Philipp Lachenmann: DELPHI Rationale


Schoeller-Junkmann Prize 2009

Dr. Özlem Gögebakan

Deutsches Institut für Ernährungsforschungng Potsdam

Glucose-dependent insulinotropic polypeptide (GIP) stimulates MCP-1 expression in adipose tissue and leads to activation of monocytes and macrophages

Background: Obesity is associated with elevated monocyte chemoattractant protein-1 (MCP-1), a chemokine contributing to subclinical inflammation, which is related to diabetes and cardiovascular disease. Overnutrition is known to promote subclinical inflammation. We hypothesized that the nutrient induced gut hormone, glucose-dependent insulinotropic peptide (GIP), which is predominantly released after energy dense food, might be involved.

Methods: Human subjects were infused with postprandial doses of GIP, or placebo, either in the fasting state, during euglycemic hyperinsulinemic clamps or during hyperglycemic hyperinsulinemic clamps. Fat biopsies and blood samples were taken before and after 4h of the clamp. MCP-1 plasma and mRNA concentrations were determined. Responses of adipocytes and/or monocytes/macrophages to GIP were investigated in cell culture.

Results: Under all 3 conditions infusions of GIP significantly increased MCP-1 mRNA expression in adipose tissue as well as circulating plasma concentrations of MCP-1 in human. GIP increased MCP-1 mRNA expression in co-culture experiments with 3T3L1-adipocytes and RAW264.7 macrophages, but not in monocultures of each cell line separately. We found that monocytes (THP-1 cells) as well as macrophages (RAW264.7 cells) expressed GIP-receptor mRNA. THP-1 cells responded to GIP with increases in cAMP and phosphorylation of p44/p42 MAP-Kinases. Conclusion: GIP, released in response to energy dense diets may directly induce MCP-1 expression and secretion in human adipose tissue. Monocytes and macrophages express functional GIP receptors and interact with adipocytes to release MCP-1. We propose a novel pathway from energy dense diet to subclinical inflammation.

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