Angiopoietin-like 4 in glucocorticoid induced insulin resistance

Glucocorticoids play a key role in metabolic adaptation during stress. The major metabolic function of glucocorticoids is to preserve plasma the glucose levels that serve as the major energy source for the brain [1]. Therefore, glucocorticoids antagonize the ability of insulin to suppress hepatic gluconeogenesis and promote glucose utilization in white adipose tissue (WAT) and skeletal muscle [1]. Thus, it is not surprising that chronic and/or excess glucocorticoid exposure causes insulin resistance. Glucocorticoids convey their signals mainly through an intracellular glucocorticoid receptor (GR), which functions as a transcription factor. Hence, the primary target genes of GR initiate the physiological and the pathophysiological responses of glucocorticoids. Identifying GR primary targets that are involved in glucocorticoid-induced insulin resistance will not only advance our understanding of the mechanisms governing glucocorticoid-induced insulin resistance, but also provide specific targets to improve insulin sensitivity. Recently, we have shown that glucocorticoidinduced insulin resistance requires participation of a GR primary target gene, angiopoietin-like 4 (Angptl4) [2]. Angptl4 encodes a secreted protein that inhibits extracellular lipoprotein lipase (LPL) [3] but promotes lipolysis in adipocytes [4]. Angptl4, which is induced by glucocorticoids, promotes the production of ceramides in the liver, which then activates protein phosphatase 2A (PP2A) and protein kinase c ζ (PKCζ) to suppress hepatic insulin signaling [2] (Fig. 1). Glucocorticoid treatment elevates expression of genes encoding enzymes in the ceramide biosynthetic program, such as serine palmitoyltransferase 1 and 2 (Spt1/2) and ceramide synthase 3-6 (Cers3-6). In Angptl4 null mice (Angptl4-/-), the ability of glucocorticoids to induce expression of Cers3-6 is impaired whereas their effect on Spt1/2 is maintained [2]. These results suggest that one of Angptl4’s roles in glucocorticoid-induced insulin resistance is to augment hepatic Cers3-6 expression. What Editorial