Role of the vagus nerve in the development and treatment of diet-induced obesity

Abstract

This review highlights evidence for a role of the vagus nerve in the development of obesity and how targeting the vagus nerve with neuromodulation or pharmacology can be used as a therapeutic treatment of obesity. The vagus nerve innervating the gut plays an important role in controlling metabolism. It communicates peripheral information about the volume and type of nutrients between the gut and the brain. Depending on the nutritional status, vagal afferent neurons express two different neurochemical phenotypes that can inhibit or stimulate food intake. Chronic ingestion of calorie-rich diets reduces sensitivity of vagal afferent neurons to peripheral signals and their constitutive expression of orexigenic receptors and neuropeptides. This disruption of vagal afferent signalling is sufficient to drive hyperphagia and obesity. Furthermore neuromodulation of the vagus nerve can be used in the treatment of obesity. Although the mechanisms are poorly understood, vagal nerve stimulation prevents weight gain in response to a high-fat diet. In small clinical studies, in patients with depression or epilepsy, vagal nerve stimulation has been demonstrated to promote weight loss. Vagal blockade, which inhibits the vagus nerve, results in significant weight loss. Vagal blockade is proposed to inhibit aberrant orexigenic signals arising in obesity as a putative mechanism of vagal blockade-induced weight loss. Approaches and molecular targets to develop future pharmacotherapy targeted to the vagus nerve for the treatment of obesity are proposed. In conclusion there is strong evidence that the vagus nerve is involved in the development of obesity and it is proving to be an attractive target for the treatment of obesity.

Figure 1. The vagus nerve enables bidirectional communication between peripheral organs and the brain

The vagus nerve innervates a plethora of peripheral organs; sensory information is communicated from each of these organs to the brain via vagal afferent fibres (red arrows), and the brain controls motor function of each organ by signalling through vagal efferent fibres (black arrows). As is indicated by the thicker red line, vagal afferent fibres outnumber vagal efferent fibres. The vagus nerve has been implicated in mediating an extensive range of physiological functions. Highlighted are some of the different functions that are attributable to the vagus nerve innervating different peripheral organs, although not all have been well characterized. This figure is not meant to represent an exhaustive list of all the functions of the vagus nerve, but rather to emphasize the complexity of vagal innervation and provide a flavour of the extensive functions the vagus nerve is involved in regulating.

Figure 2. The role of the vagus nerve in gut–brain signalling

In the presence of food, enteroendocrine cells will release anorectic hormones that inhibit food intake. In the absence of food, different enteroendocrine cells of the gut release orexigenic hormones that stimulate food intake. Vagal afferents neurons (red), located in the nodose ganglia, express chemoreceptors on their terminals in the gut that sense these hormones and mechanoreceptors that sense distension. These satiating signals are conveyed to the nucleus tractus solitarii (NTS) in the hindbrain. NTS neurons (1) are activated and reduce meal size and duration, (2) signal to higher order neurons in the forebrain to regulate reward or energy homeostasis, and/or (3) signal to the vagal efferent neurons in the dorsal motor nucleus (DMN) in the hindbrain. Vagal efferent fibres (blue) activate stimulatory or inhibitory postganglionic neurons to control digestion and absorption.

Figure 3. Plasticity in vagal afferent neurons

Approximately 40% of vagal afferent neurons innervate the gut. These neurons express two different neurochemical phenotypes that reflect the nutrient status. In response to nutrients, there is distension of the stomach and release of the satiating hormone cholecystokinin. Circulating leptin enhances the sensitivity of vagal afferent neurons to these peripheral signals, promotes vagal afferent neuron expression of receptors and neuropeptides associated with inhibiting food intake (anorexigenic phenotype – red neurons), and inhibits expression of receptors and neuropeptides associated with stimulating food intake (orexigenic phenotype – green neurons). In the absence of food, ghrelin and cannabinoids are released and inhibit expression of the anorexigenic phenotype in preference for the orexigenic phenotype in vagal afferent neurons. Release of anorexigenic neuropeptides from vagal afferent neurons to the NTS shortens the duration of meals and reduces their size, while the release of orexigenic neuropeptides prolongs meals and increases their size.

Figure 4. Loss of plasticity in vagal afferent neurons in response to chronic ingestion of a high‐fat diet

A, in lean animals, leptin (released from adipocytes or the gut) increases expression of the immediate early gene, early growth response‐1 (EGR‐1), which in the absence of gastrointestinal signals is localized in the cytoplasm. Postprandially, CCK is released and activates CCK‐A receptors on vagal afferent neurons, resulting in translocation of EGR‐1 to the nucleus. EGR‐1 induces the synthesis of the anorectic neuropeptide cocaine and amphetamine‐regulated transcript (CART), and the Y2 receptor that binds the satiating hormone PYY3‐36. Release of CART from vagal afferent neurons into the NTS activates NTS neurons resulting in meal termination. B, in animals chronically fed a high‐fat diet, circulating levels of leptin are high, but vagal afferent neurons become insensitive to it. In response to a meal, the stomach is distended and CCK is released, but leptin‐resistant vagal afferent neurons have reduced sensitivity to these peripheral signals and vagal afferent neurons and remain stuck in a fasted phenotype, expressing the cannabinoid 1 receptor (CB1) and melanin concentrating hormone‐1 receptor (MCH1R) along with melanin concentrating hormone (MCH). Release of MCH from vagal afferent neurons into the NTS increases meal size and duration. C, similarly, knocking down leptin receptors in vagal afferent neurons (VAN) is sufficient to drive hyperphagia in chow‐fed animals. In the absence of leptin signalling, there is reduced sensitivity to CCK and plasticity is lost.

Figure 5. Vagal nerve stimulation effect on body weight

A, in preclinical studies, vagal nerve stimulation (VNS) of the abdominal organs reduced body weight in lean animals and prevented weight gain in obese animals, and reduced caloric intake and increased satiation in all animals. Non‐invasive transcutaneous auricular VNS increased energy expenditure. VNS increased c‐Fos expression in the NTS, suggesting that vagal afferent neurons were activated. Gastric secretion was reduced, and gastric motility increased with VNS in a subset of lean animals. B, VNS is FDA‐approved for the treatment of refractory epilepsy and depression. Unilateral left cervical VNS with a range of different parameters reduced weight and sweet cravings in patients treated for depression or epilepsy, and this correlated to BMI. Energy expenditure was also found to be increased with left cervical VNS.

Figure 6. Vagal blockade promotes weight loss in obese subjects

A, in clinical trials of obese subjects, intermittent vagal blockade (VBLOC) significantly improved symptoms of obesity. VBLOC inhibits both afferent signalling as demonstrated by altered brain imaging and efferent function indicated by reduced pancreatic secretion and gastric contractions. In diabetic subjects VBLOC reduced body weight, glucose‐bound haemoglobin, and fasting plasma glucose levels. B, electrodes are placed on the anterior and posterior vagal trunks near the oesophago‐gastric junction along with a subcutaneously implanted neuroregulator. C, a mechanism for VBLOC‐induced weight loss is proposed. In obesity, vagal afferent neurons constitutively express the orexigenic neuropeptide melanin concentrating hormone (MCH). MCH prolongs meals, resulting in hyperphagia and weight gain. VBLOC may prevent release of MCH and MCH‐induced hyperphagia.