter
Koshland.
Our
study
provides
insight
mechanisms
underlying
establishment
maintenance
landscapes,
flexible
pipeline
for
gleaning
molecular
insights
machinery
across
cell-specific,
epigenomic
datasets.
Molecular Metabolism,
Journal Year:
2024,
Volume and Issue:
88, P. 101999 - 101999
Published: July 31, 2024
Recombinant
adeno-associated
virus
(rAAV)
vectors
are
powerful
tools
for
the
sustained
expression
of
proteins
in
vivo
and
have
been
successfully
used
mechanistic
studies
mice.
A
major
challenge
associated
with
this
method
is
to
obtain
tissue
specificity
high
levels
without
need
local
administration.
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Sept. 13, 2024
Abstract
The
dual
glucagon/glucagon-like
peptide
1
receptor
(GCGR/GLP1R)
agonists
have
superior
efficacy
in
promoting
weight
loss
and
metabolic
improvements
obesity
dysfunction-associated
steatohepatitis
(MASH)
than
current
available
mono-agonists.
However,
the
mechanisms
underlying
these
benefits
are
not
fully
understood.
While
effects
on
appetite
regulation
glucose
control
through
GLP1R
agonism
well
established,
role
of
GCGR
changes
is
less
defined.
Using
a
GCGR/GLP1R
agonist
BI
456908
selective
semaglutide,
we
could
show
that
achieved
by
engaging
hepatic
without
adversely
affecting
control.
Furthermore,
demonstrate
critical
for
facilitating
plasma
liver
lipid
clearance
stimulated
agonist.
Overall,
findings
highlight
crucial
contributions
to
combined
GCGR/GL1R
activation.
