Kisspeptin Triggers Growth Hormone Release Through NPY and Ghrelin Pathways During Fasting | Research

The takeaway

Kisspeptin stimulates growth hormone release in fasted but not fed sheep, working through neuropeptide Y pathways and requiring ghrelin to be present — revealing how reproductive and growth peptide systems interconnect.

Fed vs fasted switch
Kisspeptin robustly stimulated growth hormone in fasted sheep but had zero effect in fed animals — ghrelin presence is the key enabling factor

What the researchers found

Central kisspeptin delivery caused robust growth hormone (GH) release in fasted sheep but not in fed sheep. The proposed mechanism involves a cascade of peptide interactions:

1. During fasting, systemic ghrelin rises and NPY expression in the arcuate nucleus increases

2. Kisspeptin activates NPY neurons (confirmed by c-Fos activation)

3. NPY stimulates GHRH neurons and inhibits somatostatin neurons

4. This results in GH release

Critical evidence:

- NPY Y1 receptor antagonist (BIBO 3304) blocked kisspeptin-induced GH release

- Kisspeptin induced c-Fos in NPY and GHRH cells of the arcuate nucleus

- Kisspeptin reduced c-Fos in somatostatin cells

- Blocking ghrelin (systemically or at its receptor) eliminated or reduced kisspeptin-induced GH release

- Effects were similar at 24h and 72h fasting, indicating response to food loss rather than severe energy deficit

Why it matters

This study reveals a previously unknown connection between kisspeptin (a reproductive peptide), NPY (an appetite peptide), ghrelin (a hunger peptide), and growth hormone. This interconnection explains how the body coordinates reproductive function with nutritional and growth status — a fundamental biological question. It also has practical implications for peptide therapy, suggesting that the effects of kisspeptin or ghrelin-based treatments may vary significantly with feeding state.

How the study worked

Researchers used central (intracerebroventricular) kisspeptin delivery in female sheep under fed and fasted conditions (24h and 72h). Blood samples measured GH levels. NPY Y1 receptor antagonist pretreatment tested NPY involvement. Ghrelin blockade (systemic and receptor-level) tested ghrelin dependence. Immunohistochemistry for c-Fos identified which hypothalamic neuron populations were activated by kisspeptin.

What this study cannot tell us

This study was conducted in sheep, which share many neuroendocrine features with humans but are not identical. The central delivery route (intracerebroventricular) does not mimic normal kisspeptin signaling, which occurs locally within the hypothalamus. The study used only female sheep, and sex differences in these pathways are likely significant. The exact mechanism by which ghrelin enables kisspeptin-induced GH release requires further elucidation.

How to read the evidence

This is a well-designed animal mechanistic study using pharmacological interventions and immunohistochemistry in sheep. The multi-layered approach (receptor antagonists, ghrelin blockade, neuronal activation mapping) provides strong mechanistic evidence. However, translation to human physiology requires validation.

When this study was published

Published in 2017, this study established an important mechanistic link between kisspeptin and growth hormone that continues to influence research on peptide neuroendocrine interactions. The findings remain current and relevant.

The bigger picture

The discovery that kisspeptin connects reproductive signaling to the growth axis through NPY and ghrelin provides a mechanistic explanation for why reproductive function and growth are both suppressed during starvation. This peptide crosstalk system evolved to coordinate the body's priorities: when food is scarce, redirecting resources from reproduction to survival (via GH-mediated metabolic effects). Understanding these peptide networks is increasingly important as therapeutic peptides targeting individual components become available.

Questions still open

Does kisspeptin stimulate growth hormone release in fasted humans through the same NPY-dependent mechanism seen in sheep?
Could kisspeptin-based therapies have unintended effects on growth hormone secretion depending on patients' feeding status?
How does this peptide interaction network change with age, and could it contribute to the age-related decline in both reproductive function and GH secretion?

Common questions

What is kisspeptin and what does it normally do?

Kisspeptin is a peptide hormone produced in the hypothalamus that is the primary trigger for puberty onset and reproductive hormone release. It activates GnRH (gonadotropin-releasing hormone) neurons, controlling fertility. This study reveals kisspeptin has an additional role: stimulating growth hormone release when the body is in a fasted state, connecting reproductive signaling to the growth and metabolic systems.

Why does kisspeptin only stimulate growth hormone during fasting?

The researchers found that ghrelin — the 'hunger hormone' that rises during fasting — must be present for kisspeptin to trigger growth hormone release. Ghrelin and increased NPY expression during fasting create the necessary conditions for kisspeptin to activate this pathway. In the fed state, when ghrelin is low, kisspeptin cannot trigger the same response. This ensures growth hormone release is coordinated with the body's nutritional status.

Read the original research

Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe.

Endocrinology, 158(10), 3526-3539

View on PubMed ↗Publisher’s paper ↗

Citation

Foradori, Chad D; Whitlock, Brian K; Daniel, Jay A; Zimmerman, Arthur D; Jones, Melaney A; Read, Casey C; Steele, Barbara P; Smith, Jeremy T; Clarke, Iain J; Elsasser, Theodore H; Keisler, Duane H; Sartin, James L. (2017). Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe.. Endocrinology, 158(10), 3526-3539. https://doi.org/10.1210/en.2017-00303