Recent research published in Nature has unveiled the significant role of extracellular matrix (ECM) remodeling in the hypothalamus, particularly around neurons in the arcuate nucleus (ARC), as a contributor to insulin resistance and metabolic diseases, including obesity and diabetes.
The study highlights that insulin resistance has been traditionally associated with ECM remodeling in peripheral tissues. However, emerging evidence now suggests that similar changes can occur in the brain, specifically in the hypothalamus, which has been implicated in various neurological disorders and acute brain injuries.
A key finding is the identification of a specific ECM subtype, known as perineuronal nets (PNNs), which form around neurons producing agouti-related peptide (AgRP) in the ARC. These PNNs act as regulatory barriers that modulate neuronal excitability by interacting with extracellular molecules. The researchers noted that the presence of PNNs affects AgRP functionality, as their absence leads to altered neuronal structure.
The study’s findings indicate that during metabolic disease progression, the ECM in the ARC undergoes significant augmentation and remodeling, impeding insulin signaling and exacerbating insulin resistance in neurons. PNNs were observed to be prevalent in the ARC of mice subjected to Wisteria floribunda lectin staining, while less pronounced in the ventromedial hypothalamus (VMH).
Remarkably, the researchers documented that PNNs in the ARC exhibited a rapid turnover, particularly under obesogenic conditions. This accelerated remodeling results in increased PNN deposition and neurofibrosis, thereby disrupting insulin signaling pathways. In mice subjected to a high-fat, high-sugar (HFHS) diet for 12 weeks, PNN staining intensity rose significantly in the ARC but was not observed in the VMH or retrosplenial granular cortex, indicating a specific association with obesity.
The team referred to the excessive deposition of PNNs in the ARC as “neurofibrosis,” which they found to be a significant factor in the onset of metabolic diseases. Under normal dietary conditions, 24% of pro-opiomelanocortin neurons and 45% of AgRP neurons in the ARC were enveloped by PNNs. This proportion increased during metabolic disease progression without a corresponding increase in neuronal count, signifying that neurofibrosis predominantly develops around AgRP neurons.
Moreover, the researchers discovered a marked reduction in the expression of various ECM proteases in the mediobasal hypothalamus of obese mice, while the levels of their inhibitors were significantly elevated. This imbalance hampers the turnover of ECM components, facilitating excessive PNN accumulation. Selective disassembly of ARC PNNs using chondroitinase ABC (chABC) in diet-induced obese mice led to notable reductions in body weight, calorie intake, and adiposity.
Notably, the positive effects on glucose homeostasis were observed prior to any significant weight changes, emphasizing the direct influence of neurofibrosis on insulin signaling. Additional experiments demonstrated that neurofibrosis hampers both the entry and action of insulin.
The researchers further investigated the impact of neurofibrosis on AgRP neuron functionality, observing that 82% of AgRP neurons spontaneously fired after HFHS feeding; this frequency dropped to 33% post-disassembly of ARC PNNs. Additionally, hypothalamic inflammation was noted in diet-induced obese mice, prompting further exploration of its role in neurofibrosis through the use of anti-inflammatory adeno-associated viruses (AAVs).
The findings strongly indicate that hypothalamic inflammation is a crucial driver of neurofibrosis. Reducing neurofibrosis through inflammation inhibition led to significant improvements in metabolic disease markers, including reduced food intake, diminished adiposity, improved glycemic control, and enhanced insulin sensitivity.
To further validate the link between inflammation and neurofibrosis, the researchers induced hypothalamic inflammation in healthy mice. This manipulation resulted in increased adiposity and weight gain, confirming that inflammation-induced neurofibrosis is detrimental to metabolic health.
Exploring pharmacological approaches, the team administered fluorosamine, a small-molecule inhibitor, intracerebroventricularly to diet-induced obese mice for 10 days. This treatment resulted in decreased neurofibrosis in the ARC, alongside weight loss, improved energy expenditure, and better glycemic control. Notably, fluorosamine administration restored insulin sensitivity, highlighting its therapeutic potential for treating metabolic disorders.
In conclusion, this study identifies ECM remodeling in the ARC as a critical mechanism behind the development of metabolic diseases. The rapid turnover of PNNs underscores the dynamic nature of ECM changes and presents a promising target for innovative therapeutic strategies. By targeting neurofibrosis, interventions could effectively enhance AgRP neuron function and improve metabolic outcomes, underscoring fluorosamine’s potential as a novel treatment for obesity and diabetes.
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