Linking Inflammation to the Brain-Liver Axis
- 1University Health Network, Toronto General Research Institute, Toronto, Canada
- 2Department of Physiology, University of Toronto, Toronto, Canada
- 3Department of Medicine, University of Toronto, Toronto, Canada
- 4Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada
- Corresponding author: Tony K.T. Lam, .
P.I.M. and B.M.F. contributed equally to this work.
The upregulation of plasma inflammatory biomarkers in individuals with metabolic syndrome implies that activation of the innate immune response contributes to the pathogenesis of type 2 diabetes (1). Today, a large array of studies has demonstrated that activation of inflammatory pathways underlies obesity-associated insulin resistance at the liver and fat (2–4). However, little is known regarding whether obesity induces inflammation in the brain thereby disrupting the ability of insulin to control glucose homeostasis.
Hotamisligil et al. (5) first established a link between obesity and the increased production of inflammatory molecules by demonstrating that tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, is overexpressed in the adipose tissue of obese mice. This finding was confirmed in humans with obesity and insulin resistance (6,7). TNF-α induces peripheral insulin resistance in rodents (8,9) and alters insulin sensitivity and glucose homeostasis in humans (10,11). In fact, subjects with chronic inflammatory disease who are treated with TNF inhibitor show a 60% reduction in diabetes rates (12). Downstream of the inflammatory process lies the inhibitor of κB kinase (IKK-β) complex and its target, nuclear factor-ĸB (NF-ĸB), a transcription factor that regulates the expression of inflammatory genes (2–4) and mediates peripheral insulin resistance associated with overnutrition (2–4). In parallel, the c-Jun amino-terminal kinase (JNK), which can be activated in response to TNF-α or other stressors, is also implicated in insulin resistance of diabetic mice (2–4).
NF-ĸB–mediated gene expression is regulated in part through the Toll-like receptors (TLRs), which serve to activate proinflammatory signaling cascades upon recognition of pathogen-associated molecular patterns (2–4 …