Mice genetically modified to lack the KLHL1 gene become obese as adults and eat less food after a period of fasting than normal mice.
Mechanism
Synthesis from 1 study
Without KLHL1, brain cells that tell the body it's full become stuck in an overactive state due to too many calcium channels. When the body is hungry and then gets food again, these cells can't respond to the fullness signal, so the animal eats less than it should.
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 to stop eating. After fasting, these cells cannot be activated to drive hunger, so the animal eats less than normal when food returns.
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 activity 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 firing rate to a maximal level
POMC neurons become electrically saturated and unresponsive to leptin, which normally increases their activity to suppress appetite
Leptin resistance in POMC neurons prevents the normal post-fasting activation of satiety signaling, resulting in reduced food intake during refeeding
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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