106 Yang: The neurobiology of sugar cravings contain several ligand-binding sites. For in- stance, aspartame and cyclamate, respec- tively, bind to each of the two monomers [52]. On the functional level, sucrose inges- tion, compared to saccharin ingestion, was associated with greater activation of the higher gustatory areas such as the insula, or- bitofrontal cortex, and amygdala [53]. These pilot investigations are consistent with a revised hypothesis: Sweetness decou- pled from caloric content offers partial, but not complete, activation of the food reward pathways. Activation of the hedonic compo- nent may contribute to increased appetite. Animals seek food to satisfy the inherent craving for sweetness, even in the absence of energy need. Lack of complete satisfac- tion, likely because of the failure to activate the postingestive component, further fuels the food seeking behavior. Reduction in re- ward response may contribute to obesity. Impaired activation of the mesolimbic path- ways following milkshake ingestion was ob- served in obese adolescent girls [45]. Lastly, artificial sweeteners, precisely because they are sweet, encourage sugar craving and sugar dependence. Repeated ex- posure trains flavor preference [54]. A strong correlation exists between a person’s custom- ary intake of a flavor and his preferred inten- sity for that flavor. Systematic reduction of dietary salt [55] or fat [56] without any fla- vorful substitution over the course of several weeks led to a preference for lower levels of those nutrients in the research subjects. In light of these findings, a similar approach might be used to reduce sugar intake. Unsweetening the world’s diet [15] may be the key to reversing the obesity epidemic. Acknowledgments: This article was inspired by a discussion with Dr. Dana Small at the Neuroscience 2010 Conference, which took place at Yale University on April 10, 2010. The author thanks Michaela Panter for edito- rial support and Steve Broner for helpful sug- gestions with the manuscript. REFERENCES 1. Storey ML, Forshee RA, Anderson PA. Bev- erage consumption in the US population. J Am Diet Assoc. 2006;106:1992-2000. 2. Mattes RD, Popkin BM. Nonnutritive sweet- ener consumption in humans: effects on ap- petite and food intake and their putative mechanisms. Am J Clin Nutr. 2009;89:1-14. 3. Pedersen D. Alternative Sweeteners. Biotech- nology and food ingredients. New York: Van Nostrand Reinhold; 1991. 4. Kauffman GB, Priebe PM. The discovery of saccharin: a centennial retrospect. Ambix. 1978;25:191-207. 5. Cohen SM. Saccharin: past, present, and fu- ture. J Am Diet Assoc. 1986;86:929-31. 6. de la Peña C. Artificial sweetener as a histor- ical window to culturally situated health. Ann NY Acad Sci. 2010;1190:159-65. 7. Rubini ME. Noncaloric sweetening agents. Am J Clin Nutr. 1968;21:644-5. 8. Kaufman L. Michael Sveda, the Inventor Of Cyclamates, Dies at 87. New York Times. 1999 Aug. 9. Kroger M, Meister K, Kava R. Low-calorie Sweeteners and Other Sugar Substitutes: A Review of the Safety Issues. Comprehensive Reviews in Food Science and Food Safety. 2006;5:35-47. 10. Mazur RH, Goldkamp AH, James PA, Schlat- ter JM. Structure-taste relationships of aspar- tic acid amides. Journal of Medicinal Chemistry. 1970;13:1217-21. 11. Witt J. Discovery and development of neo- tame. World Rev Nutr Diet. 1999;85:52-7. 12. Clauss K, Lück E, von Rymon Lipinski GW. [Acetosulfam, a new sweetener. 1. synthesis and properties (author’s transl)]. Z Lebensm Unters Forsch. 1976;162:37-40. German. 13. Tate and Lyle Annual Report 2008. 2008. 14. Mintel. Ingredient Trends - US - December 2004 - Market Research Report. 15. Popkin BM, Nielsen SJ. The sweetening of the world’s diet. Obes Res. 2003;11:1325-32. 16. Schulze MB, Manson JE, Ludwig DS, Colditz GA, Colditz MJ, Willett WC, et al. Sugar- sweetened beverages, weight gain, and inci- dence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292:927-34. 17. Saris WHM. Sugars, energy metabolism, and body weight control. Am J Clin Nutr. 2003;78:850S-857S. 18. Fowler SP, Williams K, Resendez RG, Hunt KJ, Hazuda HP, Stern MP. Fueling the obe- sity epidemic? Artificially sweetened bever- age use and long-term weight gain. Obesity (Silver Spring, Md.). 2008;16:1894-1900. 19. Stellman SD, Garfinkel L. Artificial sweet- ener use and one-year weight change among women. Prev Med. 1986;15:195-202. 20. Colditz GA, Willett WC, Stampfer MJ, Lon- don SJ, Segal MR, Speizer FE. Patterns of weight change and their relation to diet in a cohort of healthy women. Am J Clin Nutr. 1990;51:1100-5. 21. Forshee RA, Storey ML. Total beverage con- sumption and beverage choices among chil- dren and adolescents. Int J Food Sci Nutr. 2003;54:297-307.