A 2017 study co-led by UCSF researchers found that a high-fat diet (HFD) is associated with the accumulation of inflammatory cells called microglia in the hypothalamus, which in turn increases the susceptibility of mice to overeat and gain excess weight. To investigate whether microglia might separately contribute to the brain’s ability to regulate blood glucose, the researchers conducted a new study. The results were surprising.
“The newest wave of diabetes medicines, including GLP-1 receptor agonists, exert their effects in part by targeting the brain,” said endocrinologist Suneil Koliwad, MD, PhD, chief of the UCSF Division of Endocrinology and Metabolism and a senior author of both studies. “Based on the striking effectiveness of these new medicines, there is interest in whether there are other ways to target the brain and then, through the autonomic nervous system, affect the way the brain governs metabolic function.”
A paradoxical finding
Again using mouse models, the researchers specifically targeted microglia in a variety of ways. Whenever they experimentally toned down the inflammatory activation of microglia, they observed that the mice had a more substantial worsening of blood sugar while on a HFD. Moreover, this excess glucose elevation occurred even though the same manipulation of microglia reduced their body weight and fat mass. Conversely, when the researchers used a genetic strategy to increase microglial pro-inflammatory signaling, the glucose tolerance of the mice unexpectedly improved whether they were lean or obese and regardless of the dietary circumstance.
The investigators went on to show that microglia in the brain influence blood glucose by helping control the signals sent by the brain to the pancreatic cells that secrete insulin (beta cells) following meal consumption. This “top-down” signaling occurs through the parasympathetic nervous system. In short, the team found that microglial activation helps determine the strength of parasympathetic signals that the brain sends to the pancreas, thus significantly influencing insulin production and therefore glucose control.
The study results indicate that microglia improve blood glucose control through a mechanism separate from the one that regulates body weight – an unanticipated finding. This offers a novel perspective on how to potentially limit the impairment of glucose tolerance commonly associated with obesity by targeting microglia, an entirely new approach to understanding and treating this metabolic disorder.
“This study shows that microglia influence the way the brain controls blood glucose in a manner that is independent of the way that they influence how the brain regulates body weight,” Koliwad said. “We found that microglia can sense dietary factors and, upon doing so, undergo a form of activation that allows them to secrete chemical mediators that influence local nerve cells. Those cells respond by triggering signals down the parasympathetic nervous system. This regulates the way the pancreas makes insulin in response to the food that’s consumed.”
This work is part of a long-standing collaboration between the Koliwad Lab and University of Washington investigators led by Joshua Thaler, MD, PhD.
Hope for a new glucose control mechanism
The Koliwad Lab investigates how innate immune cell types, such as microglia in the brain, sense nutrients in tissues throughout the body and how this sensory capacity impacts metabolic function.
“We need to have a rich array of treatment options if we are to help the increasing population of people with diabetes,” Koliwad said. “We hold a lot of hope that we can target microglia in the hypothalamus to control blood glucose. This would provide a new method that is unique and distinct from the existing approaches, most of which target the same or similar mechanisms in different ways. This work has the potential to add a new mechanism that doesn't currently exist as a drug target.”
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