Endocannabinoid Receptor-1 and Sympathetic Nervous System Mediate the Beneficial Metabolic Effects of Gastric Bypass

Abstract

SUMMARY The exact mechanisms underlying the metabolic effects of bariatric surgery remain unclear. Here, we demonstrate, using a combination of direct and indirect calorimetry, an increase in total resting metabolic rate (RMR) and specifically anaerobic RMR after Roux-en-Y gastric bypass (RYGB), but not sleeve gastrectomy (SG). We also show an RYGB-specific increase in splanchnic sympathetic nerve activity and “browning” of visceral mesenteric fat. Consequently, selective splanchnic denervation abolishes all beneficial metabolic outcomes of gastric bypass that involve changes in the endocannabinoid signaling within the small intestine. Furthermore, we demonstrate that administration of rimonabant, an endocannabinoid receptor-1 (CB1) inverse agonist, to obese mice mimics RYGB-specific effects on energy balance and splanchnic nerve activity. On the other hand, arachidonoylethanolamide (AEA), a CB1 agonist, attenuates the weight loss and metabolic signature of this procedure. These findings identify CB1 as a key player in energy regulation post-RYGB via a pathway involving the sympathetic nervous system.

A sympathetic gut connection drives the metabolic benefits of Roux-en-Y gastric bypass

“…Another question that remains is to what extent the well established shifts in the intestinal microbiota following RYGB contribute to mesenteric white fat browing. Ye et al (2020) [9] found a splanchnic nerve-mediated decrease in cecal Bacteroidetes in RYGB-operated mice, which is in line with how this bacterial phyla negatively associate with thermogenic markers in subcutaneous white fat of obese patients [27]. It is also possible that splanchnic efferents regulate microbiota residing in mesenteric white fat itself [28] following RYGB, to influence various cellular processes including thermogenesis.…”

“…Next, because the sympathetic nervous system (SNS) is a major driver of thermogenesis [13][14][15], Ye et al (2020) [9] assessed molecular markers of sympathetic tone in jejunal and mesenteric white fat samples such as the rate-limiting enzyme in noradrenaline production tyrosine hydroxylase (TH). Curiously, this revealed higher TH protein levels in human and mouse jejunal mucosa after RYGB where sympathetic nerve terminals do not normally reach.…”

“…Despite the lack of overt changes in the jejunal immune cell landscape of RYGB-operated mice reported by Ye et al (2020) [9], the possibility still exists that CB1 receptors are downregulated in distinct innate and/or adaptive immune cell types [26], which in turn could regulate the excitability of splanchnic afferent neurons innervating the jejunal mucosa through an unknown secreted factor (Figure 1). Indeed, Ye et al [9] found that denervation of the greater splanchnic nerve in itself led to weight loss in diet-induced obese mice due to reduced food intake, attesting that gutderived signals are relayed via splanchnic afferent neurons to the central nervous system to regulate energy balance. Another question that remains is to what extent the well established shifts in the intestinal microbiota following RYGB contribute to mesenteric white fat browing.…”

“…This could potentially be fulfilled by anaerobic glycosis, which occurs when glucose metabolism predominates in cells and glycolytic rates are high, and can have a sizeable impact on organismal thermogenesis [30]. Going forward, the groundbreaking study of Ye et al (2020) [9] confirms how garnering better insight into the mechanistic underpinnings of weight loss surgeries can delineate new pathways that regulate energy balance to potentially guide the development of alternative, noninvasive treatments for obesity and its comorbidities. The rerouting of ingested food caused by RYGB may 2 downregulate jejunal CB1 receptors in L-cells, peripheral vagal afferent endings, and/or immune cells.…”

“…Writing in Cell Reports , Ye et al (2020) [ 9 ] directly compared resting metabolic rates in RYGB and SG mouse models. Where their approach differs from previous preclinical and clinical studies on the subject is how they opted to perform both direct and indirect calorimetry measurements [ 8 ].…”