Skeletal muscle Nur77 and NOR1 insulin responsiveness is blunted in obesity and type 2 diabetes but improved after exercise training

Obesity and type 2 diabetes (T2 DM ) are characterized by a blunted metabolic response to insulin, and strongly manifests in skeletal muscle insulin resistance. The orphan nuclear receptors, Nur77 and NOR 1, regulate insulin‐stimulated nutrient metabolism where Nur77 and NOR 1 gene expression is increased with acute aerobic exercise and acute insulin stimulation. Whether Nur77 or NOR 1 are associated with the insulin‐sensitizing effects of chronic aerobic exercise training has yet to be elucidated. Fourteen lean healthy controls ( LHC ), 12 obese ( OB ), and 10 T2 DM individuals (T2 DM ) underwent hyperinsulinemic‐euglycemic clamps with skeletal muscle biopsies. Muscle was analyzed for Nur77 and NOR 1 gene and protein expression at basal and insulin‐stimulated conditions. Furthermore, a subcohort of 18 participants ( OB , n  = 12; T2 DM , n  = 6) underwent a 12‐week aerobic exercise intervention (85% HR max , 60 min/day, 5 days/week). In response to insulin infusion, LHC increased protein expression of Nur77 (8.7 ± 3.2‐fold) and NOR 1 (3.6 ± 1.1‐fold), whereas OB and T2 DM remained unaffected. Clamp‐derived glucose disposal rates correlated with Nur77 ( r 2  = 0.14) and NOR 1 ( r 2  = 0.12) protein expression responses to insulin, whereas age (Nur77: r 2  = 0.22; NOR 1: r 2  = 0.25) and BMI (Nur77: r 2  = 0.22; NOR 1: r 2  = 0.42) showed inverse correlations, corroborating preclinical data. In the intervention cohort, exercise improved Nur77 protein expression in response to insulin ( PRE : −1.2 ± 0.3%, POST : 6.2 ± 1.5%). Also, insulin treatment of primary human skeletal muscle cells increased Nur77 and NOR 1 protein. These findings highlight the multifactorial nature of insulin resistance in human obesity and T2 DM . Understanding the regulation of Nur77 and NOR 1 in skeletal muscle and other insulin‐sensitive tissues will create opportunities to advance therapies for T2 DM .