IGF1 Controls Appetite-Regulating Neuropeptides in the Brain, But High Insulin Levels Block This Signaling

What the researchers found

IGF1 regulates the expression of multiple appetite-controlling neuropeptides in hypothalamic neurons. In both mouse and human models, IGF1 modulated expression of AgRP, NPY, POMC, CART, spexin, galanin, and FAM237B, producing an overall appetite-suppressing (anorexigenic) profile. IGF1 receptors were found in both NPY/AgRP and POMC neurons, with higher expression in POMC neurons.

Critically, the study discovered that hyperinsulinemia (chronically high insulin levels) induces IGF1 resistance in hypothalamic neurons by reducing IGF1R protein and mRNA through over-activation of PI3K-FOXO1 signaling. This provides a novel mechanism linking metabolic disease to disrupted neuropeptide signaling in the brain.

Why it matters

Understanding how growth factor signaling regulates appetite-controlling neuropeptides is fundamental to treating obesity and metabolic disease. The discovery that high insulin levels cause IGF1 resistance in the hypothalamus creates a new framework for understanding why metabolic dysfunction leads to appetite dysregulation — and potentially identifies new therapeutic targets.

How the study worked

Researchers used RT-qPCR and single-cell RNA sequencing to characterize IGF1 receptor expression in hypothalamic neuron populations. Mouse and human cell models were treated with IGF1 to assess neuropeptide expression changes. The effects of fasting, nutrient availability, and circadian rhythms on IGF1 binding proteins were measured. Hyperinsulinemia conditions were modeled to study IGF1 resistance mechanisms via the PI3K-FOXO1 pathway.

Who was studied

Mouse and human hypothalamic neuron cell models; single-cell RNA sequencing data

What this study cannot tell us

This is primarily an in vitro/cell model study. While both mouse and human models were used, the findings need validation in intact animal models and human subjects. The complexity of hypothalamic neuropeptide circuits means that isolated cell responses may not fully predict in vivo outcomes. The hyperinsulinemia-IGF1 resistance mechanism is novel and requires independent confirmation.

How to read the evidence

This is a preliminary-grade study using cell models with both mouse and human hypothalamic neurons. The mechanistic findings are detailed and include single-cell sequencing, but validation in intact organisms is needed.

When this study was published

Published in 2025, this is very recent research providing new mechanistic insights into how metabolic hormones regulate brain neuropeptide circuits.

The bigger picture

This study connects the dots between metabolic hormones (insulin, IGF1) and brain neuropeptide circuits that control eating behavior. The finding that hyperinsulinemia causes IGF1 resistance in appetite-controlling neurons provides a molecular explanation for why metabolic dysfunction creates a vicious cycle: high insulin → impaired appetite regulation → more eating → more insulin resistance.

Questions still open

• Could restoring IGF1 sensitivity in hypothalamic neurons help break the cycle of metabolic disease and appetite dysregulation?
• Do GLP-1 receptor agonists, which reduce insulin levels, partly work by restoring IGF1 signaling in hypothalamic neurons?
• How do the circadian rhythms of IGF1 binding proteins affect daily appetite patterns and meal timing?

Common questions

Read the original research

IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological Conditions.

Endocrinology, 166(5)

Citation

He, Wenyuan; Loganathan, Neruja; Belsham, Denise D. (2025). IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological Conditions.. Endocrinology, 166(5). https://doi.org/10.1210/endocr/bqaf051