KNDy kisspeptin is required for metabolic homeostasis in female mice in an ovarian hormone-independent manner

Loss of kisspeptin from KNDy neurons in the hypothalamus causes obesity in female mice by lowering energy expenditure, not by changing food intake. This effect is sex-specific, with females more severely affected than males, and the metabolic abnormalities are partly independent of ovarian hormones.

Journal article — Knockout mouse model with diet-induced obesity. Population: Female and male Pdyn-Cre/Kiss1 fl/fl (Kiss1 Pdyn KO) mice. Interventions: diet-induced obesity; ovarian hormone depletion.

Kiss1 Pdyn KO females had more severely impaired peripheral metabolism than KO males, along with greater reproductive deficits. Abnormal glucose metabolism in these females was partly attributable to the lack of ovarian steroids. Loss of KNDy neuron kisspeptin promoted obesity through reduced energy expenditure without affecting feeding behavior. The authors conclude that KNDy kisspeptin acts as a female-biased central integrator of reproductive and metabolic signals.

This paper provides direct evidence that kisspeptin from KNDy neurons regulates metabolism in a sex-specific manner, broadening kisspeptin's known role beyond reproduction for researchers studying Kisspeptin. It does not establish a metabolic role for kisspeptin outside KNDy neurons, nor does it demonstrate causality in humans or identify the downstream molecular effectors.

Key findings

• KNDy kisspeptin knockout females had more severe peripheral metabolic impairment than knockout males.
• Females showed greater reproductive deficits than males after loss of KNDy kisspeptin.
• Loss of KNDy neuron kisspeptin promoted obesity through reduced energy expenditure without altering feeding behavior.
• Abnormal glucose metabolism in knockout females was partly attributable to the lack of ovarian steroids.

Limitations

• Findings are from a mouse model and may not directly translate to humans.
• The abstract does not report effect sizes, statistical details, or sample numbers.
• The molecular mechanism by which KNDy kisspeptin modulates energy expenditure was not identified.
• Potential compensatory changes in other kisspeptin-expressing neuron populations were not assessed.

The record

• Journal: Journal of neuroendocrinology 38(6): e70208
• Published: 2026-06-01
• PMID: 42219677 — DOI: 10.1111/jne.70208
• MeSH terms: Ovary, Hypothalamus, Neurons, Animals, Mice, Knockout, Mice, Obesity, Energy Metabolism, Homeostasis, Female, Kisspeptins
• Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development; NICHD NIH HHS
• Author countries: USA

Peptide profiles: Kisspeptin.

All indexed evidence: Kisspeptin trials & papers.

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