Abstract
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% 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 NOR1 (3.6 ± 1.1‐fold), whereas OB and T2DM remained unaffected. Clamp‐derived glucose disposal rates correlated with Nur77 (r 2 = 0.14) and NOR1 (r 2 = 0.12) protein expression responses to insulin, whereas age (Nur77: r 2 = 0.22; NOR1: r 2 = 0.25) and BMI (Nur77: r 2 = 0.22; NOR1: 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 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.
Highlights
Gene microarray studies in the past decade have brought about numerous putative therapeutic targets, especially related to obesity and type 2 diabetes (T2DM)
Skeletal muscle Nur77 and NOR1 protein expression increased in response to insulin stimulation in lean healthy controls (LHC) (Nur77: 8.7 Æ 3.2-fold, P < 0.01; NOR1: 3.6 Æ 1.1-fold, P < 0.05), but remained unchanged in OB (Nur77: 1.0 Æ 0.3-fold, P > 0.05; NOR1: 1.0 Æ 0.1-fold, P > 0.05) and T2DM (Nur77: 1.1 Æ 0.1-fold, P > 0.05; NOR1: 1.0 Æ 0.1-fold, P > 0.05) (Fig. 1A–D)
In response to 300 pM insulin, Nur77 protein expression remained unchanged at 30 minutes, but was significantly increased at 180 min (Fig. 6A; 183 Æ 12.6% compared to baseline, 1-way ANOVA, P = 0.002; Bonferroni’s Multiple Comparison post hoc test, P < 0.05.) NOR1 protein expression displayed a similar trend, but with lesser magnitude did not reach statistical significance at 180 minutes (Fig. 6B, 131 Æ 6.3% compared to baseline, 1-way ANOVA, P = 0.070). These results suggest insulin stimulates Nur77 and NOR1 protein expression in human skeletal muscle cells independent of the ß-adrenergic effect of insulin. These are the first data to show that skeletal muscle Nur77 and NOR1 protein expression is blunted in response to insulin in obesity and overt T2DM, and that aerobic exercise training improves this response
Summary
Gene microarray studies in the past decade have brought about numerous putative therapeutic targets, especially related to obesity and type 2 diabetes (T2DM). Orphan nuclear receptors represent a group of targets that have been consistently identified in these screens. Two members of the orphan nuclear receptor family, Nur and NOR1 ( known as NR4A1 and NR4A3, respectively), received particular attention due to acute gene inductions in response to insulin (Wu et al 2007) and aerobic exercise (Mahoney and Tarnopolsky 2005; Mahoney et al 2005). Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.
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