Obesity leads to insulin resistance by boosting the sympathetic nervous system’s activity and increasing the release of the stress hormone norepinephrine, suggests a recent study.
Research from Rutgers Health and additional institutions implies that stress hormones—rather than faulty cellular insulin signaling—might be the main reason behind diabetes connected to obesity.
Published in Cell Metabolism, this research could significantly shift our understanding of the mechanisms behind obesity-induced insulin resistance and potential treatment strategies.
“We have been examining the fundamental processes by which obesity triggers diabetes. Given that diabetes costs the U.S. over $300 billion annually, this inquiry is critically important,” stated Christoph Buettner, chief of endocrinology, metabolism, and nutrition at Rutgers Robert Wood Johnson Medical School and the leading author of the study.
Traditionally, scientists believed that obesity leads to diabetes by hindering the insulin signaling pathways in liver and fat cells. However, the new findings reveal that excess eating and weight gain activate the body’s sympathetic nervous system—responsible for the “fight or flight” response—causing increased levels of stress hormones like norepinephrine and epinephrine that undermine insulin’s function, even though the insulin signaling process remains intact.
The researchers noticed that overeating in typical mice raises norepinephrine levels within days, demonstrating how swiftly excess food can trigger the sympathetic nervous system.
To investigate the effects of this increased hormone production on disease progression, they used a newly engineered strain of mice that are genetically similar to normal mice but unable to produce stress hormones called catecholamines outside of their brains and central nervous systems.
When these mice were given a diet rich in fats and sugars that typically induces obesity, they ingested the same amount of calories and became just as overweight as normal mice, yet they did not develop metabolic diseases.
“We were excited to find that our modified mice consumed just as much food, which demonstrates that the differences in insulin sensitivity and the absence of metabolic disease are not due to eating less or having lower obesity levels, but rather because their stress hormone levels were significantly lower. These mice don’t produce excess stress hormones to prohibit insulin’s actions; hence, insulin resistance doesn’t occur as obesity progresses.”
This discovery may clarify why some obese individuals develop diabetes while others do not and explain why stress can exacerbate diabetes even with minimal weight gain.
“Various stressors—financial troubles, relationship issues, the anxieties of living in unsafe conditions, discrimination, or even the bodily stress from excessive drinking—can all increase the likelihood of diabetes and interact with the metabolic stress of obesity,” Buettner explained.
“Our conclusion that obesity primarily contributes to metabolic diseases through heightened stress hormone levels offers new perspectives on the shared origins of these factors that elevate diabetes risk. Stress and obesity essentially operate through the same fundamental mechanism in promoting diabetes, driven by the actions of stress hormones.”
While it’s well-known that catecholamines can hinder insulin action, the new study implies that this might be the core reason behind insulin resistance in cases of obesity. Although stress hormones have long been recognized to work against insulin by increasing blood sugar and lipid levels, it was unexpectedly found that insulin signaling can remain operational even when one is insulin-resistant, such as in obesity. The enhanced activity of stress hormones effectively accelerates blood sugar and fat levels, overpowering insulin’s “braking” effect despite it remaining constant.
“Some of my colleagues were initially surprised to learn that insulin resistance can exist even when cellular insulin signaling is functional. However, it’s essential to note that the stress hormones’ effects are mediated through different signaling pathways compared to insulin signaling. This distinction explains why insulin’s ability to control the release of sugar and fat into the blood is compromised, even with functional signaling, because stress signaling predominates.”
The study suggests that treatments aimed at lowering catecholamines—which refer to the stress-related hormones and neurotransmitters from the sympathetic nervous system and adrenal gland—might offer potential for the prevention or management of diabetes. Nevertheless, existing medications that block these hormones, often used for high blood pressure, have not shown significant improvements in diabetes management. This might be due to their ineffectiveness at blocking relevant receptors or their complex interactions in the brain and body, Buettner noted.
Buettner and the study’s lead author, Kenichi Sakamoto, an assistant professor of endocrinology at Robert Wood Johnson Medical School, are planning to conduct human trials to validate their results. They are also investigating the role of the sympathetic nervous system in different diabetes types, including Type 1.
“We would like to examine whether short-term overconsumption—similar to what many experience during holiday seasons by gaining a few pounds—enhances insulin resistance through increased sympathetic nervous system activity,” Buettner added.
The insights gained might lead to innovative treatment methods for combating insulin resistance, diabetes, and metabolic disorders, focusing on minimizing stress hormones rather than solely enhancing insulin signaling.
“We hope this research provides a new perspective on insulin resistance,” Buettner said. “It may also clarify why current diabetes medications, aside from insulin itself, do not directly enhance cellular insulin signaling.”
