The Brain Controls Insulin Action

Insulin regulates blood glucose primarily by two mechanisms:

1. Suppressing glucose production by the liver
2. Enhancing glucose uptake by other tissues, particularly muscle and liver

Since the cells contained in liver, muscle and other tissues respond directly to insulin stimulation, most people don't think about the role of the brain in this process.  An interesting paper just published in Diabetes reminds us of the central role of the brain in glucose metabolism as well as body fat regulation (1).  Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin's ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin's ability to cause muscle to take up glucose is mediated by its effect on the brain. 


They went further, showing that an obesity-promoting diet suppresses the brain's ability to regulate peripheral glucose.  It has been known for a long time that these diets cause insulin and leptin resistance in the brain of animal models, and that this loss of hormone sensitivity contributes to the development of obesity.  Now, this paper suggests that brain insulin resistance contributes to whole-body insulin resistance under these conditions.

This isn't the first study to demonstrate that the brain regulates glucose metabolism in the rest of the body.  My excellent colleague Dr. Greg Morton recently wrote a detailed review paper on leptin's actions in the brain to regulate blood glucose (2)*, in which he described some previous studies that showed:

• Suppressing insulin signaling in the hypothalamus (in the brain) causes insulin resistance in the liver
• Increasing insulin signaling in the hypothalamus enhances the suppression of glucose production by the liver

Furthermore, Dr. Christoph Buettner published a paper this year showing that infusing insulin into the brain influences lipolysis, the release of fatty acids by fat tissue (3)**.  This demonstrates that the brain has direct control over the amount of fat leaving fat cells. 

All tissues contain nerves that are connected to the brain and allow the brain to monitor and influence various tissue processes.  In the 21st century, as our knowledge advances, I believe that mainstream research and clinical practice will come to see obesity, the metabolic syndrome and diabetes as disorders that are critically dependent on the functions of the brain.  This has already occurred for obesity, and diabetes may be next.


* Dr. Morton has been studying the fascinating phenomenon that leptin infused into the brains of rats can totally rescue them from "type 1" diabetes, even if they have no pancreatic beta cells left.  After a few days of leptin treatment, the rats have totally normal fasting blood glucose and normal glucose tolerance, despite the fact that they have no insulin whatsoever.  This demonstrates the powerful ability of the brain to regulate glucose metabolism in the whole body.  I will note that they use high doses of leptin-- this isn't an effect that a normal circulating concentration of leptin can produce. 

** One of the models he used to study this is the NIRKO mouse, which lacks insulin receptors specifically in the brain. These mice "exhibit unrestrained lipolysis and decreased de novo lipogenesis in [white adipose tissue] (4)."  To understand the full irony of this, consider that these mice are more susceptible to obesity than normal mice (5).  In other words, they get fatter than normal mice despite increased fat release from fat cells.  This illustrates the limitations of focusing on lipolysis to understand obesity.  Lipolysis doesn't reduce fat stores if the fat isn't being burned after its release, because it just does a loop through the circulation and ends up back in the fat tissue again (or possibly in muscle or liver, which is worse) via an increased rate of fatty acid esterification.  Changes in fat mass have to result from changes that alter the amount of energy entering or leaving the body, unless you're building a whole lot of muscle or storing fat in your liver/muscles (bad).  The body is designed to store excess energy in fat tissue at all costs, because failing to do so causes severe metabolic problems (e.g., lipodystrophy).  Therefore, excess energy will be stored in fat cells regardless of the amount of lipolysis occurring, as long as esterification is not severely impaired.  It appears that the body has redundant mechanisms for getting fat into fat cells (reducing noradrenaline produced by nerve terminals, increasing insulin, increasing ASP), demonstrating the importance of this process, although it is not fully redundant since uncontrolled type 1 diabetes causes excessive fat loss.