Hypoxia Decreases Insulin Signaling Pathways in Adipocytes

• DOI: 10.2337/db08-0457
• Publication Date: 2008-11-05T02:15:34Z
• Authors: Claire Regazzetti; Pascal Peraldi; Thierry Grémeaux; Rosanna Najem-Lendom; Issam Ben-Sahra; Mireille Cormont; Frédéric Bost; Yannick Le Marcha...; Jean-François Tanti; Sophie Giorgetti-...
• Keywords: MESH: Signal Transduction; Glycerol; MESH: Cell Hypoxia; Interleukin-1beta; Mice; MESH: Interleukin-1beta; MESH: Basic Helix-Loop-Helix Transcription Factors; Adipocytes; Basic Helix-Loop-Helix Transcription Factors; Insulin; MESH: Animals; Phosphorylation; [SDV.BDD]Life Sciences [q-bio]/Development Biology; 0303 health sciences; MESH: Reactive Oxygen Species; Cobalt; Cell Hypoxia; 3. Good health; MESH: Glucose; Signal Transduction; MESH: Receptor, Insulin; MESH: Biological Transport; Lipolysis; Blotting, Western; MESH: Insulin; MESH: Protein Tyrosine Phosphatases; MESH: Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line; 03 medical and health sciences; MESH: Glycerol; MESH: Hypoglycemic Agents; 3T3-L1 Cells; [SDV.BDD] Life Sciences [q-bio]/Development Biology; MESH: Blotting, Western; Animals; Humans; Hypoglycemic Agents; MESH: Lipolysis; MESH: Mice; MESH: Adipocytes; MESH: Humans; MESH: Phosphorylation; Interleukin-6; Biological Transport; Hypoxia-Inducible Factor 1, alpha Subunit; MESH: Interleukin-6; MESH: 3T3-L1 Cells; MESH: Cell Line; MESH: Cobalt; Glucose

OBJECTIVE—Obesity is characterized by an overgrowth of adipose tissue that leads to the formation of hypoxic areas within this tissue. We investigated whether this phenomenon could be responsible for insulin resistance by studying the effect of hypoxia on the insulin signaling pathway in adipocytes. RESEARCH DESIGN AND METHODS—The hypoxic signaling pathway was modulated in adipocytes from human and murine origins through incubation under hypoxic conditions (1% O2) or modulation of hypoxia-inducible factor (HIF) expression. Insulin signaling was monitored through the phosphorylation state of several key partners of the pathway and glucose transport. RESULTS—In both human and murine adipocytes, hypoxia inhibits insulin signaling as revealed by a decrease in the phosphorylation of insulin receptor. In 3T3-L1 adipocytes, this inhibition of insulin receptor phosphorylation is followed by a decrease in the phosphorylation state of protein kinase B and AS160, as well as an inhibition of glucose transport in response to insulin. These processes were reversible under normoxic conditions. The mechanism of inhibition seems independent of protein tyrosine phosphatase activities. Overexpression of HIF-1α or -2α or activation of HIF transcription factor with CoCl2 mimicked the effect of hypoxia on insulin signaling, whereas downregulation of HIF-1α and -2α by small interfering RNA inhibited it. CONCLUSIONS—We have demonstrated that hypoxia creates a state of insulin resistance in adipocytes that is dependent upon HIF transcription factor expression. Hypoxia could be envisioned as a new mechanism that participates in insulin resistance in adipose tissue of obese patients.