Gut-Brain Cross-Talk in Metabolic Control

Abstract

Because human energy metabolism evolved to favor adiposity over leanness, the availability of palatable, easily attainable, and calorically dense foods has led to unprecedented levels of obesity and its associated metabolic co-morbidities that appear resistant to traditional lifestyle interventions. However, recent progress identifying the molecular signaling pathways through which the brain and the gastrointestinal system communicate to govern energy homeostasis, combined with emerging insights on the molecular mechanisms underlying successful bariatric surgery, gives reason to be optimistic that novel precision medicines that mimic, enhance, and/or modulate gut-brain signaling can have unprecedented potential for stopping the obesity and type 2 diabetes pandemics.

Keywords: appetite; bariatric surgery; brain; diabetes; energy balance; gut; metabolic syndrome; obesity; pharmacology; satiety.

Figure 1. Contribution of Genetic Heritage and Modern Lifestyle to Body Weight

Body weight and metabolic health are determined by the interaction of genetic susceptibility and environmental influences. Major contributors to human adiposity include dietary quality and palatability, exercise habits, smoking, alcohol consumption, age, sleep, and pharmacology. These factors both directly and indirectly impact energy intake and/or energy expenditure to govern energy homeostasis.

Figure 2. Gut-Brain Cross-Talk in Eating Behavior

Gut hormones and afferent neurons are key signals in gut-brain communication and human energy metabolism. Brain regions, traditionally divided into homeostatic (hypothalamus and NTS) and hedonic (VTA – Nac), sense diverse humoral factors and generate signals in cooperation with cognitive processes and information arising from visual, gustatory and olfactory stimuli to influence feeding behavior. PFC, prefrontal cortex; NAc, nucleus accumbens; VTA, ventral tegmental area; Hypo, hypothalamus; NTS, nucleus tractus solitaries.

Figure 3. Gut-Brain Adjustments following Bariatric Surgery

Cartoon overview of the biological adjustments in the gut-brain axis following bariatric surgery in obese subjects. In the gut, meal-induced peptides and microbiota are significantly altered following bariatric surgery. These adjustments contribute to improved glycemic control and to numerous behavioral adjustments that collectively contribute to reduced caloric intake following the surgery.

Figure 4. Understanding Gut-Brain Cross-Talk: Therapeutic Targets for Treating Metabolic Disease

Current and promising therapeutic targets for treating obesity, type 2 diabetes, and associated co-morbidities are summarized. Future efforts hope to identify refined polypharmacy approaches intended to match the efficacy of the bariatric surgeries to cure obesity and diabetes. LepR, leptin receptor; InsR, insulin receptor; TrkB, tyrosine receptor kinase B; IGF1R, insulin-like growth factor 1 receptor; GLP-1R, glucagon-like peptide-1 receptor; FGFRs, fibroblast growth factor receptors; MC4R, melanocortin receptor 4; GHSR, growth hormone secretagogue receptor; D2R, dopamine receptor D2; 5-HTR, serotonin receptors; AChR, acetylcholine receptors; CB1, cannabinoid receptor type 1; NPY-R, neuropeptide Y receptors; CTR, calcitonin receptor; BRS-3, Bombesin receptor subtype 3; AJP, Apelin receptor; GcGR, glucagon receptor; TNFR, tumor necrosis factor receptors; LDLR, low-density lipoprotein receptor; CaSR, calcium sensing receptor; GPR, G protein-coupled receptor; TRPM5, transient receptor potential cation channel subfamily M member 5; CCK-B, cholecystokinin B receptor; SSTR, somatostatin receptor; ACh-M, muscarinic acetylcholine receptors; GIP-R, gastric inhibitory polypeptide receptor; CX3CR1, fractalkine receptor.