Chronic oxytocin administration inhibits food intake, increases energy expenditure, and produces weight loss in fructose-fed obese rhesus monkeys

Abstract

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.

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

“…Nevertheless, these discrepancies are unlikely to have influenced the major overall conclusion because oxytocin also produced consistent and preferential reductions of weight gain in HFD-fed rats that were both age and weight matched to chow-fed controls in study 3. In addition, the HFD used in this study and other studies (23,53,59,103,104) also contains more sucrose (6.7% kcal from sucrose) relative to chow (3.7% kcal from sucrose), and although relatively small, it may have also contributed to the enhanced effectiveness of oxytocin in this model (2,10,38,61,68). However, we found that chronic 3V infusions of oxytocin reduce weight gain, body adiposity, and energy consumption in DIO rats irrespective of whether sucrose is added to their HFD.…”

“…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.…”

“…Decreased food intake appears to contribute to the ability of oxytocin to reduce body weight in rodents (23,53,59,103,104 (10,51,61), but also high-fat diets (HFDs) (23,53,59,103,104). Conversely, defective oxytocin signaling is linked to increased intake of fat (103,104) and carbohydrates, including sugar (2,38,51,61,68) suggesting a physiological role for oxytocin to limit consumption of fat and sugar.…”

“…Recent studies indicate that in addition to suppressing food intake, oxytocin may also reduce body weight in rodents and nonhuman primates by increasing energy expenditure (10,63,90,99,(102)(103)(104). Conversely, animals with either partial or complete loss in oxytocin signaling show decreased energy expenditure (18,45,93,99,104) and brown adipose tissue thermogenesis (18,45,93).…”

Central and peripheral control of food intake

“…Each of these peptides acts to decrease food intake, increase the metabolic rate, or both (Morton et al 2012;Blevins et al 2015;Moore et al 2015). Th e CRH is a 41 amino acid peptide, which is widely distributed throughout the brain, but is particularly abundant in the medial parvocellular division of the PVN (Sawchenko et al 1985).…”