New research reveals how extracellular matrix (ECM) buildup in the brain’s hypothalamus leads to insulin resistance, paving the way for innovative therapies targeting obesity and diabetes.
Study: Pathogenic hypothalamic extracellular matrix promotes metabolic disease. Image Credit: Sebastian Kaulitzki / Shutterstock
In a recent study published in the journal Nature, researchers reported that pathogenic hypothalamic extracellular matrix (ECM) remodeling within the hypothalamus, specifically around neurons in the arcuate nucleus (ARC), promotes metabolic disease.
Insulin resistance is closely linked to ECM remodeling in peripheral tissues, where fibrosis (excess ECM deposition) impairs insulin signaling and action. Conventionally, fibrosis was believed to only occur in peripheral tissues. Nevertheless, increasing evidence indicates that ECM remodeling can also occur in the brain, particularly in the hypothalamus, and has been observed in severe neurological diseases and after acute brain injury.
Recent reports suggest the formation of a unique ECM subtype, perineuronal nets (PNNs), around neurons expressing agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus (ARC). These PNNs serve as a regulatory barrier that controls the excitability of neurons by binding to extracellular molecules. PNN formation influences AgRP function, as its loss results in higher fiber density and changes in cell numbers.
The study and findings
In the present study, researchers reported that the ECM of ARC becomes augmented and remodeled during metabolic disease development, specifically impeding insulin penetrance, which directly contributes to insulin resistance within neurons. They observed PNN throughout the mediobasal hypothalamus in mice following Wisteria floribunda lectin staining. PNN staining was prominent in the ARC but significantly less, albeit notable, in the ventromedial hypothalamus (VMH).
Notably, the researchers also discovered that PNNs in the ARC exhibit a rapid turnover, much faster than in other brain regions. This rapid remodeling under obesogenic conditions accelerates the deposition of PNNs and promotes neurofibrosis, leading to dysfunction in insulin signaling. The intensity and area of PNN staining increased in diet-induced obese (DIO) mice following high-fat, high-sugar (HFHS) diet feeding for 12 weeks. PNN remodeling after HFHS diet feeding was not detected in the VMH or retrosplenial granular cortex (RSG), suggesting that obesity-related ECM remodeling was ARC-specific.
The researchers termed the excess ARC PNN deposition and remodeling as "neurofibrosis," which significantly contributes to metabolic disease. Under chow-fed conditions, 24% of pro-opiomelanocortin neurons and 45% of AgRP neurons in the ARC were ensheathed within the PNN. This proportion specifically increased for AgRP neurons during the progression of metabolic disease, even without an increase in the number of neurons, indicating that neurofibrosis develops around AgRP neurons in metabolic disease.
The researchers found that the expression of various ECM proteases was significantly reduced in the mediobasal hypothalamus in obese mice compared to lean mice, whereas the expression of their inhibitors was significantly elevated. This reduced turnover of ECM components, driven by the suppression of proteases, promotes excessive PNN accumulation. Next, the team selectively disassembled ARC PNN in DIO mice by treating them with chondroitinase ABC (chABC) and observed progressive weight loss, lower calorie intake, and reduced adiposity.
However, vehicle-treated, pair-fed mice did not show similar adiposity or body weight decreases. Importantly, the study demonstrated that the benefits of ARC neurofibrosis disassembly on glucose homeostasis were observed before changes in body weight, underscoring the direct impact of neurofibrosis on insulin signaling. Further experiments indicated that neurofibrosis impedes insulin entry and signaling.
Next, the team assessed the effect of neurofibrosis on the function of AgRP neurons. Following HFHS feeding, over 82% of AgRP neurons spontaneously fired, which was reduced to 33% after ARC PNN disassembly. Correspondingly, resting membrane potential and firing frequency were significantly reduced. Besides, the researchers noted diet-induced hypothalamic inflammation in DIO mice.
As such, they investigated its role in neurofibrosis using anti-inflammatory adeno-associated viruses (AAVs) expressing soluble tumor necrosis factor (TNF) receptor 1α (TNFR1α) and transforming growth factor β (TGFβ) receptor (TGFβR) in the ARC before DIO onset. Inhibition of hypothalamic inflammatory factors altered the gene expression of ECM-remodeling proteases and their inhibitors.
The results strongly suggest that hypothalamic inflammation is a key driver of neurofibrosis. Attenuating neurofibrosis by inhibiting inflammation caused a significant reduction in metabolic disease markers, such as lower food intake, reduced adiposity, diminished body weight gain, higher satiety, improved glycemic control, greater insulin sensitivity, and higher energy expenditure. Next, hypothalamic inflammation was induced in healthy mice by administering AAVs to elevate the expression of TNFα and TGFβ.
As such, inflammation-induced neurofibrosis in lean mice resulted in increased adiposity, weight gain, lower energy expenditure, impaired glycemic control, insulin resistance, lower satiety, and hyperphagia. These findings underscore the central role of neurofibrosis in linking inflammation to metabolic dysfunction. Finally, the researchers used fluorosamine, a small-molecule inhibitor, to explore the pharmacological potential of targeting neurofibrosis. Fluorosamine was intracerebroventricularly administered to DIO mice for 10 days.
This treatment significantly attenuated neurofibrosis within the ARC, promoted weight loss, increased energy expenditure, decreased adiposity, enhanced glycemic control, and suppressed food intake. Remarkably, the administration of fluorosamine restored insulin sensitivity and improved metabolic outcomes, even in late-stage type 2 diabetes, highlighting its therapeutic potential. Furthermore, intranasal fluorosamine administration attenuated ARC neurofibrosis, with similar metabolic improvements as with intracerebroventricular injection.
Conclusions
The study identified pathogenic ECM remodeling within the ARC of the brain, highlighting it as a mechanism of metabolic disease development. The rapid turnover of PNNs in the ARC suggests a dynamic role for ECM remodeling in disease progression, offering a promising target for therapeutic interventions. Abrogating ARC neurofibrosis restored AgRP neuron function and improved hunger regulation, satiety, glycemic control, and energy expenditure.
Overall, these findings validate neurofibrosis as a critical target for treating obesity and diabetes, with fluorosamine demonstrating significant potential as a novel treatment approach.
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