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Overduin J.,Cornell University | Overduin J.,Office of Research and Development Medical Research Service | Overduin J.,University of Washington | Gibbs J.,Cornell University | And 3 more authors.
Peptides | Year: 2014

Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study 1, rats (N = 10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmol/kg) or vehicle before a 4-h test-food presentation. At most doses, both CCK-8 and CCK-58 similarly reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9 nmol/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 min after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK-58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK's role in food intake regulation may require re-examination. © 2014 Published by Elsevier Inc.

Blevins J.E.,Office of Research and Development Medical Research Service | Blevins J.E.,University of Washington | Ho J.M.,Office of Research and Development Medical Research Service | Ho J.M.,University of Washington
Reviews in Endocrine and Metabolic Disorders | Year: 2013

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. © 2013 Springer Science+Business Media New York (outside the USA).

Baskin D.G.,Office of Research and Development Medical Research Service | Baskin D.G.,University of Washington | Kim F.,University of Washington | Gelling R.W.,Diabetes Drug Discovery Research | And 7 more authors.
Endocrinology | Year: 2010

Evidence suggests that release of oxytocin in the nucleus tractus solitarius (NTS) of the hindbrain from descending projections that originate in the paraventricular nucleus can inhibit food intake by amplifying the satiety response to cholecystokinin (CCK). To further evaluate this mechanism in rats, we used a novel cytotoxin, saporin conjugated to oxytocin (OXY-SAP), a compound designed to destroy cells that express oxytocin receptors (OXYr). OXY-SAP was injected directly into the NTS to lesion neurons that express OXYr and that are implicated in potentiating CCK's satiety effects. The control consisted of injection of saporin conjugated to a nonsense peptide. We found that OXY-SAP was cytotoxic to human uterine smooth muscle cells in vitro, demonstrating that OXY-SAP can lesion cells that express OXYr. Using laser capture microdissection and real-time quantitative PCR, we demonstrated that OXYr mRNA levels were reduced in the NTS after OXY-SAP administration. Moreover, we found that OXY-SAP attenuated the efficacy of CCK-8 to reduce food intake and blocked the actions of an OXYr antagonist to stimulate food intake. The findings suggest that OXY-SAP is an effective neurotoxin for in vivo elimination of cells that express OXYr and is potentially useful for studies to analyze central nervous system mechanisms that involve the action of oxytocin on food intake and other physiological processes. Copyright © 2010 by The Endocrine Society.

Blevins J.E.,Office of Research and Development Medical Research Service | Blevins J.E.,University of Washington | Graham J.L.,University of California at Davis | Morton G.J.,University of Washington | And 5 more authors.
American Journal of Physiology - Regulatory Integrative and Comparative Physiology | Year: 2015

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. © 2015 the American Physiological Society

Morton G.J.,University of Washington | Thatcher B.S.,Office of Research and Development Medical Research Service | Reidelberger R.D.,Creighton University | Ogimoto K.,University of Washington | And 6 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012

Growing evidence suggests that oxytocin plays an important role in the regulation of energy balance and that central oxytocin administration induces weight loss in dietinduced obese (DIO) animals. To gain a better understanding of how oxytocin mediates these effects, we examined feeding and neuronal responses to oxytocin in animals rendered obese following exposure to either a high-fat (HFD) or low-fat diet (LFD). Our findings demonstrate that peripheral administration of oxytocin dosedependently reduces food intake and body weight to a similar extent in rats maintained on either diet. Moreover, the effect of oxytocin to induce weight loss remained intact in leptin receptor-deficient Koletsky (fa k/fa k) rats relative to their lean littermates. To determine whether systemically administered oxytocin activates hindbrain areas that regulate meal size, we measured neuronal c-Fos induction in the nucleus of the solitary tract (NTS) and area postrema (AP). We observed a robust neuronal response to oxytocin in these hindbrain areas that was unexpectedly increased in rats rendered obese on a HFD relative to lean, LFD-fed controls. Finally, we report that repeated daily peripheral administration of oxytocin in DIO animals elicited a sustained reduction of food intake and body weight while preventing the reduction of energy expenditure characteristic of weight-reduced animals. These findings extend recent evidence suggesting that oxytocin circumvents leptin resistance and induces weight-loss in DIO animals through a mechanism involving activation of neurons in the NTS and AP, key hindbrain areas for processing satiety-related inputs. © 2012 the American Physiological Society.

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