Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration

Abstract

The interaction between metabolic dysfunction and inflammation is central to the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Obesity-related conditions like type 2 diabetes and non-alcoholic fatty liver disease exacerbate this relationship. Peripheral lipid accumulation, particularly in the liver, initiates a cascade of inflammatory processes that extend to the brain, influencing critical metabolic regulatory regions. Ceramide and palmitate, key lipid components, along with lipid transporters lipocalin-2 and apolipoprotein E, contribute to neuroinflammation by disrupting blood-brain barrier integrity and promoting gliosis. Peripheral insulin resistance further exacerbates brain insulin resistance and neuroinflammation. Preclinical interventions targeting peripheral lipid metabolism and insulin signaling pathways have shown promise in reducing neuroinflammation in animal models. However, translating these findings to clinical practice requires further investigation into human subjects. In conclusion, metabolic dysfunction, peripheral inflammation, and insulin resistance are integral to neuroinflammation and neurodegeneration. Understanding these complex mechanisms holds potential for identifying novel therapeutic targets and improving outcomes for neurodegenerative diseases.

Figure 1

Peripheral metabolic dysfunction propagates inflammation to the brain. Free fatty acids or lipids from a high-fat diet or obesity induce metabolic dysfunction and decreased cellular bioenergetics in the liver, leading to increased hyperinsulinemia, insulin resistance, as well as reduced insulin signaling. This results in a detrimental increase in lipid accumulation and elevated inflammatory cytokines such as TNF and activation of the NF-κB inflammatory pathway. Excessive lipids and cytokines can be transported through blood to the brain to propagate inflammation. This leads to insulin resistance and reduced insulin signaling, dysregulated glucose and lipid metabolism, increased reactive oxygen species, neuroinflammation, accumulation of toxic protein aggregates, as well as glial activation and neuronal death. Created with BioRender.com. APOE: Apolipoprotein E; NF-κB: nuclear factor-kappa B; TNF: tumor necrosis factor.

Figure 2

Peripheral lipid accumulation and insulin resistance propagate inflammation in the brain. Lipids: Liver dysfunction leads to peripheral lipid accumulation, which can traverse the BBB and induce neuroinflammation in the brain, characterized by lipid peroxidation, protein aggregation, and activation of microglia and astrocytes. Lipid transporters: Lipid transporters like lipocalin-2 bind to receptors on brain cells, initiating signaling cascades that upregulate inflammatory cytokine expression. Insulin resistance: Peripheral insulin resistance disrupts insulin signaling pathways, impacting glucose metabolism, and neuronal function, and promoting neuroinflammation. Inflammation: Inflammatory cytokines released from the liver enter circulation, affecting brain inflammatory pathways, and exacerbating inflammation and cellular dysfunction. Created with BioRender.com. Akt: Akt kinase; HMGB1: high mobility group box 1 protein; IL-18: interleukin 18; IL-1β: interleukin 1β; IL-6: interleukin 6; NF-κB: nuclear factor-kappa B; NLRP3: nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3; PI3K: phosphoinositide 3-kinase; RAGE: receptor for advanced glycation endproducts; STAT3: signal transducer and activator of transcription 3; TLR4: Toll-like receptor 4; TNF: tumor necrosis factor.

Figure 3

Therapeutic strategies that can modulate metabolic dysfunction and inflammation in the periphery and the brain. To address metabolic dysfunction and inflammation in the brain, therapeutic interventions like TNF/TNFR1 inhibitors targeting TNF signaling, soluble gp130 to inhibit IL-6 signaling, and intranasal insulin delivery can be employed. In the liver, lysosome-targeted agents can be used to mitigate lipid accumulation, while FXR agonists regulate liver lipid metabolism and inflammation. GLP-1 agonists, utilized clinically and in research, enhance insulin signaling in both liver and brain tissues. Created with BioRender.com. FXR: Farnesoid X receptor; GLP-1: glucagon-like peptide 1; gp130: glycoprotein 130; IL-6R: interleukin 6 receptor; TNF: tumor necrosis factor; TNFR1: tumor necrosis factor receptor 1.