Inter-organ communication: a gatekeeper for metabolic health

Abstract

Multidirectional interactions between metabolic organs in the periphery and the central nervous system have evolved concomitantly with multicellular organisms to maintain whole-body energy homeostasis and ensure the organism's adaptation to external cues. These interactions are altered in pathological conditions such as obesity and type 2 diabetes. Bioactive peptides and proteins, such as hormones and cytokines, produced by both peripheral organs and the central nervous system, are key messengers in this inter-organ communication. Despite the early discovery of the first hormones more than 100 years ago, recent studies taking advantage of novel technologies have shed light on the multiple ways used by cells in the body to communicate and maintain energy balance. This review briefly summarizes well-established concepts and focuses on recent advances describing how specific proteins and peptides mediate the crosstalk between gut, brain, and other peripheral metabolic organs in order to maintain energy homeostasis. Additionally, this review outlines how the improved knowledge about these inter-organ networks is helping us to redefine therapeutic strategies in an effort to promote healthy living and fight metabolic disorders and other diseases.

Keywords: energy homeostasis; inter-organ communication; metabolism; obesity.

Figure 1. Inter‐organ communication under feeding conditions

Food ingestion stimulates the secretion of several molecules such as GLP‐1, secretin and LEAP2. These gut hormones signal to the brain to reduce food intake. FGF19 is produced by the intestine and reduces bile acid (BA) synthesis. GLP‐1 and secretin will also stimulate insulin (and reduce glucagon) secretion by the pancreas. In turn, insulin will promote glycogen production and glucose uptake in muscle, decrease glucose production and increase lipogenesis in liver, and increase glucose uptake and lipogenesis from circulating glucose and triglycerides (TGs) in WAT. Leptin, produced by white adipocytes, will act in the CNS to repress food intake. Moreover, insulin can target the brain in order to decrease lipolysis in WAT and glucose production in liver.

Figure 2. Inter‐organ communication under fasting conditions

Ghrelin is a gut hormone secreted under fasting conditions. It targets the brain to increase food intake. Pancreatic glucagon secretion is also increased by ghrelin, and directly by low blood glucose levels. Glucagon will target the liver to decrease glycolysis and increase hepatic gluconeogenesis and glycogenolysis, as well as WAT to increase lipolysis. Ghrelin can promote adiposity by increasing WAT lipid synthesis and reducing WAT fatty acid (FA) oxidation. Fasting also stimulates the secretion of the adipokines asprosin and adiponectin that will act through the brain to decrease energy expenditure and promote food intake. Asprosin can also increase hepatic gluconeogenesis, whereas adiponectin reduces lipogenesis and increases hepatic FA oxidation. Increased hepatic FGF21 levels under fasting conditions increase lipolysis in WAT.

Figure 3. Inter‐organ communication under cold exposure

Cold stimuli, sensed by neurons in the skin, activate the thermoregulatory hypothalamic regions of the brain that will secrete orexin and BMP8B to stimulate BAT thermogenesis. Moreover, the SNS is responsible for the local production of NE in BAT. The hypothalamic–pituitary–thyroid axis is also activated in response to cold and promotes the release of thyroid hormones (T3 and T4) in order to contribute to the activation of BAT thermogenesis. Cold exposure can also trigger muscle shivering and thus the production of the myokine irisin. Irisin can in turn stimulate BAT thermogenesis. If cold exposure is sustained over time, WAT undergoes browning and can contribute to thermogenesis. Irisin is one of the molecules that can trigger this process. In addition, cold‐dependent hepatic FGF21 and BA secretion contribute to the browning of WAT. Finally, FGF21 can be produced by WAT; and BMP8b and FGF21 can be produced by BAT, after cold activation and promote thermogenesis in a paracrine manner.