D-
allulose, a rare
sugar, has been proposed to have potential benefits in addressing metabolic disorders such as
obesity and
type 2 diabetes (T2D). However, the precise mechanisms underlying these effects remain poorly understood. We aimed to elucidate the mechanisms by which D-
allulose influences
obesity-induced
insulin resistance. We conducted gene set enrichment analysis on the liver and white adipose tissue of mice exposed to a high-fat diet (HFD) along with the white adipose tissue of individuals with
obesity. Our study revealed that D-
allulose effectively suppressed IFN-γ, restored
chemokine signaling, and enhanced macrophage function in the livers of HFD-fed mice. This implies that D-
allulose curtails liver
inflammation, alleviating
insulin resistance and subsequently impacting adipose tissue. Furthermore, D-
allulose supplementation improved mitochondrial
NADH homeostasis and translation in both the liver and white adipose tissue of HFD-fed mice. Notably, we observed decreased
NADH homeostasis and mitochondrial translation in the omental tissue of
insulin-resistant obese subjects compared to their
insulin-sensitive counterparts. Taken together, these results suggest that supplementation with
allulose improves
obesity-induced
insulin resistance by mitigating the disruptions in macrophage and mitochondrial function. Furthermore, our data reinforce the crucial role that mitochondrial energy expenditure plays in the development of
insulin resistance triggered by
obesity.