Abstract
With the prevalence of obesity, non-nutritive sweeteners (NNS) have been widely used as sugar substitutes as they deliver a sweet taste without excessive caloric load. However, it is increasingly recognized that NNS are not inert compounds and may cause long-term metabolic perturbations. Endoplasmic reticulum (ER) stress has emerged as a critical link in the development of obesity and type 2 diabetes. In this study, we investigated the effects of NNS found in common diet beverages (i.e., sucralose, aspartame, acesulfame potassium) and a natural sweetener (i.e., rebaudioside A) on ER stress in the hypothalamic cell line mHypoE-N43/5 in vivo and on axonal outgrowth ex vivo. Sucralose, aspartame, and acesulfame potassium caused elevated ER stress gene expression in mHypoE-N43/5 cells, with sucralose and acesulfame potassium having the most potent effect. Moreover, acesulfame potassium treatment reduced axon outgrowth from arcuate nucleus explants and this effect was attenuated with the ER stress-relieving drug tauroursodeoxycholic acid. Furthermore, sucralose induced cytotoxicity and acesulfame potassium increases caspase3/7 activity at high concentrations in mHypoE-N43/5 cells. In contrast, rebaudioside A only had moderate effects on hypothalamic ER stress and no adverse effects on axon outgrowth, cytotoxicity, or caspase3/7 activity. Together, our data reveal that commonly consumed NNS cause cellular stress in hypothalamic cells disrupting axon outgrowth and that these biological alterations are not seen with rebaudioside A. These data provide biological plausibility for some NNS to adversely impact metabolic health and identifies rebaudioside A as a sweetener with lower detrimental biological impact on hypothalamic cells.
Highlights
Dramatic changes in our nutritional environment have most likely contributed to the recent obesity epidemic
activating transcription factor 4 (Atf4), Atf6, and CCAAT-enhancer-binding protein homologous protein (Chop) were highly induced at concentrations of 5– 20 mM sucralose-treated cells but there were no significant changes in Xbp1 levels (Figure 1A)
To address this critical data gap, we investigated the direct effect of nutritive sweeteners (NNS) on hypothalamic Endoplasmic reticulum (ER) stress in vitro
Summary
Dramatic changes in our nutritional environment have most likely contributed to the recent obesity epidemic. This epidemic is concerning for an individual’s quality of life and imparts significant health care burdens. Recent data indicated that NNS consumption is associated with increased weight gain in rodents [1,2,3] and humans [4, 5], and glucose intolerance [4,5,6]. Human data shows the presence of NNS in blood after ingestion and in breast milk [7], suggesting that NNS circulate throughout the body and are likely present during perinatal development. One possible explanation for the lack of clear success in weight loss from NNS consumption may be the possibility that NNS alter central nervous pathways that control energy balance, such as the hypothalamus
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