The Arcuate Nucleus at Rest — Two Neuron Populations in Balance
Placeholder: baseline hunger and fullness signals held in dynamic equilibrium.
- ~30%: POMC/CART activity (placeholder baseline)
- ~68%: AgRP/NPY activity (placeholder baseline)
- ~2%: GLP-1R occupancy (placeholder, pre-dose)
- Elevated: Net appetite drive (placeholder fasting state)
POMC/CART neurons
Placeholder: anorexigenic neurons, low tonic activity at baseline.
AgRP/NPY neurons
Placeholder: orexigenic neurons dominate signaling before treatment.
Circuit balance
Placeholder: reciprocal inhibition sets the fasting appetite set point.
Semaglutide Crosses Into the Hypothalamus and Binds GLP-1 Receptors
Placeholder: circulating drug reaches arcuate nucleus receptors.
- ~38%: Receptor occupancy (placeholder mid-binding)
- yes: Circumventricular access (placeholder BBB-permeable zone)
- GLP-1R: Receptor type (placeholder class-B GPCR)
- minutes–hours: Binding onset (placeholder timescale)
Crossing the barrier
Placeholder: median eminence permeability allows central access.
Receptor docking
Placeholder: agonist occupies GLP-1 receptors on both neuron types.
Dose dependence
Placeholder: higher dose raises steady-state receptor occupancy.
POMC/CART Activated, AgRP/NPY Inhibited — the Circuit Flips
Placeholder: receptor activation drives opposite effects on each population.
- ~66%: POMC/CART activity (placeholder mid-shift)
- ~38%: AgRP/NPY activity (placeholder mid-shift)
- reciprocal: Signal direction (placeholder opposing shift)
- Neutral: Net appetite drive (placeholder transition point)
POMC excitation
Placeholder: alpha-MSH output rises as POMC neurons fire more.
AgRP inhibition
Placeholder: orexigenic firing rate drops under GLP-1R activation.
Cross-inhibition loosens
Placeholder: AgRP normally suppresses POMC; that brake eases.
Satiety Strengthens While Hunger Drive Weakens
Placeholder: combined neuron shift produces a stronger net fullness signal.
- ~80%: POMC/CART activity (placeholder strengthened)
- ~24%: AgRP/NPY activity (placeholder weakened)
- MC4R: Downstream target (placeholder melanocortin pathway)
- Suppressed: Net appetite drive (placeholder state)
Melanocortin output
Placeholder: alpha-MSH activates MC4R on second-order neurons.
Hunger drive decline
Placeholder: orexigenic tone falls well below baseline levels.
Signal integration
Placeholder: hypothalamus reads net balance as energy sufficiency.
Reduced Caloric Intake and a Weight-Loss Trajectory Over Weeks
Placeholder: sustained central suppression compounds into weight loss.
- 0–20: Weeks modeled (placeholder therapy window)
- declining: Caloric intake trend (placeholder trajectory)
- declining: Weight trajectory (placeholder cumulative)
- Suppressed: Net appetite drive (placeholder sustained state)
Weeks compound
Placeholder: cumulative weeks deepen the appetite-drive suppression.
Intake reduction
Placeholder: fewer daily calories consumed without deliberate restriction.
Weight trajectory
Placeholder: steady downward trend over the modeled 20 weeks.
Placeholder key insight: central hypothalamic shift, not gut alone, drives sustained suppression.