In mice lacking the KLHL1 gene, specific brain cells called POMC neurons fire more frequently and start at a higher electrical baseline, which makes them more active overall and prevents leptin from...
Mechanism
Synthesis from 1 study
Without KLHL1, brain cells that signal fullness overactivate due to too many calcium channels, leaving them unable to respond to the fullness hormone leptin. This causes the brain to ignore signals that the body has eaten enough.
Most probable mechanism
When KLHL1 is missing, T-type calcium channels build up in fullness-sensing brain cells, causing them to fire nonstop and stay overly active. Because they are already firing at maximum capacity, the hormone leptin cannot make them any more active, so the brain does not signal fullness even when the body has eaten enough.
KLHL1 protein is absent, removing its normal suppression of T-type calcium channel expression
T-type calcium channel CaV3.1 protein levels increase significantly in hypothalamic POMC neurons
Increased CaV3.1 channels enhance T-type current density and shift voltage dependence to favor sustained calcium influx at resting membrane potential
Sustained calcium influx through CaV3.1 channels depolarizes the resting membrane potential and triggers spontaneous burst-firing activity
Elevated basal excitability and continuous firing prevent further depolarization by leptin-activated TRPC1/5 channels
Leptin signaling through STAT3 and PI3K pathways remains intact but fails to increase neuronal activity due to maximal baseline excitation
Evidence from Studies
Supporting (1)
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Genetic Deletion of KLHL1 Leads to Hyperexcitability in Hypothalamic POMC Neurons and Lack of Electrical Responses to Leptin
Contradicting (0)
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