Hypothalamic Satiety Resistance is a state of impaired responsiveness in the appetite-regulating neurons of the hypothalamus to circulating satiety hormones and neural signals that typically indicate fullness and energy sufficiency. Despite adequate levels of hormones like leptin and insulin, the central nervous system fails to register the satiety signal correctly, resulting in a persistent drive to eat and an inability to terminate a meal appropriately. This is a core pathology in many forms of chronic weight gain and metabolic dysfunction.
Origin
This term is central to neuroendocrinology, focusing on the hypothalamus, the brain region responsible for maintaining energy homeostasis. ‘Satiety’ refers to the feeling of fullness and satisfaction that inhibits further eating. ‘Resistance’ denotes the failure of the target tissue (hypothalamic neurons) to respond to the signaling molecules, mirroring the concept of insulin resistance in peripheral tissues. The discovery of leptin and its central action was key to defining this resistance state.
Mechanism
The mechanism primarily involves inflammation and gliosis within the arcuate nucleus of the hypothalamus, which houses key neurons that integrate hunger and satiety signals. Pro-inflammatory cytokines can physically interfere with the transport of satiety hormones, such as leptin and insulin, across the blood-brain barrier and impair the downstream signaling pathways of their respective receptors on POMC neurons. This resistance prevents the activation of the ‘stop eating’ signal, leading to a sustained orexigenic state and chronic positive energy balance, regardless of the body’s actual energy stores.
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