Key Points
- To determine whether adipose-specific overexpression of monocyte chemoattractant protein-1 (MCP-1) drives adipose macrophage infiltration and systemic insulin resistance.
- Generated transgenic mice overexpressing MCP-1 driven by the adipocyte P2 (aP2) promoter.
- Assessed adipose macrophage accumulation via immunohistochemistry and flow cytometry, measured inflammatory cytokines (TNF-alpha, IL-6) and plasma non-esterified fatty acids, and evaluated insulin sensitivity using hyperinsulinemic euglycemic clamp studies.
- Analyzed insulin-induced Akt phosphorylation in skeletal muscle and liver, and measured ex vivo muscle glucose uptake following MCP-1 and MEK inhibitor (U0126) treatments.
- aP2-MCP-1 transgenic mice exhibited elevated plasma MCP-1, increased macrophage accumulation in adipose tissues, higher adipose TNF-alpha and IL-6 mRNA levels, and elevated plasma non-esterified fatty acids.
- Hyperinsulinemic euglycemic clamp studies demonstrated reduced glucose disappearance rates, increased endogenous glucose production, and blunted insulin-induced Akt phosphorylation in liver and skeletal muscle of transgenic mice.
- Direct MCP-1 pretreatment inhibited insulin-stimulated glucose uptake in isolated skeletal muscle, an effect partially reversed by the MEK inhibitor U0126.
Structured PICO
PPopulationTransgenic mice overexpressing monocyte chemoattractant protein-1 (MCP-1) under the adipocyte P2 (aP2) promoter (aP2-MCP-1 mice) and wild-type mice
IInterventionAdipose tissue overexpression of monocyte chemoattractant protein-1 (MCP-1)
OOutcomeMacrophage accumulation in adipose tissues and insulin resistance (assessed via hyperinsulinemic euglycemic clamp)surrogate
Overexpression of MCP-1 in adipose tissue induces macrophage recruitment and systemic insulin resistance, suggesting both paracrine and endocrine roles for MCP-1 in metabolic dysfunction.