Cellular sludge around hunger neurons linked to worsening diabetes and obesity
Researchers uncover how the buildup of extracellular matrix proteins and sugars prevents insulin from reaching hunger-regulating neurons, leading to disrupted metabolism and increased risk of obesity.
In a recent study published in Nature, researchers reveal a novel mechanism by which hypothalamic inflammation drives fibrotic remodeling in perineuronal nets (PNNs), a specialized extracellular matrix (ECM) of the hypothalamic arcuate nucleus (ARC), to induce metabolic dysfunction.
Background
Elevated blood glucose levels trigger beta cells of the pancreas to release more insulin. This hormone circulates to the ARC, which controls physiological processes. A loss of insulin sensitivity increases dietary intake, leading to fat accumulation and obesity. The ECM, a network of proteins and sugars, disrupts insulin’s reach to hunger-regulating ARC neurons, contributing to obesity.
The ECM is a dynamic structure essential for tissue function. However, pathological changes can lead to increased fibrosis in the ECM in the form of perineural nets surrounding the Agouti-Related Protein (AgRP)-releasing neurons within the ARC of the hypothalamus. The fibrotic buildup prevents insulin activity. Studies report that insulin resistance can result in metabolic diseases like obesity and insulin-independent diabetes.
About the study
The present study investigated the remodeling of the ARC extracellular matrix in metabolic diseases such as obesity.
Researchers fed mice regular chow or high-fat, high-sugar (HFHS) diets. They used the HFHS diet to induce diabetes in mice. They monitored blood glucose and used mice to show stable blood glucose values for further experiments.
Researchers performed immunohistochemistry to study whether neuroinflammation caused net formation around the AgRP neurons of the hypothalamus. Stereotaxic injections in mice induced and inhibited hypothalamic inflammation. Wisteria floribunda lectin (WFA) stains labeled the perineural nets in the ECM of HFHS-fed mice.
Researchers disrupted insulin receptors in AgRP neurons to understand the causal link between neurofibrosis and metabolic dysfunction. To determine whether obesity promotes insulin resistance, researchers administered insulin-fluorescein isothiocyanate (FITC) and measured its entry and signaling in the hypothalamic neurons. Metabolic measurements included fasting glucose or plasma insulin and adiposity.
Researchers investigated whether inflammation in the hypothalamus enhanced the development of perineural nets and fibrotic buildup in the ECM of its neurons. To do so, they administered adeno-associated viruses (AAVs) expressing receptors for tumor necrosis factor-alpha (TNF-α) and tumor growth factor beta (TGF-β). TNF-α increases inflammation, whereas TGF-β is anti-inflammatory. The receptors would bind to their proteins, artificially increasing their expression. Researchers co-administered these AAVs with chondroitinase ABC (chABC), an enzyme that dissolves perineural nets.
Patch clamp electrophysiology experiments assessed insulin’s interaction with PNN in vitro. Researchers genotyped murine samples to quantify genetic expression in the ECM of lean and obese mice’s mediobasal hypothalamus. To explore its therapeutic potential, fluorosamine, a drug that prevents chondroitin sulfate synthesis, was administered intranasally and injected into the cerebrospinal fluid of mice for ten days.
Results
In obese mice, the ECM accumulates in the form of perineural nets around ARC neurons. Perineural nets, once formed around these ‘hunger neurons’ facilitate their maturation. These mature neurons in the hypothalamic arcuate nucleus release AgRP, the neuropeptide that leads to fibrosis in the ECM. Obese rats, HFHS-fed mice, and genetically modified metabolic disease models showed increased formation of perineural nets around AgRP neurons.
The fibrotic nets reduced insulin levels in the arcuate nucleus and inhibited signaling activities by insulin receptors. A reduction in insulin function increased the firing of the AgRP-releasing hunger neurons. However, insulin levels were restored after breaking down the perineural nets using enzymes. The breakdown also increased potassium ion concentrations. As a result, AgRP neuron firing was reduced. Restoring insulin levels also led to improved glucose metabolism and reduced weight.
The fibrotic nets around the hunger neurons downregulated the expression of genes that encode insulin receptors in the AgRP neurons. The finding indicated that ECM remodeling with fibrosis around the neurons impairs metabolic functions by increasing insulin resistance or lowering insulin activity. However, the results in obese mice indicated that the perineural nets did not affect the activities of leptin, a hormone that regulates body weight.
Obesity increases the levels of inflammatory TNF-α but reduces the expression of anti-inflammatory TGF-β. Increased body weight also reduces the expression of metalloproteinases. Metalloproteinases are enzymes that can digest the fibrotic nets around the hunger neurons. Suppressing inflammation in the hypothalamus using AAVs improved metalloproteinase expression.
Fluorosamine restored insulin sensitivity and regular ECM formation in the hypothalamic neurons. Subsequently, the body weight was reduced, and metabolic function improved. The findings indicate that drugs that lower hypothalamic inflammation and prevent fibrotic buildup in the ECM could improve metabolism by improving insulin and metalloproteinase functions.
Conclusion
Based on the findings, ECM remodeling in the hypothalamus may lead to metabolic disease. Drugs and enzymes that can disrupt the perineural nets that form around the AgRP neurons could improve metabolism and reduce weight by improving insulin activity.
