Data from: Long-acting and selective oxytocin peptide analogues show anti-diabetic and anti-obesity effects in male mice

Oxytocin (OXT) has been shown to suppress appetite, induce weight loss,
improve glycemic control and lipid metabolism in several species including
humans, monkeys and rodents. However, OXT’s short half-life in circulation
and lack of receptor selectivity limit its application and efficacy. Here
we report an OXT peptide analogue (OXTGly) that is potent and selective
for the oxytocin receptor (OXTR). OXT, but not OXTGly, activated
vasopressin receptors in vitro and acutely increased blood pressure in
vivo when administered i.p.. OXT suppressed food intake in mice, while
OXTGly had a moderate effect on food intake when administered i.p. or
i.c.v.. Both OXT (i.p.) and OXTGly (i.p.) improved glycemic control in
glucose tolerance tests. In addition, both OXT (i.p.) and OXTGly (i.p.)
stimulated insulin, glucagon-like peptide 1 (GLP-1) and glucagon secretion
in mice. We generated lipid conjugated OXT (acylated-OXT) and OXTGly
(acylated-OXTGly) and demonstrated that these molecules have significantly
extended half-lives in vivo. Compared to OXT, two-week treatment of diet
induced obese (DIO) mice with acylated-OXT (s.c.) resulted in enhanced
body weight reduction, an improved lipid profile, and gene expression
changes consistent with increased lipolysis and decreased gluconeogenesis.
Treatment with acylated-OXTGly (s.c.) also resulted in a statistically
significant weight loss, albeit to a lesser degree compared to
acylated-OXT treatment. In conclusion, we demonstrate that selective
activation of the OXTR pathway results in both acute and chronic metabolic
benefits, while potential activation of vasopressin receptors by
non-selective OXT analogues causes physiological stress that contributes
to additional weight loss.