Editors' ChoiceMetabolism

How sweet it isn’t

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Science Signaling  26 Jul 2016:
Vol. 9, Issue 438, pp. ec169
DOI: 10.1126/scisignal.aah6249

Non-nutritive sweeteners such as sucralose have been linked to metabolic dysfunction in both model organisms and humans. Wang et al. showed that non-nutritive sweeteners trigger a neuronal circuit that stimulates appetite and causes sweet taste sensitization. Compared with Drosophila fed a standard control diet (sucrose and yeast), Drosophila fed a sucralose-sweetened diet for 5 days or more ate more food when switched to the standard diet, found sucrose more attractive [called sucrose or sweet taste sensitization, as measured by the proboscis extension response (PER) assay], and showed impaired glucose tolerance. The effects of sucralose on food intake and sucrose sensitization, which were reversible, required the sweet taste receptor Gr64a in sweet taste neurons, insulin, and the insulin receptor InR The neurotransmitters octopamine and its receptor Oamb, which mediate a reward pathway in flies, operated downstream of insulin signaling in the effects of sucralose feeding. Similar to octopamine, dopamine functions in reward pathways and was necessary downstream of insulin and octopamine signaling in the effects of sucralose feeding. Two dopamine receptors were required, DopEcR and DopR2, the latter of which was present on neurons producing neuropeptide F, an appetite-stimulating neurotransmitter that is the fly ortholog of neuropeptide Y in mammals. Knockdown of NPFR (which encodes the receptor for neuropeptide F) in sweet taste-responsive neurons abolished the ability of sucralose feeding to stimulate appetite and sucrose sensitization. Sorbitol is a source of tasteless sugar calories, and addition of sorbitol prevented the sucralose-supplemented diet from increasing appetite, suggesting that the discrepancy between perceived and actual caloric intake was responsible for appetite stimulation. The energy sensor AMPK in dopaminergic neurons and NPF-producing neurons was activated by the sucralose-sweetened diet and was required for its effects on appetite and sucrose sensitization. Fasting in wild-type flies induced sucrose sensitization and a neuronal response was similar to that caused by sucralose feeding (a response that required DopEcR). The effect of sucralose was evolutionarily conserved, because mice ate more food after sucralose feeding, an effect that was not seen in NPY knockout mice. Thus, non-nutritive sweeteners in reduced-calorie food items may paradoxically stimulate appetite and make sweet food more attractive.

Q.-P. Wang, Y. Q. Lin, L. Zhang, Y. A. Wilson, L. J. Oyston, J. Cotterell, Y. Qi, T. M. Khuong, N. Bakhshi, Y. Planchenault, D. T. Browman, M. T. Lau, T. A. Cole, A. C. N. Wong, S. J. Simpson, A. R. Cole, J. M. Penninger, H. Herzog, G. G. Neely, Sucralose promotes food intake through NPY and a neuronal fasting response. Cell Metab. 24, 75–90 (2016). [PubMed]

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