Alpha-ketoglutarate supplementation differently modifies hematological parameters and oxidative stress in mice fed a standard diet and high-fat high-fructose diet.

Long-term consumption of high-calorie diets can lead to metabolic disorders. In this study, we evaluated the effects of an eight-week standard (control), high-fat high-fructose (HFFD), alpha-ketoglutarate (AKG)-supplemented (1% in drinking water), and combined diet (HFFD + AKG) on hematological and oxidative stress parameters across tissues of male C57BL/6J mice. Both HFFD and AKG decreased erythrocyte count and altered leukocyte profile, increasing neutrophils and monocytes while decreasing lymphocytes. HFFD increased visceral fat mass and intensified oxidative stress in adipose tissue, as indicated by elevated lipid peroxide (LOOH) levels. LOOH levels in adipose tissue of AKG- and HFFD + AKG-fed mice matched control. HFFD or AKG lowered glutathione peroxidase and NAD(P)H-quinone oxidoreductase 1 (NQO1) activities in adipose tissue relative to control, unlike HFFD + AKG-fed counterparts. The heart showed an adaptive response to HFFD, with increased glutathione-S-transferase (GST), glucose-6-phosphate dehydrogenase, and NQO1 activities, and lower levels of oxidized glutathione (GSSG). AKG increased reduced glutathione (GSH) levels and elevated GPx and GST activities in the heart, whereas HFFD + AKG-fed mice had lower LOOH levels than HFFD-fed counterparts. Similarly, HFFD and AKG decreased GSSG and increased GSH in skeletal muscle. Both AKG- and HFFD + AKG-fed mice had lower carbonyl protein levels in muscle compared to control and HFFD-fed mice. Like adipose, muscle of HFFD- and AKG-fed mice had lower NQO1 activity compared to control, unlike HFFD + AKG group. These findings suggest AKG may mitigate HFFD-induced oxidative stress and modulate hematological parameters, with tissue- and diet-dependent effects, suggesting its role as an antioxidant under metabolic stress and a regulator of baseline redox homeostasis.