Bariatric surgeries, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy, are highly effective at treating obesity and many of its associated metabolic complications. However, the mechanisms by which gastric bypass affects these metabolic parameters is unclear. New research implicates the sympathetic nervous system and endocannabinoid receptor 1 (CB1) in these effects.

“Our lab is trying to understand the molecular pathways behind the metabolic regulation of variable bariatric surgeries,” explains corresponding author Mohamad Mokadem. Previous studies had indicated that RYGB resulted in reduced food intake and increased energy expenditure (leading to weight loss) and that pre-ganglionic sympathetic motor neurons were involved in mediating weight loss following RYGB. However, the exact details of these mechanisms were unclear, and it was not known whether similar effects were seen with other types of bariatric surgery.

Credit: Sam Whitham/Springer Nature Limited

In mouse models of RYGB and sleeve gastrectomy, the researchers used direct and indirect calorimetry to assess total energy expenditure and resting metabolic rate. Only RYGB induced an increase in energy expenditure, specifically in resting metabolic rate. “Using molecular screening tools, radiolabelled glucose uptake under PET scan imaging and neurophysiologic recording of nerve fibres we showed that only visceral mesenteric adipose displays evidence of increased sympathetic tone and active thermogenesis after RYGB,” says Mokadem.

The researchers also found that the effects of RYGB on energy balance and nerve activity could be mimicked by administering a CB1 inverse agonist (rimonabant) to obese mice. Conversely, administering a CB1 agonist (anandamide) to mice that underwent RYGB reduced the weight loss and metabolic improvements seen with RYGB. The researchers suggest that these findings demonstrate that RYGB downregulates CB1 in the intestine, which activates splanchnic sympathetic nerve activity to induce ‘browning’ of visceral white adipose tissue. This sympathetic-mediated thermogenesis results in increased resting metabolic rate, which eventually leads to weight loss.

“The first interesting and significant finding of our study was how delicate this brain–gut regulation of sympathetic-mediated thermogenesis post-RYGB is,” explains Mokadem. “The mesentery was selectively activated but the pancreas, for example, was spared, keeping glucose homeostasis in control.” Interestingly, CB1 activity was not altered in the hypothalamus after RYGB, which suggests that peripheral, rather than central, CB1 has a role in energy regulation after RYGB. The effect of rimonabant on energy balance is mitigated in the setting of splanchnic denervation, further supporting these findings.

“We are currently trying to localize the important regulatory tissues within the intestines that express CB1 and are also trying to identify which cellular pathway is most important for the metabolic effects of RYGB,” concludes Mokadem.