Intake of
sugars, especially the
fructose component, is strongly associated with the development of
obesity and
metabolic syndrome, but the relative role of taste versus metabolism in driving preference, intake, and metabolic outcome is not fully understood. We aimed to evaluate the preference for sweet substances and the tendency to develop
metabolic syndrome in response to these
sugars in mice lacking functional taste signaling [P2X2 (P2X purinoreceptor 2)/P2X3 (P2X purinoreceptor 3) double knockout mice (DKO)] and mice unable to metabolize
fructose (
fructokinase knockout mice). Of interest, our data indicate that despite their inability to taste sweetness, P2X2/3 DKO mice still prefer caloric
sugars (including
fructose and
glucose) to water in long-term testing, although with diminished preference compared with control mice. Despite reduced intake of caloric
sugars by P2X2/3 DKO animals, the DKO mice still show increased levels of the
sugar-dependent
hormone FGF21 (
fibroblast growth factor 21) in plasma and liver. Despite lower
sugar intake, taste-blind mice develop severe features of
metabolic syndrome due to reduced sensitivity to
leptin, reduced ability to mobilize and oxidize
fats, and increased hepatic de novo lipogenesis. In contrast to P2X2/3 DKO and wild-type mice,
fructokinase knockout mice, which cannot metabolize
fructose and are protected against
fructose-induced
metabolic syndrome, demonstrate reduced preference and intake for all
fructose-containing
sugars tested but not for
glucose or
artificial sweeteners. Based on these observations, we conclude that
sugar can induce
metabolic syndrome in mice independently of its sweet properties. Furthermore, our data demonstrate that the metabolism of
fructose is necessary for
sugar to drive intake and preference in mice.