Hypothalamic Kiss1 Neurons Critically Modulate Energy Balance and Appetite via Distinct Arc and AVPV/PeN Populations

The hypothalamic-pituitary-gonadal (HPG) axis, crucial for reproduction, is intricately linked to metabolic status. Kisspeptin, encoded by the Kiss1 gene, is a well-established regulator of reproductive physiology, but its role in central energy homeostasis is increasingly recognized. Current understanding of metabolic disorders often overlooks the nuanced interplay between reproductive and metabolic signaling pathways. This review addresses the gap by detailing how specific Kiss1 neuronal populations integrate peripheral metabolic cues to influence energy balance, offering novel insights beyond its known reproductive functions.

This review synthesizes current understanding of distinct Kiss1 neuronal populations located in the arcuate nucleus (Arc) and anteroventral periventricular/periventricular nucleus (AVPV/PeN) of the hypothalamus. It systematically examines their specific roles in regulating energy balance, appetite, and energy expenditure. The authors analyzed existing literature to delineate the neural circuitry and molecular mechanisms by which these Kiss1 neurons integrate peripheral metabolic hormone signals, including leptin, adiponectin, insulin, and ghrelin, to modulate central energy homeostasis pathways.

The review highlights that Arc Kiss1 neurons primarily suppress appetite by activating POMC neurons and inhibiting AgRP/NPY neurons. Concurrently, they enhance energy expenditure through excitatory projections to the paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH). In stark contrast, AVPV/PeN Kiss1 neurons exert an inhibitory GABAergic regulation on PVN and DMH neurons, suggesting a suppressive modulatory function that generally opposes the excitatory metabolic effects of Arc Kiss1 neurons. Peripheral metabolic hormones dynamically modulate Kiss1 neuronal activity, either directly via specific receptors or indirectly through POMC/AgRP pathways. > These findings underscore that Kiss1 neurons act as crucial integrators of peripheral metabolic signals, playing a pivotal role in maintaining metabolic homeostasis. This dual, often opposing, action of distinct Kiss1 populations reveals a complex regulatory network.