Modified UCN2 Peptide Acts as an Insulin Sensitizer in Skeletal Muscle of Obese Mice

Abstract

The neuropeptide urocortin 2 (UCN2) and its receptor corticotropin-releasing hormone receptor 2 (CRHR2) are highly expressed in skeletal muscle and play a role in regulating energy balance and glucose metabolism. We investigated a modified UCN2 peptide as a potential therapeutic agent for the treatment of obesity and insulin resistance, with a specific focus on skeletal muscle. High-fat–fed mice (C57BL/6J) were injected daily with a PEGylated UCN2 peptide (compound A) at 0.3 mg/kg subcutaneously for 14 days. Compound A reduced body weight, food intake, whole-body fat mass, and intramuscular triglycerides compared with vehicle-treated controls. Furthermore, whole-body glucose tolerance was improved by compound A treatment, with increased insulin-stimulated Akt phosphorylation at Ser473 and Thr308 in skeletal muscle, concomitant with increased glucose transport into extensor digitorum longus and gastrocnemius muscle. Mechanistically, this is linked to a direct effect on skeletal muscle because ex vivo exposure of soleus muscle from chow-fed lean mice to compound A increased glucose transport and insulin signaling. Moreover, exposure of GLUT4-Myc–labeled L6 myoblasts to compound A increased GLUT4 trafficking. Our results demonstrate that modified UCN2 peptides may be efficacious in the treatment of type 2 diabetes by acting as an insulin sensitizer in skeletal muscle.

Akt+ IKKα/β+ Rab5+ Signalosome Mediate the Endosomal Recruitment of Sec61 and Contribute to Cross-Presentation in Bone Marrow Precursor Cells

“…Akt, a pivotal signal transducer for growth and survival, can be activated at Thr-308 and Ser-473 regulatory sites [ 33 , 34 ]. Balasuriya et al found that Thr-308 phosphorylation increase Akt1’s catalytic rate 1500-fold [ 35 ], confirming that Thr-308 phosphorylation, but not Ser-473, is required for Akt activation.…”

Modified UCN2 peptide treatment improves skeletal muscle mass and function in mouse models of obesity‐induced insulin resistance

“…Modified human UCN2 peptides (Compounds A and B) are based on the previously reported Compound 8 26 and synthesized using established solid‐phase peptide synthesis protocols as described. 25 , 26 While Compound B corresponds to the Compound 8, Compound A has a further modification, with a cystine residue at position 29, where a polyethylene glycol (PEG) 20 000 is attached through an acetamide‐base linker. Formulated aliquots of the peptides in phosphate‐buffered saline were stored at −20°C.…”

“…The pharmacokinetic properties of Compound A have been described 25 and have a half‐life of 22.3 h. The pharmacokinetic properties of Compound B have been described 26 and result in a considerably shorter half‐life of ~30 min.…”

“…After 19 weeks on HFD, mice were randomized into sedentary and wheel running groups as described, 25 for 14 days during the treatment period.…”

“… 25 This was attributed to a direct insulin sensitizing effect of UCN2 on skeletal muscle. 25 Given that UCN2 peptides and CRHR2 agonists modulate skeletal muscle metabolism and hypertrophy, we hypothesized that UCN2 treatment will increase skeletal muscle mass and functional properties in models of insulin resistance and obesity. We investigated the effects of two modified UCN2 peptides in the regulation of skeletal muscle mass and function in diet‐induced obesity and leptin‐deficient ob/ob mice, as well as in preserving muscle function during casting immobilization.…”