Role of oxytocin signaling in the regulation of body weight

Abstract

Obesity and its associated metabolic disorders are growing health concerns in the US and worldwide. In the US alone, more than two-thirds of the adult population is classified as either overweight or obese [1], highlighting the need to develop new, effective treatments for these conditions. Whereas the hormone oxytocin is well known for its peripheral effects on uterine contraction during parturition and milk ejection during lactation, release of oxytocin from somatodendrites and axonal terminals within the central nervous system (CNS) is implicated in both the formation of prosocial behaviors and in the control of energy balance. Recent findings demonstrate that chronic administration of oxytocin reduces food intake and body weight in diet-induced obese (DIO) and genetically obese rodents with impaired or defective leptin signaling. Importantly, chronic systemic administration of oxytocin out to 6 weeks recapitulates the effects of central administration on body weight loss in DIO rodents at doses that do not result in the development of tolerance. Furthermore, these effects are coupled with induction of Fos (a marker of neuronal activation) in hindbrain areas (e.g. dorsal vagal complex (DVC)) linked to the control of meal size and forebrain areas (e.g. hypothalamus, amygdala) linked to the regulation of food intake and body weight. This review assesses the potential central and peripheral targets by which oxytocin may inhibit body weight gain, its regulation by anorexigenic and orexigenic signals, and its potential use as a therapy that can circumvent leptin resistance and reverse the behavioral and metabolic abnormalities associated with DIO and genetically obese models.

Fig. 1

A schematic of proposed CNS circuitry involved in oxytocin regulation of energy balance. Leptin activates pPVN oxytocin neurons through a MC4R-dependent mechanism resulting in the release of oxytocin in the hindbrain. Oxytocin is proposed to activate ascending cNTS NA and GLP-1 neuronal projections to the PVN and NAc (denoted by purple arrows to PVN and NAc) as well as POMC neurons. These combined effects are proposed to reduce body weight by reducing food intake and increasing energy expenditure. Abbreviations: α-1R Alpha-1 adrenoceptor, ARC Arcuate nucleus, CART Cocaine-amphetamine-regulated transcript, CCK Cholecystokinin, GLP-1 Glucagon-like peptide-1, GLP-1R Glucagon-like peptide-1 receptor, LepRb Long form of the Leptin receptor, MC4R Melanocortin 4 receptor, NA Noradrenergic, NAc Nucleus accumbens, NTS Nucleus of the solitary tract, OXY Oxytocin, OXTR Oxytocin receptor, PrRP Prolactin releasing peptide, PVN Paraventricular nucleus, POMC Proopiomelanocortin