Abstract
Background: Oxytocin is a hypothalamic neuropeptide that participates in the network of appetite regulation. Recently the oxytocin signaling pathway has emerged as an attractive target for treating obesity. However, the short half-life limits its development as a clinical therapeutic. Here we provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide.Methods: ASK1476 features two specific amino acid substitutions in positions 7 and 8 combined with a short polyethylene glycol spacer. Short time dose escalation experiments testing increasing doses of 3 days each were performed in diet-induced overweight (DIO) male rats assessing effects on body weight as well as changes in food intake. Furthermore, DIO rats were tested for changes in body weight, food intake, temperature, and locomotor activity over 28 days of treatment (oxytocin, ASK1476, or vehicle).Results: In dose escalation experiments, significant reductions in food intake relative to baseline were detected beginning with doses of 15 nmol/kg ASK1476 (−15.2 ± 2.3 kcal/d, p = 0.0017) and 20 nmol/kg oxytocin (−11.2.9 ± 2.4 kcal/d, p = 0.0106) with corresponding significant changes in body weight (ASK1476: −5.2 ± 0.8 g, p = 0.0016; oxytocin: −2.6 ± 0.7 g, p = 0.0326). In long-term experiments, there was no difference on body weight change between 120 nmol/kg/d ASK1476 (−71.4 ± 34.2 g, p = 0.039) and 600 nmol/kg/d oxytocin (−91.8 ± 32.2 g, p = 0.035) relative to vehicle (706.9 ± 28.3 g), indicating a stronger dose response for ASK1476. Likewise, both ASK1476 and oxytocin at these doses resulted in similar reductions in 28-day cumulative food intake (ASK1476: −562.7 ± 115.0 kcal, p = 0.0001; oxytocin: −557.1 ± 101.3 kcal, p = 0.0001) relative to vehicle treatment (2716 ± 75.4 kcal), while no effects were detected on locomotor activity or body temperature.Conclusion: This study provides proof-of-concept data demonstrating an oxytocin analog with extended in vivo stability and improved potency to reduce food intake and body weight in DIO animals which could mark a new avenue in anti-obesity drug interventions.
Highlights
73 million people in the United States are overweight or obese (Ogden et al, 2012), which is the second leading cause of preventable death, at a cost to the U.S health-care system of 147 billion dollars per year or 9% of all medical expenditures (Finkelstein, 2014), and by 2030 nearly 1 in 2 adults will have obesity in the US (Ward et al, 2019)
The often modest reductions in body weight are due to compensatory adaptations that increase levels of appetite-stimulating hormones, decrease levels of appetite-suppressing hormones, and reduced energy expenditure (Hill et al, 2012)
OXT is produced in the paraventricular nucleus (PVN) and supra-optic nucleus (SON) of the hypothalamus, OXT deficiency is plausible in individuals with hypothalamic and pituitary tumors (Gebert et al, 2018; Aulinas et al, 2019)
Summary
73 million people in the United States are overweight or obese (Ogden et al, 2012), which is the second leading cause of preventable death, at a cost to the U.S health-care system of 147 billion dollars per year or 9% of all medical expenditures (Finkelstein, 2014), and by 2030 nearly 1 in 2 adults will have obesity in the US (Ward et al, 2019). Diet and exercise can reduce body weight by as much as 10% (Wadden et al, 1999; Zibellini et al, 2016) and improve health (Magkos et al, 2016) over the short-term but results in subpar long-term weight loss (Wu et al, 2009; Barte et al, 2010; Dombrowski et al, 2014). The oxytocin (OXT) signaling pathway has emerged as an attractive target for treating obesity (Blevins and Baskin, 2015). There is growing evidence that peripheral administration of OXT reduces food intake, enhances energy expenditure, and prevents or reduces weight gain in diet-induced obese and genetically obese rodent models, and reduces food intake and body weight in diet-induced obese nonhuman primates (Maejima et al, 2011; Morton et al, 2012; Blevins et al, 2015) as well as obese humans (Zhang et al, 2013; Hsu et al, 2018). We provide results from testing a long-lasting, potent and selective oxytocin analog ASK1476 on its efficacy to reduce food intake and body weight in comparison to the native oxytocin peptide
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