A potential new mechanism has been found by researchers in which obesity induces insulin resistance, a central driver of type 2 diabetes and metabolic diseases. The study findings suggest that overnutrition-induced sympathetic nervous system (SNS) overactivation may be a primary pathway leading to insulin resistance, rather than impairments in cellular insulin signaling. This was previously the most widely accepted explanation.
In the study, published in Cell Metabolism, Sakamoto and colleagues examined the ways in which the SNS, known for its role in the body’s fight-or-flight response, could influence metabolic disorders. The role of SNS in obesity has been controversial, with some studies reporting increased SNS activity in obese individuals, while others have noted the opposite. By using direct measurements of SNS activity, such as nerve recordings and norepinephrine (NE) turnover, they sought to resolve this discrepancy and clarify the SNS’s impact on insulin sensitivity.
The mouse model study involved a targeted deletion of the tyrosine hydroxylase gene in peripheral tissues, resulting in mice referred to by researchers as THΔper mice. This gene deletion specifically disrupts catecholamine production, such as norepinephrine and epinephrine, in peripheral tissues while leaving central nervous system functions intact. This allowed researchers to observe the effects of decreased sympathetic nervous system (SNS) activity in peripheral tissues without impacting the brain’s control over the SNS.
In this study, THΔper and wild-type (WT) mice were fed a high-fat diet (HFD) to investigate the effects of overnutrition. WT mice developed insulin resistance with increased body fat, glucose intolerance, and elevated fasting glucose levels, driven by increased sympathetic nervous system (SNS) activity and elevated norepinephrine (NE) levels, which impaired lipolysis in white fat. In contrast, THΔper mice, which had reduced peripheral catecholamine production, showed better glucose tolerance, normal fasting glucose, and improved insulin sensitivity without changes in insulin signaling pathways, indicating protection against insulin resistance. With long-term HFD, WT mice developed catecholamine resistance and multiple metabolic issues, including inflammation and adipocyte dysfunction, while THΔper mice maintained healthier adipose tissue, smaller adipocytes, and lower NE and glucagon levels despite similar weight gain, suggesting reduced SNS activity protected them from metabolic damage.
Similarly, a study by Russo et al. explored the role of the autonomic nervous system, particularly sympathetic activation, in regulating appetite, energy expenditure, and glucose homeostasis. They emphasized the regulatory effects of leptin on SNS activity and energy balance, underscoring the bi-directional relationship between sympathetic activation and insulin resistance. This study reinforced the notion that SNS overactivation is central to obesity and insulin resistance, particularly in contexts where appetite and glucose metabolism are disrupted.
The findings of the study mark a significant shift in understanding obesity-induced insulin resistance, highlighting SNS overactivation as a key contributor rather than solely relying on impairments in cellular insulin signaling. This research suggests that targeting SNS activity may offer a promising strategy for preventing or treating type 2 diabetes, especially in at-risk individuals. However, further studies are necessary to explore the implications of these findings in humans and to develop potential therapies aimed at moderating SNS activity to prevent metabolic diseases.
References
- Sakamoto K, Butera MA, Zhou C, Maurizi G, Chen B, Ling L, et al. Overnutrition causes insulin resistance and metabolic disorder through increased sympathetic nervous system activity. Cell Metabolism [Internet]. 2024 Oct 21 [cited 2024 Nov 5]; Available from: https://www.sciencedirect.com/science/article/pii/S1550413124003760
- Russo B, Menduni M, Borboni P, Picconi F, Frontoni S. Autonomic Nervous System in Obesity and Insulin-Resistance—The Complex Interplay between Leptin and Central Nervous System. International Journal of Molecular Sciences. 2021 May 14;22(10):5187.