One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance

Gao, Mei Hua; Giamouridis, Dimosthenis; Lai, N. Chin; Walenta, Evelyn; Paschoal, Vivian A.; Kim, Young Chul; Miyanohara, Atsushi; Guo, Tracy; Liao, Min; Liu, Li; Tan, Zhen; Ciaraldi, Theodore P.; Schenk, Simon; Bhargava, Aditi; Oh, Da Young; Hammond, H. Kirk

doi:10.1172/jci.insight.88322

Cited by 26 publications

(61 citation statements)

References 28 publications

(36 reference statements)

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“…Despite lower insulin levels during a GTT, compound A treatment enhanced glucose tolerance during a GTT compared with vehicle-treated obese mice, indicating that UCN2 treatment improves insulin sensitivity. This is consistent with an earlier study reporting that Ucn2 gene transfer improves glycemia and insulin sensitivity in HFDfed and db/db mice (17). Collectively, these results implicate peripheral action of UCN2 therapies for the treatment of obesity and insulin resistance.…”

Section: Discussionsupporting

confidence: 92%

“…Thus, strategies to activate CRHR2 in peripheral tissues appear to have positive effects on energy homeostasis. In accordance with our results, Ucn2 adeno-associated virus gene transfer attenuates weight gain in HFD-fed mice (17). Our results represent a pharmacological approach to activating the CRHR2 peripherally with a PEGylated UCN2 compound, whereas genetic models/approaches represent a supraphysiological event that may not portray the normal activity of the pathway.…”

Section: Discussionsupporting

confidence: 90%

“…Moreover, we found that compound A acutely promoted GLUT4 translocation, which may account for the increased glucose clearance during the GTT as well as enhanced glucose uptake in isolated skeletal muscle. Improved glucose homeostasis by Ucn2 gene transfer in HFD-fed mice was attributed to increased GLUT4 translocation (17). Along with increased skeletal muscle glucose uptake, glycogen content was unaltered (data not shown), suggesting that compound A improved glucose metabolism by increasing glucose oxidation.…”

Section: Discussionmentioning

confidence: 91%

“…In contrast, whole-body Ucn3 transgenic mice are protected from HFD-induced obesity (15), and transient overexpression of Ucn3 in skeletal muscle enhances glucose metabolism through increased insulin signaling (16). In addition, Ucn2 overexpression through systemic virus delivery improves whole-body insulin sensitivity in HFD-fed rodents (17). Accordingly, activating CRHR2 during obesity can also enhance glucose homeostasis.…”

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confidence: 99%

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

et al. 2019

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

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

et al. 2019

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“…Urocortin 2 (Ucn2) gene transfer fulfills these criteria in insulin resistant mice. 13 In the present study, we ask whether Ucn2 gene transfer-in the absence of exogenous insulin-can normalize glycemic control in two murine models of insulin deficiency.…”

Section: Introductionmentioning

confidence: 99%

Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency

Gao

Giamouridis

Lai

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Type 1 diabetes affects 20 million patients worldwide. Insulin is the primary and commonly the sole therapy for type 1 diabetes. However, only a minority of patients attain the targeted glucose control and reduced adverse events. We tested urocortin 2 gene transfer as single-agent therapy for insulin deficiency using two mouse models. Urocortin 2 gene transfer reduced blood glucose for months after a single intravenous injection, through increased skeletal muscle insulin sensitivity, increased insulin release in response to glucose stimulation, and increased plasma insulin levels before and during euglycemic clamp. The combined increases in both insulin availability and sensitivity resulted in improved glycemic indices-events that were not anticipated in these insulin-deficient models. In addition, urocortin 2 gene transfer reduced ocular manifestations of long-standing insulin deficiency such as vascular leak and improved retinal function. Finally, mortality was reduced by urocortin 2 gene transfer. The mechanisms for these beneficial effects included increased activities of AMP-activated protein kinase and Akt (protein kinase B) in skeletal muscle, increased skeletal muscle glucose uptake, and increased insulin release. These data suggest that urocortin 2 gene transfer may be a viable therapy for new onset type 1 diabetes and might reduce insulin needs in later stage disease.

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Urocortin stimulates the ERK1/2 signaling pathway and the proliferation of HeLa cells via CRF receptor 1

et al. 2023

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Corticotropin‐releasing factor (CRF) stimulates adrenocorticotropic hormone (ACTH) secretion from the pituitary gland and is an essential regulator of the hypothalamic–pituitary–adrenocortical axis. Isoforms of CRF receptor are known to mediate the effects of urocortin stress ligands on the regulation of stress responses, anxiety, and feeding behavior; however, urocortin stress ligands also influence cell proliferation. In view of the tumor‐promoting capacity of prolonged stress, here we investigated (a) the effect of urocortin on cell proliferative signaling via extracellular signal‐regulated kinase 1/2, (b) the expression and cellular distribution of the specific CRF receptor isoforms, and (c) the intracellular localization of phosphorylated ERK1/2 in HeLa cells. Stimulation of cell proliferation was observed in the presence of 10 n m urocortin. Our data also suggest that MAP kinase MEK, the transcription factors E2F‐1 and p53, and PKB/Akt are involved in this process. These findings may have therapeutic relevance for the targeted treatment of various malignancies.

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One-time injection of AAV8 encoding urocortin 2 provides long-term resolution of insulin resistance

Cited by 26 publications

References 28 publications

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

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

Urocortin 2 Gene Transfer Improves Glycemic Control and Reduces Retinopathy and Mortality in Murine Insulin Deficiency

Urocortin stimulates the ERK1/2 signaling pathway and the proliferation of HeLa cells via CRF receptor 1

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