Long-Acting and Selective Oxytocin Peptide Analogs Show Antidiabetic and Antiobesity Effects in Male Mice

Area of Science:

• Endocrinology and Metabolism
• Pharmacology
• Molecular Biology

Background:

• Oxytocin (OXT) exhibits metabolic benefits including appetite suppression and weight loss.
• Limitations of OXT include a short half-life and lack of receptor selectivity, activating both OXT and vasopressin receptors.
• This restricts OXT's therapeutic efficacy and can cause adverse effects like increased blood pressure.

Purpose of the Study:

• To develop and characterize a potent and selective OXT analog (OXT^Gly) for the OXT receptor (OXTR).
• To evaluate the metabolic effects of OXT^Gly and lipid-conjugated analogs (acylated-OXT and acylated-OXT^Gly) in vivo.
• To compare the efficacy of selective OXTR activation versus non-selective OXT treatment in a mouse model of diet-induced obesity.

Main Methods:

• In vitro receptor activation assays and in vivo studies in mice.
• Administration of OXT, OXT^Gly, acylated-OXT, and acylated-OXT^Gly via intraperitoneal (IP) or subcutaneous (SC) routes.
• Assessment of food intake, glucose tolerance, insulin, glucagon-like peptide 1, and glucagon secretion, along with lipid profiles and gene expression analysis.

Main Results:

• OXT^Gly demonstrated selectivity for OXTR, unlike OXT which activated vasopressin receptors and increased blood pressure.
• Both OXT and OXT^Gly improved glycemic control and stimulated insulin and incretin secretion.
• Lipid-conjugated analogs exhibited extended half-lives; acylated-OXT treatment in obese mice led to significant weight reduction, improved lipid profiles, and altered gene expression favoring lipolysis.

Conclusions:

• Selective OXTR activation by OXT^Gly confers acute and chronic metabolic advantages.
• Non-selective OXT analogs activate vasopressin receptors, causing physiological stress that may contribute to weight loss but also adverse effects.
• Targeting OXTR specifically offers a promising therapeutic strategy for metabolic disorders with reduced side effects.