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 (T2DM) are characterized by a blunted metabolic response to insulin, and strongly manifests in skeletal muscle insulin resistance. The orphan nuclear receptors, Nur77 and NOR1, regulate insulin‐stimulated nutrient metabolism where Nur77 and NOR1 gene expression is increased with acute aerobic exercise and acute insulin stimulation. Whether Nur77 or NOR1 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 T2DM individuals (T2DM) underwent hyperinsulinemic‐euglycemic clamps with skeletal muscle biopsies. Muscle was analyzed for Nur77 and NOR1 gene and protein expression at basal and insulin‐stimulated conditions. Furthermore, a subcohort of 18 participants (OB, n = 12; T2DM, n = 6) underwent a 12‐week aerobic exercise intervention (85% HRmax, 60 min/day, 5 days/week). In response to insulin infusion, LHC increased protein expression of Nur77 (8.7 ± 3.2‐fold) and NOR1 (3.6 ± 1.1‐fold), whereas OB and T2DM remained unaffected. Clamp‐derived glucose disposal rates correlated with Nur77 (r2 = 0.14) and NOR1 (r2 = 0.12) protein expression responses to insulin, whereas age (Nur77: r2 = 0.22; NOR1: r2 = 0.25) and BMI (Nur77: r2 = 0.22; NOR1: r2 = 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 NOR1 protein. These findings highlight the multifactorial nature of insulin resistance in human obesity and T2DM. Understanding the regulation of Nur77 and NOR1 in skeletal muscle and other insulin‐sensitive tissues will create opportunities to advance therapies for T2DM.Obesity and type 2 diabetes are characterized by a blunted metabolic response to insulin. The orphan nuclear receptors, Nur77 and NOR1, regulate insulin‐stimulated nutrient metabolism. We show the skeletal muscle Nur77 and NOR1 response to insulin is blunted in obesity and type 2 diabetes, but is partially rescued after an aerobic exercise intervention. Future research on the therapeutic potential of Nur77 and NOR1 in metabolic disease is warranted.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148401/1/phy214042.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148401/2/phy214042_am.pd