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IGF1 Signaling Regulates Neuropeptide Expression in Hypothalamic Neurons Under Physiological and Pathological
Wenyuan He1, Neruja Loganathan1, Denise D Belsham1,2,3
1Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
Endocrinology
|March 19, 2025
Summary
Hypothalamic neurons respond to insulin-like growth factor 1 (IGF1), influencing appetite regulation. However, high insulin levels can cause IGF1 resistance in these neurons, impacting metabolic control.
Area of Science:
- Neuroscience
- Endocrinology
- Metabolism
Background:
- Insulin-like growth factor 1 (IGF1) is vital for metabolism and aging, yet its brain functions, particularly in the hypothalamus, are not fully understood.
- The hypothalamus regulates crucial physiological processes including appetite and energy balance.
Purpose of the Study:
- To investigate the response of hypothalamic neurons to IGF1.
- To determine how IGF1 signaling in the hypothalamus is modulated.
- To explore the impact of hyperinsulinemia on hypothalamic IGF1 sensitivity.
Main Methods:
- Quantitative real-time PCR (RT-qPCR) and single-cell RNA sequencing were used to analyze gene expression.
- Experiments were conducted in mouse and human models.
- Signaling pathways, including phosphoinositide 3-kinase/forkhead box O1 (PI3K-FOXO1), were investigated.
Main Results:
- IGF1 receptor (Igf1r) mRNA expression was detected in hypothalamic neurons, with higher levels in pro-opiomelanocortin (POMC) neurons compared to neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons.
- IGF1 binding proteins (Igfbp3, Igfbp5) were expressed, with Igfbp5 levels modulated by nutritional status and circadian rhythms.
- IGF1 administration induced an anorexigenic gene expression profile in the hypothalamus.
- Hyperinsulinemia led to IGF1 resistance by downregulating IGF1R and Irs2 via PI3K-FOXO1 pathway activation.
Conclusions:
- Hypothalamic neurons are responsive to IGF1 under normal physiological conditions.
- Hyperinsulinemia represents a novel mechanism contributing to cellular IGF1 resistance in the hypothalamus.
- These findings highlight the complex regulation of hypothalamic IGF1 signaling and its potential disruption in metabolic disorders.
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