Non-nutritive Sweeteners Induce Hypothalamic ER Stress Causing Abnormal Axon Outgrowth

Area of Science:

• Neuroscience
• Metabolic Health
• Cellular Biology

Background:

• Non-nutritive sweeteners (NNS) are widely used in diet beverages to reduce caloric intake.
• Emerging evidence suggests NNS may disrupt metabolic homeostasis and contribute to conditions like obesity and type 2 diabetes.
• Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of metabolic disorders.

Purpose of the Study:

• To investigate the impact of common NNS (sucralose, aspartame, acesulfame potassium) and rebaudioside A on ER stress.
• To assess the effects of these sweeteners on axonal outgrowth in hypothalamic cells.
• To determine the potential cellular toxicity and apoptotic effects of NNS.

Main Methods:

• Cultured hypothalamic cell line (mHypoE-N43/5) and arcuate nucleus explants were treated with NNS.
• Gene expression of ER stress markers was analyzed.
• Axon outgrowth was measured.
• Cytotoxicity and caspase3/7 activity assays were performed.

Main Results:

• Sucralose, aspartame, and acesulfame potassium elevated ER stress gene expression in hypothalamic cells.
• Acesulfame potassium significantly reduced axon outgrowth, an effect mitigated by tauroursodeoxycholic acid.
• Sucralose induced cytotoxicity, and acesulfame potassium increased caspase3/7 activity at high concentrations.
• Rebaudioside A demonstrated moderate ER stress effects with no significant adverse impact on axon outgrowth or cell viability.

Conclusions:

• Commonly consumed NNS induce cellular stress in hypothalamic cells, impairing axon outgrowth.
• These findings suggest a biological mechanism by which NNS may negatively affect metabolic health.
• Rebaudioside A appears to have a lower detrimental biological impact on hypothalamic cells compared to artificial NNS.