Sugar causes obesity and metabolic syndrome in mice independently of sweet taste

Am J Physiol Endocrinol Metab. 2020 Aug 1;319(2):E276-E290. doi: 10.1152/ajpendo.00529.2019. Epub 2020 Jun 23.


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.

Keywords: fructokinase; fructose; metabolic syndrome; sugar; sweet taste.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dietary Sucrose / administration & dosage
  • Dietary Sucrose / adverse effects*
  • Food Preferences / physiology
  • Fructose / administration & dosage
  • Fructose / adverse effects
  • Male
  • Metabolic Syndrome / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / etiology*
  • Receptors, Purinergic P2X2 / deficiency
  • Receptors, Purinergic P2X2 / physiology
  • Receptors, Purinergic P2X3 / deficiency
  • Receptors, Purinergic P2X3 / physiology
  • Taste / physiology*


  • Dietary Sucrose
  • Receptors, Purinergic P2X2
  • Receptors, Purinergic P2X3
  • Fructose