Shedding Heat on Oxytocin

More than a century ago, Sir Henry Dale demonstrated that a component of the pituitary causes contractions of the mammalian uterus (1), hence his coining the term “oxytocic,” derived from the Greek for “quick birth,” for its activity. The discovery that a component of the pituitary causes milk secretion followed within a few years (2, 3). By 1930, oxytocin (OXT) was separated from vasopressin into pitocin and pitressin, respectively, at Parke Davis and made available for research (4). That a single peptide was responsible for these uterine and mammary actions was definitively confirmed upon the sequencing and synthesis of the peptide, 9 amino acids in length (5). Vincent du Vigneaud was awarded a Nobel Prize for this work. The cloning and sequencing of the rat OXT gene 30 years later (6), followed by cloning of the single OXT receptor (OXTR) (7), enabled the tremendous contributions of molecular biology, including studies on the regulation of the genes' expression and the creation of OXT (8, 9) and OXTR (10, 11) gene knockouts (KOs; below).

Although research has continued apace on the role of OXT in parturition (12) and lactation (13), its roles in various behaviors have grabbed much of the spotlight lately. For example, studies showed that OXT influences feeding behavior (14) and social recognition (15) in rats. Studies of predominantly monogamous or polygamous prairie voles established the role for OXT and the OXTR in social bonding (16). Studies using mouse KOs of OXT or OXTR indicated, for example, the importance of the medial amygdala in social recognition (17) and of the central amygdala in fear conditioning (18). Female mice with inactivation of the OXT gene also display deficits in social memory indicated by the absence of a normal Bruce effect (19) and rejection of parasitized males (20). These types of studies contributed to the recent focus on OXT and the OXTR in human diseases. For example, genome-wide association studies (GWAS) indicated various degrees of linkage between the OXTR and autism (21–24). In addition, numerous studies appeared of human social behaviors after, generally, acute intranasal administration of OXT (25).

As noted above, brain studies have been getting the most attention. However, very interesting studies are uncovering unsuspected roles for OXT in the periphery as well. OXT and OXTR are expressed in the male reproductive tract where OXT affects a number of functions, including spermiation and testicular steroidogenesis (26). OXT may inhibit inflammation by inhibiting neutrophils (eg, Reference 27). Recent studies also demonstrated that OXT is necessary for normal bone formation (28) and it enables the estrogen-induced bone formation through OXTR in osteoblasts (29).

In this issue of Endocrinology, Nishimori and colleagues (30) demonstrate that OXT is necessary for normal thermoregulation in mice, perhaps by acting both peripherally and centrally. OXTR KO mice exposed to 5°C failed to maintain body temperature as well as wild-type littermates, similar to their results in OXT KO mice (31). They also did not lose as much body weight during this cold exposure, presumably secondary to reduced fat metabolism. Proper thermoregulation was restored upon viral expression of OXTR in the dorso- and ventromedial hypothalamus. Interestingly, OXT and OXTR are expressed in preadipocytes of brown adipose tissue (BAT) and in mature adipocytes of white adipose tissue. Finally, ß3- and α2A-adrenergic receptors are reduced and elevated, respectively, in BAT of OXTR KO mice. These receptor changes may also contribute peripherally to altered fat metabolism.

Appropriately, this study raises questions the solutions to which will be eagerly awaited. For example, why are changes seen in the BAT morphology in OXTR but not OXT KOs (especially as obesity occurs in both), and why in males but not females (32)? Do weight and BAT morphology (and BAT adrenergic receptor levels) return to normal upon viral expression of OXTR in the hypothalamus? Are other hormone systems that are involved in thermoregulation (eg, thyroid) impacted by the OXTR inactivation? These are just a few avenues of investigation that may be stimulated by this intriguing report.