Mice without the KLHL1 gene develop obesity as adults and eat less in the first hour after being hungry, compared to normal mice, showing differences in how the hypothalamus controls hunger and...
Mechanism
Synthesis from 1 study
Without KLHL1, brain cells that signal fullness become stuck in an overactive state due to excess calcium channels, so they ignore the hormone that tells the body it needs food. This stops hunger from kicking in after fasting, leading to less eating and gradual weight gain.
Most probable mechanism
When KLHL1 is missing, brain cells that signal fullness become overactive due to too many calcium channels, so they stop responding to the hormone that tells the body it's full. This prevents the brain from triggering hunger after fasting, causing reduced eating and weight gain over time.
KLHL1 protein is absent, removing its normal suppression of the CaV3.1 T-type calcium channel gene
CaV3.1 T-type calcium channels are overexpressed in hypothalamic POMC neurons
Increased CaV3.1 channel density enhances T-type current density and shifts voltage dependence, creating a larger window current at resting membrane potential
Sustained calcium influx through CaV3.1 channels depolarizes POMC neurons and elevates basal excitability to a maximal level
POMC neurons are electrically saturated and cannot be further depolarized by leptin binding to its receptor
Leptin fails to activate POMC neurons, preventing downstream suppression of hunger signals and reducing motivation to eat after fasting
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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