Retinol Binding Protein 4 is a Biomarker and Cause of Insulin Resistance and Metabolic Syndrome through Activation of the Innate and Adaptive Immune Systems

Retinol Binding Protein 4 is a Biomarker and Cause of Insulin Resistance and Metabolic Syndrome through Activation of the Innate and Adaptive Immune Systems

Retinol Binding Protein 4 is a Biomarker and Cause of Insulin Resistance and Metabolic Syndrome through Activation of the Innate and Adaptive Immune Systems (#23)

Barbara B Kahn ¹ , Pedro Moraes-Vieira ¹

Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

Serum retinol-binding protein 4 (RBP4) is the main vitamin A (retinol) transport protein in the blood. Many clinical studies link elevated serum RBP4 levels to metabolic diseases including obesity, insulin-resistance, type 2 diabetes (T2D), and cardiovascular disease. Large epidemiologic studies demonstrate that elevated circulating RBP4 levels are a biomarker for these diseases. Elevation of RBP4 levels causes insulin resistance, whereas lowering RBP4 levels improves insulin sensitivity. Serum RBP4 levels are elevated in pre-diabetic people even before overt hyperglycemia occurs. The possibility that RBP4 causes insulin resistance in humans is supported by genetic data.

The immune system plays an important role in obesity-related insulin resistance. The mechanism for RBP4-induced insulin resistance involves inflammation. In humans, RBP4 levels in serum and adipose tissue strongly correlate with subclinical inflammation, including pro-inflammatory cytokine levels. RBP4 impairs insulin signaling in adipocytes indirectly by inducing pro-inflammatory cytokine production from macrophages through the c-Jun N-terminal protein kinase-dependent pathway. Transgenic mice overexpressing RBP4 have increased numbers of adipose tissue macrophages and CD4 T-cells. Transfer of antigen-presenting cells treated with RBP4 ex vivo into normal mice is sufficient to cause insulin resistance. Thus, RBP4-mediated activation of the innate immune system elicits an adaptive immune response resulting in insulin resistance. These effects are not mediated through a known RBP4 receptor, STRA6, but involve Toll-Like Receptor 4. Blockade of antigen presentation with CTLA4-Ig (cytotoxic T-lymphocyte associated antigen 4-Ig; a drug used to treat immune-mediated diseases) is sufficient to improve systemic insulin resistance and adipose tissue inflammation in RBP4-overexpressing mice. This indicates that the RBP4-induced insulin resistance associated with obesity could be improved by blocking antigen presentation and subsequent T-cell activation. Alternatively, insulin resistance and adipose inflammation could be ameliorated by lowering serum RBP4 levels.

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Authors contributing to this presentation.

Kahn, B.B

Barbara Kahn, MD is the George R. Minot Professor of Medicine at Harvard Medical School, Vice-Chair for Research Strategy in the Dept. of Medicine at Beth Israel Deaconess Medical Center (BIDMC) and a Senior Associate member of the Broad Institute of MIT and Harvard. Dr. Kahn received her MD from Stanford University and an MS in Health Sciences from the University of California at Berkeley. She did a General Medicine Fellowship at the University of Calif. Davis and an Endocrine Fellowship at NIH. She was Chief of the Diabetes Unit and subsequently, Chief of the Division of Endocrinology, Diabetes, and Metabolism at BIDMC during which time she expanded the research and clinical programs of the Division. Dr. Kahn is a world renowned scientist whose work has elucidated the molecular mechanisms underlying obesity and type 2 diabetes. Her discoveries have had a major impact on understanding the role of the adipose cell as an endocrine organ that regulates systemic insulin sensitivity and diabetes risk. Her lab also demonstrated that AMP-activated-protein-kinase regulates neural and peripheral circuits controlling adiposity and fuel homeostasis. Most recently, Dr. Kahn’s lab, with Alan Saghatelian, discovered a novel class of lipids with anti-diabetic and anti-inflammatory effects. Dr. Kahn has received many awards including the Outstanding Scientific Achievement Award and the Mosenthal Award from ADA; the Jacobaeus Prize from the Novo Nordisk Foundation and the Karolinska Institute; the Charles Best Award from University of Toronto; and the Gerald Aurbach Award from Endocrine Society. In 2016, she will be receiving the Award Lectureship from the Journal of Lipid Research and the Banting Medal for Scientific Achievement which is the highest scientific achievement award bestowed by the American Diabetes Association. Dr. Kahn is an elected member of the ASCI, AAP, and National Academy of Medicine, and a Fellow of the AAAS.

Retinol Binding Protein 4 is a Biomarker and Cause of Insulin Resistance and Metabolic Syndrome through Activation of the Innate and Adaptive Immune Systems (#23)

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Kahn, B.B

Moraes-Vieira, P

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