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

Abstract

-Based largely on a number of short-term administration studies, growing evidence suggests that central oxytocin is important in the regulation of energy balance. The goal of the current work is to determine whether long-term third ventricular (3V) infusion of oxytocin into the central nervous system (CNS) is effective for obesity prevention and/or treatment in rat models. We found that chronic 3V oxytocin infusion between 21 and 26 days by osmotic minipumps both reduced weight gain associated with the progression of high-fat diet (HFD)-induced obesity and elicited a sustained reduction of fat mass with no decrease of lean mass in rats with established diet-induced obesity. We further demonstrated that these chronic oxytocin effects result from 1) maintenance of energy expenditure at preintervention levels despite ongoing weight loss, 2) a reduction in respiratory quotient, consistent with increased fat oxidation, and 3) an enhanced satiety response to cholecystokinin-8 and associated decrease of meal size. These weightreducing effects persisted for approximately 10 days after termination of 3V oxytocin administration and occurred independently of whether sucrose was added to the HFD. We conclude that long-term 3V administration of oxytocin to rats can both prevent and treat dietinduced obesity. obesity; food intake; energy expenditure; oxytocin PUBLISHED DATA suggest that in addition to its well-recognized peripheral effects on uterine contraction during parturition and milk ejection during lactation (33), the nonapeptide oxytocin plays an important role in the regulation of energy homeostasis (23,53,59,103,104). 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). Importantly, both acute and chronic administration of oxytocin is sufficient to bypass impaired leptin signaling to reduce weight gain or body weight in both DIO (23,53,59,103,104) and genetically obese rodent models (1,42,47,54,59,73) as well as weight loss in DIO rhesus monkeys (10) and humans (105). While collectively these findings are indicative of an important physiological role for oxytocin in energy homeostasis, the mechanisms underlying this function have not been fully elucidated.The effects of central nervous system (CNS) administration of oxytocin to reduce body weight gai...

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…In HFDinduced obese male and female mice (body fat mass: 36%), 10 days of oxytocin treatment decreased abdominal and subcutaneous fat up to 15-20% without reducing muscle mass [39]. Similar effects of oxytocin on fat mass are found in other studies using HFD-induced obese mice/rats [25,29,31,32] and genetically obese models such as db/db [131] and ob/ob mice [37]. 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.…”

“…We found that mice showed increased energy expenditure with decreased respiratory quotient (RQ) during the light phase of the treatment period [23]. The RQ decrease by oxytocin treatment was also confirmed in rats, monkeys, and humans [25,32,34,35,135]. This reduction of BW by oxytocin may also be mediated by the induction of diet-induced thermogenesis [31,47].…”

“…This BW degradation was found to be the consequence of reduced energy intake and fat mass [23,39]. On the other hand, the effect of oxytocin on BW degradation was smaller in lean mice or rats fed a normal chow diet [32,37,39]. This phenomenon was also observed in Zucker lean and fatty rats [137] and Koletsky rats [28].…”

The effects of oxytocin on eating behaviour and metabolism in humans

“…Preclinical studies indicate that oxytocin induces lipolysis 14,18 and fat oxidation 18,37,86 , which in turn, independent of food intake, lead to reduced body fat and weight 18 . Notably, oxytocin reduces visceral and liver fat 37 , which are metabolically important fat depots that are associated with an increased risk of the metabolic syndrome and cardiovascular disease 87 .…”

“…Unlike existing pharmacological options, which primarily target food consumption or absorption, oxytocin not only reduces food intake but, in diet induced obese rodent and nonhuman primate models, also promotes energy expenditure, which enables maintenance of weight reduction 14,18,38,86 . How oxytocin increases energy expenditure is not yet clear; however, some preclinical evidence suggests that oxytocin may lead to preferential preservation of lean body mass, a key determinant of energy expenditure, despite weight loss 86 ; activation of brown fat 32-34 ; and/or the conversion of white adipose tissue to beige fat that is capable of thermogenesis 90,95 .…”