Divergent Effects of Oxytocin Treatment of Obese Diabetic Mice on Adiposity and Diabetes

Abstract

Oxytocin has been suggested as a novel therapeutic against obesity, because it induces weight loss and improves glucose tolerance in diet-induced obese rodents. A recent clinical pilot study confirmed the oxytocin-induced weight-reducing effect in obese nondiabetic subjects. Nevertheless, the mechanisms involved and the impact on the main comorbidity associated with obesity, type 2 diabetes, are unknown. Lean and ob/ob mice (model of obesity, hyperinsulinemia, and diabetes) were treated for 2 weeks with different doses of oxytocin, analogues with longer half-life (carbetocin) or higher oxytocin receptor specificity ([Thr4,Gly7]-oxytocin). Food and water intake, body weight, and glycemia were measured daily. Glucose, insulin, and pyruvate tolerance, body composition, several hormones, metabolites, gene expression, as well as enzyme activities were determined. Although no effect of oxytocin on the main parameters was observed in lean mice, the treatment dose-dependently reduced food intake and body weight gain in ob/ob animals. Carbetocin behaved similarly to oxytocin, whereas [Thr4,Gly7]-oxytocin (TGOT) and a low oxytocin dose decreased body weight gain without affecting food intake. The body weight gain-reducing effect was limited to the fat mass only, with decreased lipid uptake, lipogenesis, and inflammation, combined with increased futile cycling in abdominal adipose tissue. Surprisingly, oxytocin treatment of ob/ob mice was accompanied by a worsening of basal glycemia and glucose tolerance, likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These results impose careful selection of the conditions in which oxytocin treatment should be beneficial for obesity and its comorbidities, and their relevance for human pathology needs to be determined.

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

“…In addition, chronic central or systemic oxytocin increases epididymal white adipose tissue expression of hormone sensitive lipase (a key mediator of adipocyte lipolysis) (1, 23) while reducing expression of fatty acid synthase (an enzyme linked to lipogenesis) in rats (1). While it remains to be determined whether chronic CNS infusions of oxytocin increase circulating levels (23) in sufficient concentrations to trigger a peripheral effect on lipolysis, it is possible that these effects in our model may be attributed, in part, to a direct effect on adipocytes (60,83,94) where OTRs are expressed (1,31,32,60,83,94,101) or an indirect mechanism. The mechanism underlying these effects may involve outgoing polysynaptic sympathetic nervous system projections from PVN oxytocin neurons to both inguinal (86) and epididymal white adipose tissue (86,89).…”

“…Unfortunately, existing pharmacotherapeutic strategies to treat obesity are relatively ineffective and there is widespread need for improved treatments. We and others have previously shown that chronic systemic administration of oxytocin elicits weight loss or reductions of weight gain in DIO and genetically obese rodent models, DIO nonhuman primates, and obese humans through mechanisms that include reduction of food intake (1,10,23,49,53,59,104,105), increased energy expenditure (10), increases in lipolysis (1,8,23), and/or reductions in RQ (23,49,53). (23,49,53).…”

“…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 Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…Nasal treatment of oxytocin was also reported to decrease food intake in both mice and humans [24,35,36]. However, this reduction of BW is not only induced by food intake reduction; oxytocin also induces lipolysis in adipose tissue and decreases fat mass [29,34,[37][38][39][40]. Recent studies have clarified the various new mechanisms of oxytocin's anorexigenic effects through the CNS and promotion of catabolic reactions on peripheral tissues.…”

Modulation of Fatty Acid Oxidation and Glucose Uptake by Oxytocin in Adipocytes

“…Animals developed obesity when they were deficient of OT or OT receptors [15] [16]. Peripheral OT treatment reduced adipose tissue proportion and also ameliorated food intake, fatty liver, as well as glucose intolerance in ob/ob mice [17] [18] [19]. Adipocyte size was smaller after treating with OT, the lipogenic related genes fatty acid binding protein 4 (FABP4), peroxisomal proliferator activated receptor gamma (PPARγ), glucose transporter 4 (GLUT4), and leptin mRNA levels in adipose tissues were increased in rats, indicating that OT treatment improves nutrient provision in adipose tissue [20].…”