Regulation of body weight: Lessons learned from bariatric surgery

Abstract

Background: Bariatric or weight loss surgery is currently the most effective treatment for obesity and metabolic disease. Unlike dieting and pharmacology, its beneficial effects are sustained over decades in most patients, and mortality is among the lowest for major surgery. Because there are not nearly enough surgeons to implement bariatric surgery on a global scale, intensive research efforts have begun to identify its mechanisms of action on a molecular level in order to replace surgery with targeted behavioral or pharmacological treatments. To date, however, there is no consensus as to the critical mechanisms involved.

Scope of review: The purpose of this non-systematic review is to evaluate the existing evidence for specific molecular and inter-organ signaling pathways that play major roles in bariatric surgery-induced weight loss and metabolic benefits, with a focus on Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), in both humans and rodents.

Major conclusions: Gut-brain communication and its brain targets of food intake control and energy balance regulation are complex and redundant. Although the relatively young science of bariatric surgery has generated a number of hypotheses, no clear and unique mechanism has yet emerged. It seems increasingly likely that the broad physiological and behavioral effects produced by bariatric surgery do not involve a single mechanism, but rather multiple signaling pathways. Besides a need to improve and better validate surgeries in animals, advanced techniques, including inducible, tissue-specific knockout models, and the use of humanized physiological traits will be necessary. State-of-the-art genetically-guided neural identification techniques should be used to more selectively manipulate function-specific pathways.

Keywords: Bile acid signaling; Energy balance regulation; Gut hormones; Gut microbiome; Gut-brain communication; Neural controls of food intake.

Figure 1

Comparative effectiveness of obesity treatments over time. Expected average changes in body weight and BMI of hypothetical male and female obese patients at age 40 over 20 years either untreated or treated with standard behavioral techniques and lifestyle changes (light green) in combination with standard anti-obesity drugs (red), hypocaloric diets (green), glucagon-like peptide receptor agonists (GLP1RAs, purple), combination pharmacotherapy (blue), or bariatric surgery (black). Based on non-systematically selected, mostly RCT studies. Note that except for bariatric surgery, most studies were limited to less than 3 years follow-up and typically show weight regain after cessation of interventions.

Figure 2

Schematic diagram depicting the principal pathways and mechanisms potentially involved in the effects of bariatric surgery on body weight and diabetes resolution. 1) Changes in energy metabolism and expenditure are determined by fecal energy loss, gut metabolic demands, and energy used by muscle, brown fat, and other tissues. 2) The altered gut generates changes in circulating hormones and other molecules as well as changes in neural signals carried by primary afferent neurons of vagal and dorsal root ganglia origin that affect all other organs including the brain. 3) In turn, the brain orchestrates changes in behavioral output including changes in energy intake and food choice, which affect both energy balance and gut luminal environment. 4) Changes in autonomic and endocrine outflow from the brain can affect all organs including the gut.

Figure 3

Major candidate signaling mechanisms underlying weight loss-dependent and weight loss-independent beneficial effects of bariatric surgery. Mechanisms affecting body weight through changes in eating behavior and glucose homeostasis through central pathways are shown in yellow-brown. Mechanisms leading to metabolic improvements independent of body weight/adiposity are shown in green. Framing of signaling molecules indicates that their role has been directly tested in transgenic mouse models, or with chronic pharmacological or surgical blockade. Yellow frames indicate evidence for at least partial involvement in effects on food intake and body weight/adiposity with either RYGB or VSG (microbiome, bile acids, leptin/LepR, MC4R, celiac branch of vagus nerve, CGRP neurons in LPBN). Green frames indicate evidence for involvement in improved glucose homeostasis (GLP-1/GLP1R). Purple frames indicate controversial outcomes (TGR5, FXR, PYY/Y2R). Gray frames indicate no effect on outcome of bariatric surgery (Ghrelin, GLP-2, GDF-15, FGF21, brain 5HTR2c, brain GLP1R, brain Y2R, common hepatic branch of vagus nerve). Note that many other hormones besides GLP-1 can activate vagal afferent neurons. Abbreviations, Brain: AGRP, Agouti-related protein; AP, area postrema; CeA, central amygdala; LPBN, lateral parabrachial nucleus; ME, median eminence; NTS, nucleus tractus solitarius; POMC, pro-opio-melanocortin. Periphery: CCK, cholecystokinin; FGF19, FGF21, fibroblast growth factors 19 and 21; FXR farnesoid nuclear receptor; GDF15, growth and differentiation factor-15; GIP, gastric inhibitory polypeptide; NT, neurotensin; OEA, oleyl-ethanolamide; SCT, secretin; GLP-1, glucagon-like peptide-1; GLP1R, glucagon-like peptide-1 receptor; GLP-2, glucagon-like peptide-2.

Figure 4

Mechanisms of bile acid metabolism and signaling potentially involved in the effects of bariatric surgery. Left: Schematic diagram showing the major components of enterohepatic bile acid homeostasis. After synthesis from cholesterol in the liver and transport via the bile duct and gall bladder to the intestinal lumen, where they are mainly involved in lipid absorption, taurine and glycine-conjugated primary bile acids such as TCA and TCDCA are modified to secondary bile acids such as DCA and LCA by microbiota. Ninety percent of bile acids are then re-absorbed by enterocytes in the distal intestine via the apical sodium bile acid co-transporter (ASBT) and a small fraction is lost in the stool. Re-absorbed bile acids are then transported back to the liver to provide feedback control over bile acid synthesis together with the gut hormone FGF-19/15 which is stimulated via the nuclear farnesoid bile acid receptor (FXR) in enterocytes. Activation of the Takeda G-protein coupled receptor (TGR5) by bile acids stimulates the release of GLP-1 from enteroendocrine cells and activates vagal afferents. From the hepato-portal circulation, bile acids also gain access to the general circulation, where they interact with FXR and TGR5 in other organs and tissues, notably in brown fat tissue to generate heat, and in the brain, where they can affect food intake and autonomic/endocrine outflow. Right: After RYGB and following bile diversion to the distal ileum, total bile acids are increased and bile acid composition changes both intraluminal and in the plasma, due to changes in the luminal environment and microbiome. Increased re-uptake of bile acids such as β-muricholic acid (βMA), a potent FXR agonist, leads to increased GLP-1 release and improvement in insulin secretion. Increased bile acid concentrations in the lamina propria lead to increased activation of vagal afferents that suppress food intake. The effects of changes in systemic bile acid signaling after RYGB and bile diversion are not known.