Despite compelling evidence that oxytocin (OT) is effective in reducing body weight (BW) in diet-induced obese (DIO) rodents, studies of the effects of OT in humans and rhesus monkeys have primarily focused on noningestive behaviors. The goal of this study was to translate findings in DIO rodents to a preclinical translational model of DIO. We tested the hypothesis that increased OT signaling would reduce BW in DIO rhesus monkeys by inhibiting food intake and increasing energy expenditure (EE). Male DIO rhesus monkeys from the California National Primate Research Center were adapted to a 12-h fast and maintained on chow and a daily 15% fructose-sweetened beverage. Monkeys received 2× daily subcutaneous vehicle injections over 1 wk. We subsequently identified doses of OT (0.2 and 0.4 mg/kg) that reduced food intake and BW in the absence of nausea or diarrhea. Chronic administration of OT for 4 wk (0.2 mg/kg for 2 wk; 0.4 mg/kg for 2 wk) reduced BW relative to vehicle by 3.3 ± 0.4% (≈0.6 kg; P < 0.05). Moreover, the low dose of OT suppressed 12-h chow intake by 26 ± 7% (P < 0.05). The higher dose of OT reduced 12-h chow intake by 27 ± 5% (P < 0.05) and 8-h fructose-sweetened beverage intake by 18 ± 8% (P < 0.05). OT increased EE during the dark cycle by 14 ± 3% (P < 0.05) and was associated with elevations of free fatty acids and glycerol and reductions in triglycerides suggesting increased lipolysis. Together, these data suggest that OT reduces BW in DIO rhesus monkeys through decreased food intake as well as increased EE and lipolysis.

-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...

Oxytocin (OT) administration elicits weight loss in diet-induced obese (DIO) rodents, nonhuman primates, and humans by reducing energy intake and increasing energy expenditure. Although the neurocircuitry underlying these effects remains uncertain, OT neurons in the paraventricular nucleus are positioned to control both energy intake and sympathetic nervous system outflow to interscapular brown adipose tissue (BAT) through projections to the hindbrain nucleus of the solitary tract and spinal cord. The current work was undertaken to examine whether central OT increases BAT thermogenesis, whether this effect involves hindbrain OT receptors (OTRs), and whether such effects are associated with sustained weight loss following chronic administration. To assess OT-elicited changes in BAT thermogenesis, we measured the effects of intracerebroventricular administration of OT on interscapular BAT temperature in rats and mice. Because fourth ventricular (4V) infusion targets hindbrain OTRs, whereas third ventricular (3V) administration targets both forebrain and hindbrain OTRs, we compared responses to OT following chronic 3V infusion in DIO rats and mice and chronic 4V infusion in DIO rats. We report that chronic 4V infusion of OT into two distinct rat models recapitulates the effects of 3V OT to ameliorate DIO by reducing fat mass. While reduced food intake contributes to this effect, our finding that 4V OT also increases BAT thermogenesis suggests that increased energy expenditure may contribute as well. Collectively, these findings support the hypothesis that, in DIO rats, OT action in the hindbrain evokes sustained weight loss by reducing energy intake and increasing BAT thermogenesis.

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, lepr(b), in the ARC of leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats. Successful expression of adenovirus containing lepr(b) (Ad-lepr(b)) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-lepr(b) into the ARC restored low hypothalamic levels of lepr(b) mRNA to values approximating those of wild-type (Fa(k)/Fa(k)) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fa(k)/fa(k) rats injected with a control adenovirus (Ad-lacZ) (P < 0.05 for each comparison). In contrast, Ad-lepr(b) delivery to either the lateral hypothalamic area of fa(k)/fa(k) rats or to the ARC of wild-type Fa(k)/Fa(k) rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

The capacity to adjust energy intake in response to changing energy requirements is a defining feature of energy homeostasis. Despite the identification of leptin as a key mediator of this process, the mechanism whereby changes of body adiposity are coupled to adaptive, short-term adjustments of energy intake remains poorly understood. To investigate the physiological role of leptin in the control of meal size and the response to satiety signals, and to identify brain areas mediating this effect, we studied Koletsky (fa k /fa k ) rats, which develop severe obesity due to the genetic absence of leptin receptors. Our finding of markedly increased meal size and reduced satiety in response to the gut peptide cholecystokinin (CCK) in these leptin receptor-deficient animals suggests a critical role for leptin signaling in the response to endogenous signals that promote meal termination. To determine if the hypothalamic arcuate nucleus (ARC) (a key forebrain site of leptin action) mediates this leptin effect, we used adenoviral gene therapy to express either functional leptin receptors or a reporter gene in the area of the ARC of fa k /fa k rats. Restoration of leptin signaling to this brain area normalized the effect of CCK on the activation of neurons in the nucleus of the solitary tract and area postrema, key hindbrain areas for processing satiety-related inputs. This intervention also reduced meal size and enhanced CCK-induced satiety in fa k /fa k rats. These findings demonstrate that forebrain signaling by leptin, a long-term regulator of body adiposity, limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals. IntroductionThe discovery of leptin (1) and the hypothalamic neurons on which it acts (2-6) has begun to clarify how information regarding body energy stores is communicated to the brain and is subsequently "transduced" into behavioral and metabolic responses (7,8). Much of this progress is due to the identification of specific neurons in the arcuate nucleus (ARC) of the hypothalamus that serve as sensors of whole-body energy status and initiate downstream responses designed to maintain fuel stores at a constant level (7,8). Although many regions of the brain are involved in energy homeostasis, circuits that begin in the ARC are some of the best understood at the molecular level (9-11). Despite this progress, little is known about how the hypothalamic actions of leptin ultimately influence feeding behavior on a meal-to-meal basis.The consumption of food during single meals is governed by mechanisms that act over short time intervals to control the initiation and termination of food ingestion. Whereas the timing of meal initiation is sensitive to a variety of both intrinsic and extrinsic factors (e.g., time of day, social and emotional factors, and food availability) and is consequently quite variable, meal termination is a more reproducible, biologically determined process (12). Central to the mechanism underlying meal termination is the perception