Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats

Abstract

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into ad libitum fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [11C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [11C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.

The Phantom Satiation Hypothesis of Bariatric Surgery

“…For instance, duodenal-jejunal exclusion, a procedure that leaves the stomach intact, is significantly less effective at reducing feeding or body weight in animals and humans ( Geloneze et al, 2009 ; Kindel et al, 2011 ; Alvarez et al, 2020 ). In further support of our model, adding gastric vagotomy to gastrectomy does not produce further weight-loss in laboratory rodents ( Hankir et al, 2016 ; Dezfuli et al, 2018 ). This is logical considering that gastric vagotomy already occurred in bypassed subjects.…”

Roux-en-Y gastric bypass in rat reduces mu-opioid receptor levels in brain regions associated with stress and energy regulation

“…Rats receiving RYGB display higher morphine self-administration rates than lean, obese, and caloric intake-matched counterparts [16]. The downregulated MOR signaling reported here and by others supports this notion [33]. No studies have of yet investigated the effect of administered MOR agonists or antagonists on feeding or motivated behavior following RYGB, which could provide further insight into the induced changes in reward signaling.…”

“…RYGB has been shown to reduce preferences for highly palatable sugars and fat in rats, an effect that had been initially attributed to altered reward functions [29, 30], while more recent works in rats and human debate that notion [31, 32]. Moreover, RYGB surgery in HF diet-fed rats has been demonstrated to reduce brain MOR availability in the hypothalamus, amygdala, and striatum as measured by [ 11 C]carfentanil PET imaging, and reduce MOR protein expression in the striatum and prefrontal cortex, compared to those receiving sham surgery [33] These changes in opioid signaling were accompanied by decreased HF diet intake and preference in the RYGB group.…”

Neural and Molecular Mechanisms Involved in Controlling the Quality of Feeding Behavior: Diet Selection and Feeding Patterns

“…Subcutaneous administration of the non-selective opioid receptor antagonist, naltrexone, reduced the acquisition of fat reinforcement, but not the expression of learned reinforcement [ 167 ]. In rats, a roux-en-Y gastric bypass markedly suppressed fat intake and preference, and downregulated MOR protein levels in the striatal and prefrontal areas [ 168 ]. Overall, the current literature has suggested that the opioid system plays a major role in fat preference.…”