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 weight-reducing 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 diet-induced obesity.

Keywords: energy expenditure; food intake; obesity; oxytocin.

Fig. 1.

Effects of chronic third ventricular (3V) oxytocin infusions on food intake, body weight gain, and body composition in high-fat diet (HFD)-fed and chow-fed rats. Ad libitum fed rats were either placed on HFD (60% kcal from fat; N = 5–6/group) or maintained on chow (N = 8–9/group) at onset of continuous infusions of vehicle or oxytocin (16 nmol/day). A and E: change in body weight gain in animals maintained on HFD or chow; B and F: change in fat mass and lean mass in animals maintained on HFD or chow; C and G: change in daily energy intake (kcal/day) in animals maintained on HFD or chow; D and H: change in weekly energy intake (kcal/wk) in animals maintained on HFD or chow. Note week 4 data represent data across only 5 days. Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.

Fig. 2.

Effects of chronic 3V oxytocin infusions on food intake, body weight gain, and body composition in HFD-fed and chow-fed rats. Ad libitum fed rats were maintained on HFD (60% kcal from fat; N = 6–8/group) or chow (n = 8–9/group) for 2.5 mo before receiving continuous infusions of vehicle or oxytocin (16 nmol/day). A and E: change in body weight gain in animals maintained on HFD or chow; B and F: change in fat mass and lean mass in animals maintained on HFD or chow; C and G: daily energy intake (kcal/day); D and H: change in weekly energy intake (kcal/wk) in animals maintained on HFD or chow. Note week 4 data represent data across only 5 days. Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.

Fig. 3.

Effects of chronic 3V oxytocin infusions on food intake, body weight, and body composition in rats with established diet-induced obesity. Ad libitum fed rats were either maintained on HFD (60% kcal from fat; N = 7–8/group) or chow (N = 7–8/group) for 4.5 mo before receiving continuous infusions of vehicle or oxytocin (16 nmol/day). A and E: change in body weight in HFD-fed diet-induce obese (DIO) or chow-fed control animals; B and F: change in body weight gain in HFD-fed DIO or chow-fed control animals; C and G: change in fat mass and lean mass in HFD-fed DIO or chow-fed control animals; D and H: daily energy intake (kcal/day) in HFD-fed DIO or chow-fed control animals. Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.

Fig. 4.

Effects of chronic 3V oxytocin infusions on energy expenditure, locomotor activity, and respiratory quotient (RQ) in DIO rats. Ad libitum fed DIO rats received continuous infusions of vehicle or oxytocin (16 nmol/day) over 21 days and were maintained on HFD (60% kcal from fat; N = 7–8/group). A: 24-h profile of energy expenditure during vehicle or oxytocin infusions; B: energy expenditure measurements during the light, dark, and throughout the 24-h period; C: 24-h profile of locomotor activity; D: locomotor activity measurement during the light, dark, and throughout the 24-h period; E: 24-h profile of RQ; F: RQ measurement during the light, dark, and throughout the 24-h period. Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.

Fig. 5.

A–F: effects of chronic 3V oxytocin infusions on meal patterns in DIO rats or on cholecystokinin (CCK-8)-elicited satiety in HFD-fed rats. Ad libitum fed DIO rats received continuous infusions of vehicle or oxytocin (16 nmol/day) and were maintained on HFD (60% kcal from fat; N = 7–8/group). A: change in energy intake (kcal/day); B: meal size; C: meal frequency; D: meal duration; E: intermeal interval; F: rats (6-h fasted) received continuous infusions of oxytocin vehicle or oxytocin (16 nmol/day) in combination with intraperitoneal injections of CCK-8 (immediately prior to start of dark cycle). Data are expressed as means ± SE. A–E: *P < 0.05 oxytocin vs. vehicle, F: *P < 0.05 oxytocin vehicle + CCK-8 vs. oxytocin + CCK-8.

Fig. 6.

A–D: effects of chronic 3V oxytocin infusions on food intake, body weight gain,. and body composition in DIO rats maintained on a HFD lacking sucrose. DIO rats were maintained on HFD (60% kcal from fat; N = 8–10/group) for 4.5 mo before receiving continuous infusions of vehicle or oxytocin (16 nmol/day). A subset of these rats was euthanized on day 28 while minipumps were left in place in the remaining rats until day 38 as indicated below. E–H: effects of treatment cessation on food intake, body weight gain, and body composition in DIO rats maintained on a HFD lacking sucrose. DIO rats were maintained on HFD (60% kcal from fat; N = 3–5/group) for the duration of the washout study. Minipumps were removed on day 38 (indicated by arrow) from DIO rats that had previously received continuous infusions of vehicle or oxytocin (16 nmol/day). A and E: change in body weight gain; B and F: change in fat mass and lean mass; C and G,: daily energy intake (kcal/day); D and H: change in weekly energy intake (kcal/wk). Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle. For Washout, *P < 0.05 postoxytocin vs. postvehicle.

Fig. 7.

Effects of chronic subcutaneous oxytocin infusions on food intake, body weight gain, 2-h saccharin preference ratio, and kaolin intake in chow-fed rats. Ad libitum fed rats received continuous infusions of vehicle or oxytocin (0, 50, 100, 200 nmol/day) and were maintained on chow (N = 7–9/group). A: change in body weight gain in animals maintained on chow; B: change in daily chow intake (g/day); C: intake of saccharin using two-bottle conditioned taste aversion test; D: daily kaolin consumption (N = 6–10/group). Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.

Fig. 8.

Effects of chronic subcutaneous oxytocin infusions on body weight gain in HFD-fed and chow-fed rats. Ad libitum fed rats received continuous infusions of vehicle or oxytocin (50 nmol/day) across 3 or 13 days and were maintained on chow or HFD (60% kcal from fat; N = 6–12/group). A and B: change in body weight gain in animals maintained on chow or HFD; C and D: daily energy intake (kcal/ay). Data are expressed as means ± SE. *P < 0.05 oxytocin vs. vehicle.