Hypooxytocinaemia in obese Zucker rats relates to oxytocin degradation in liver and adipose tissue

Abstract

The metabolic action of oxytocin has recently been intensively studied to assess the ability of the peptide to regulate energy homeostasis. Despite the obvious weight-reducing effect of oxytocin observed in experimental studies, plasma oxytocin levels were found to be unchanged or even elevated in human obesity. The aim of our study was to evaluate the changes in the oxytocin system in Zucker rats, an animal model closely mirroring morbid obesity in humans. Plasma oxytocin levels were measured in obese Zucker rats and lean controls by enzyme immunoassay after plasma extraction. The expression of oxytocin and oxytocin receptor (OXTR) was assessed at the mRNA and protein levels by quantitative real-time PCR and immunoblotting respectively. Plasma and tissue activity of oxytocinase, the main enzyme involved in oxytocin degradation, were measured by fluorometric assay using an arylamide derivate as the substrate. Obese Zucker rats displayed a marked reduction in plasma oxytocin levels. Elevated liver and adipose tissue oxytocinase activity was noticed in obese Zucker rats. Hypothalamic oxytocin gene expression was not altered by the obese phenotype. OXTR mRNA and protein levels were upregulated in the adipose tissue of obese animals in contrast to the reduced OXTR protein levels in skeletal muscle. Our results show that obesity is associated with reduced plasma oxytocin due to increased peptide degradation by liver and adipose tissue rather than changes in hormone synthesis. This study highlights the importance of the oxytocin system in the pathogenesis of obesity and suggests oxytocinase inhibition as a candidate approach in the therapy of obesity.

Chronic CNS oxytocin signaling preferentially induces fat loss in high-fat diet-fed rats by enhancing satiety responses and increasing lipid utilization

“…Body composition was measured at the end of the washout study. Oxytocin continued to reduce weight gain in this subset of animals between infusion days [29][30][31][32][33][34][35][36][37][38][39] (Fig. 6E).…”

“…In addition, chronic central or systemic oxytocin increases epididymal white adipose tissue expression of hormone sensitive lipase (a key mediator of adipocyte lipolysis) (1, 23) while reducing expression of fatty acid synthase (an enzyme linked to lipogenesis) in rats (1). While it remains to be determined whether chronic CNS infusions of oxytocin increase circulating levels (23) in sufficient concentrations to trigger a peripheral effect on lipolysis, it is possible that these effects in our model may be attributed, in part, to a direct effect on adipocytes (60,83,94) where OTRs are expressed (1,31,32,60,83,94,101) or an indirect mechanism. The mechanism underlying these effects may involve outgoing polysynaptic sympathetic nervous system projections from PVN oxytocin neurons to both inguinal (86) and epididymal white adipose tissue (86,89).…”

“…Transgenic mice with deficient oxytocin (18) or oxytocin receptor (OTR) signaling (93) exhibit adult-onset obesity, and copy number variations associated with the OTR gene (OXTR) are linked with an early-onset obesity phenotype in humans (96). Furthermore, impaired oxytocin release within the hypothalamic paraventricular nucleus (PVN) is evident in dietinduced obese (DIO) mice (103), which could lead to defects in peripheral release of oxytocin, and potentially explain the decreased circulating levels in DIO mice (103,104), genetically obese rodents (32,73), as well as obese humans and individuals with Type 2 diabetes (74). Moreover, the pathogenesis of PraderWilli syndrome, a rare human genetic disorder characterized by hyperphagia and severe obesity, is linked to a reduced size and number of PVN oxytocin neurons (91).…”

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…This suggests that the cause of decreased BW induced by oxytocin treatment depends not only on the decreased food intake, but also on the stimulation of lipolysis. Oxytocin receptors are expressed in various tissues, including adipose tissue [38,92], and previous articles reported that oxytocin increases lipolysis and fatty acid β-oxidation by acting directly on adipose tissue in rats [29,136]. Blevins et al [34] demonstrated that, in addition to rodents, subcutaneous oxytocin treatment reduces BW in diet-induced obesity primates (rhesus monkey) with decreased food intake, increased energy expenditure, and lipolysis.…”

“…Nasal treatment of oxytocin was also reported to decrease food intake in both mice and humans [24,35,36]. However, this reduction of BW is not only induced by food intake reduction; oxytocin also induces lipolysis in adipose tissue and decreases fat mass [29,34,[37][38][39][40]. Recent studies have clarified the various new mechanisms of oxytocin's anorexigenic effects through the CNS and promotion of catabolic reactions on peripheral tissues.…”