Chronic suppression of μ-opioid receptor signaling in the nucleus accumbens attenuates development of diet-induced obesity in rats

Abstract

Objective: To test the hypothesis that micro-opioid receptor signaling in the nucleus accumbens contributes to hedonic (over)eating and obesity. To investigate the effects of chronic micro-opioid antagonism in the nucleus accumbens core or shell on intake of a palatable diet, and the development of diet-induced obesity in rats.

Methods and design: Chronic blockade of micro-opioid receptor signaling in the nucleus accumbens core or shell was achieved by means of repeated injections (every 4-5 days) of the irreversible receptor antagonist beta-funaltrexamine (BFNA) over 3-5 weeks. The diet consisted of either a choice of high-fat chow, chocolate-flavored Ensure and regular chow (each nutritionally complete) or regular chow only. Intake of each food item, body weight and body fat mass were monitored throughout the study.

Results: The BFNA injections aimed at either the core or shell of the nucleus accumbens resulted in significantly attenuated intake of palatable diet, body weight gain and fat accretion, compared with vehicle control injections. The injection of BFNA in the core did not significantly change these parameters in chow-fed control rats. The injection of BFNA in the core and shell differentially affected intake of the two palatable food items: in the core, BFNA significantly reduced the intake of high-fat, but not of Ensure, whereas in the shell, it significantly reduced the intake of Ensure, but not of high-fat, compared with vehicle treatment.

Conclusions: Endogenous micro-opioid receptor signaling in the nucleus accumbens core and shell is necessary for palatable diet-induced hyperphagia and obesity to fully develop in rats. Sweet and non-sweet fatty foods may be differentially processed in subcomponents of the ventral striatum.

Fig. 1

Nucleus accumbens administration of β-funaltrexamine (BFNA) attenuates palatable diet-induced body weight gain. Separate groups of rats (n = 4–7/group) received multiple injections of BFNA (10 nmol/side) or vehicle (arrows) into the nucleus accumbens core (left panel) or shell (right panel) and were fed either a three-choice palatable diet consisting of liquid Ensure, high-fat chow, and regular chow (diet), or just regular chow (core injections only). Compared to vehicle control injections, BFNA significantly attenuated palatable diet-induced body weight gain starting at day 10 with core injections and at day 9 with shell injections (# p<0.05, based on ANOVA and Bonferroni-adjusted multiple posthoc comparisons). Core injections of BFNA did not change body weight gain on regular chow diet. Body weight gain was significantly increased by the palatable diet compared to chow diet (* p<0.05).

Fig. 2

Nucleus accumbens administration of BFNA attenuates palatable diet-induced fat mass gain. Compared to vehicle control injections, BFNA (for details of injections see legend to Fig. 1) attenuated palatable food-induced gain in total fat mass (as measured with NMR; A, C) and reduced total fat pad weights (B, D) with both core and shell injections (# p<0.05). Core injections of BFNA did not change fat mass gain and fat pad weights on regular chow diet. However, fat mass and fat pad weights were significantly increased by the palatable diet compared to chow diet (* p<0.05). IWAT, inguinal; EWAT, epididymal; RPWAT, retroperitoneal; VWAT, visceral abdominal; Total WAT=total white adipose tissue.

Fig. 3

Nucleus accumbens administration of BFNA attenuates palatable food intake. Multiple core injections of BFNA (for details of injections see legend to Fig. 1) significantly reduce intake of high-fat diet but not Ensure (A, B), while shell injections reduce intake of Ensure but not high-fat diet (D, E) (# p<0.05, based on repeated measures ANOVA followed by Bonferroni-adjusted multiple comparisons). Total energy intake from all dietary components was also significantly reduced with BFNA injections into either core (C) or shell (F), compared with vehicle control injections.

Fig. 4

Nucleus accumbens core and shell administration of BFNA differentially affects high-fat and Ensure intake. A: Percentage of total calorie intake from Ensure (white bars), high-fat chow (gray bars), and regular chow (black bars) for vehicle and BFNA treated rats with accumbens core and shell injections. B: Percent inhibition of Ensure and high-fat diet intake by BFNA in the core and shell. * p < 0.05 between suppression of ensure and high-fat intake.

Fig. 5

Histological verification of nucleus accumbens injection sites. Location of injection sites aimed at the nucleus accumbens core (left panel) and shell (right panel) superimposed on images from a stereotaxic atlas (35). Note that rats with shell injections were only tested with palatable food. Two rats with bilateral injection cannulas located in the caudal shell (gray triangles) and injected with BFNA did not show reduced body weight and food intake and were not included in the analysis.

Fig. 6

Functional verification of accumbens core injection sites. Two-hour high-fat intake of rats with bilateral cannulas aimed at either the core or shell of the nucleus accumbens and assigned to either chronic vehicle or BFNA-treatment. Intake for left and right cannula injections was tested separately and the mean intake from both sides was used for each rat. BFNA stimulated high-fat intake to a similar extent in all 4 groups.