Disruption of the sugar-sensing receptor T1R2 attenuates metabolic derangements associated with diet-induced obesity.

Sweet taste receptors (STRs) on the tongue mediate gustatory sweet sensing, but their expression in the gut, pancreas and adipose tissue suggests a physiological contribution to whole-body nutrient sensing and metabolism. However, little is known about the function and contribution of these sugar sensors during metabolic stress induced by over-nutrition and subsequent obesity. Here we investigate the effects of high fat/ low carbohydrate diet (HF/LC diet) on glucose homeostasis and energy balance in mice with global disruption of the sweet taste receptor protein, T1R2. We assessed body composition, energy balance, glucose homeostasis and tissue-specific nutrient metabolism in T1R2 knock-out (T1R2-KO) mice fed a HF/LC diet for 12-weeks. HF/LC diet fed T1R2-KO mice gained a similar amount of body mass as WT mice, but have reduced fat mass and increased lean mass relative to WT mice. T1R2-KO mice are also hyperphagic and hyperactive. Ablation of the T1R2 sugar sensor protected mice from HF/LC diet-induced hyperinsulinemia and altered substrate utilization, including increased rates of glucose oxidation and decreased liver triglyceride (TG) accumulation, despite normal intestinal fat absorption. Finally, STRs (T1r2/T1r3) are upregulated in the adipose tissue of WT mice in response to HF/LC diet and their expression positively correlates with fat mass and glucose intolerance. The chemosensory receptor, T1R2, plays an important role in glucose homeostasis during diet-induced obesity through the regulation of yet to be identified molecular mechanisms that alter energy disposal and utilization in peripheral tissues.