To date types of glucose transport protein have

To date, 14 types of glucose transport protein have been discovered, each having its own specific functions with different distributions [33]. Among these, GLUT4 is particularly important for maintaining glucose metabolism homeostasis and insulin sensitivity, since it is involved in glucose transport into myocytes and adipocytes in response to insulin or exercise stimuli [33]. The results of ours and other studies revealed that the abdominal or intracerebroventricular injection of M35, anantagonistof GAL receptor 1–3, significantly increased insulin resistance and inhibitedGLUT4mRNA andprotein expressionin muscle and adipose tissues of type 2 diabetic rats, indicating that blocking-up GAL receptors impaired insulin-induced glucose disposal [15], [16], [21]. More interestingly, the GLUT4 contents in the plasma membranes were markedly decreased in muscles and adipocytes of M35-treated type 2 diabetic rats, implicating that central GAL not only enhances GLUT4 and GLUT4 mRNA GSK503 australia levels, but also accelerates GLUT4 translocation from intracellular membrane compartments to plasma membranes in muscles and adipocytes [15], [16], [21]. In line with these, the current results showed that the central injection of M1145 or M871 respectively increased or decreased GLUT4 and GLUT4 mRNA expression in muscles and adipocytes compared with the diabetic controls, suggesting that central GAL via activating GALR2 promoted GLUT4 expression to elevate glucose uptake in muscles and adipocytes. PGC-1α is a key regulator of glucose metabolism and GLUT4 expression [34], [35]. The PGC-1α can enhance the GLUT4 expression to increase glucose clearance [36], and ectopic expression of PGC-1α in skeletal muscles and adipocytes induces low GLUT4 expression [36]. In the present study, our results showed that central injection of M1145 up-regulated PGC-1α mRNA levels in skeletal muscles and adipocytes of type 2 diabetic rats, suggesting that central GAL via activation of GALR2 enhanced PGC-1α levels to boost GLUT4 expression and subsequent glucose uptake, i.e. central GALR2 ameliorated insulin resistance via activation of the PGC-1α/GLUT4 signaling pathway. Therefore, our results supported that PGC-1α might be critical for GALR2’s function and is required for the consequent anti-hyperglycemic effects of GALR2. In conclusion, the results of the current study showed that central injection of M1145 or M871 respectively increased or decreased glucose infusion rates in hyperinsulinemic euglycemic clamp tests, PGC-1α and GLUT4 expression in skeletal muscles and adipocytes, but attenuated or enhanced the plasma inflammatory factors and glucose concentration in type 2 diabetic rats. These results suggest that activation of central GALR2 can drive a programme of ameliorating systemicinsulin resistance mainly in skeletal muscles and adipocytes.Moreover, these results suggest that activation of central GALR2 ameliorates insulin resistance and promotes glucose uptake and metabolism in skeletal muscles and adipocytes mainly through the PGC-1α/GLUT4 pathways. These contribute to our understanding of the central effects of GALR2 on glucose uptake and insulin sensitivity, and provide a possibility of using GALR2 agonist to treat insulin resistance in clinic.
Introduction Galanin is a 29-amino acid (30 in human) neuropeptide, which is widely distributed in peripheral and central nervous system (Tatemoto et al., 1983). Previous studies reported that galanin and its receptors might be involved in the transmission and modulation of nociceptive information in the central nervous system (Yu et al., 2001, Liu and Hökfelt, 2002, Hua et al., 2004, Wiesenfeld-Hallin et al., 2005, Gu et al., 2007, Xu et al., 2008, Jin et al., 2010). Our previous study showed that intra-nucleus accumbens (NAc) injection of galanin increased the hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulation in intact rats, indicating that galanin might play an antinociceptive role in the NAc (Xu et al., 2012a).