Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Abstract

bTo investigate the mechanisms by which elevated retinol-binding protein 4 (RBP4) causes insulin resistance, we studied the role of the high-affinity receptor for RBP4, STRA6 (stimulated by retinoic acid), in insulin resistance and obesity. In high-fat-diet-fed and ob/ob mice, STRA6 expression was decreased 70 to 95% in perigonadal adipocytes and both perigonadal and subcutaneous adipose stromovascular cells. To determine whether downregulation of STRA6 in adipocytes contributes to insulin resistance, we generated adipose-Stra6 ؊/؊ mice. Adipose-Stra6 ؊/؊ mice fed chow had decreased body weight, fat mass, leptin levels, insulin levels, and adipocyte number and increased expression of brown fat-selective markers in white adipose tissue. When fed a highfat diet, these mice had a mild improvement in insulin sensitivity at an age when adiposity was unchanged. STRA6 has been implicated in retinol uptake, but retinol uptake and the expression of retinoid homeostatic genes (encoding retinoic acid receptor ␤ [RAR␤], CYP26A1, and lecithin retinol acyltransferase) were not altered in adipocytes from adipose-Stra6 ؊/؊ mice, indicating that retinoid homeostasis was maintained with STRA6 knockdown. Thus, STRA6 reduction in adipocytes in adipose-Stra6 ؊/؊ mice fed chow resulted in leanness, which may contribute to their increased insulin sensitivity. However, in wild-type mice with high-fat-diet-induced obesity and in ob/ob mice, the marked downregulation of STRA6 in adipocytes and adipose stromovascular cells does not compensate for obesity-associated insulin resistance.T hree hundred fifty million people worldwide have diabetes (1), and the impact will be staggering if we do not develop more effective methods for early detection and treatment. Serum retinol-binding protein 4 (RBP4) is elevated in humans and rodents with insulin resistance and type 2 diabetes (2-4), and data suggest that it may play a causative role (4, 5). Injection of purified RBP4 or overexpression of RBP4 in mice causes insulin resistance (4). Furthermore, a gain-of-function polymorphism in the RBP4 promoter is associated with an 80% increased risk of developing diabetes in humans (5). In addition, epidemiologic studies in several ethnic backgrounds indicate that elevated RBP4 is an early marker of prediabetes (6) and metabolic syndrome (7,8) and is associated with a 3.6-fold increased risk of myocardial infarction (9).The mechanisms by which RBP4 causes insulin resistance and whether the actions of RBP4 depend on a receptor are questions of high interest in the field. STRA6 is a high-affinity cell surface receptor for RBP4 that mediates vitamin A uptake (10). STRA6 is highly expressed in blood-organ barriers and in the brain, eye, kidney, testis, and female reproductive tract, and it is absent from the liver (11). STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathwa...

Transport of vitamin A across blood‐tissue barriers is facilitated by STRA6

“…8 B ). Absence of an effect of STRA6 deficiency on retinoid content of WAT is consistent with the very low expression levels of the RBP4 receptor in this tissue (15, 26).…”

“…Furthermore, we investigated the effects of our experimental conditions in tissues with low levels of Stra6 mRNA expression, such as WAT and lung, or with no expression at all, such as liver (15, 26). In these tissues, we observed no differences between genotypes with regard to RE stores when dietary vitamin A is removed.…”

An Alternative Retinoic Acid-responsive Stra6 Promoter Regulated in Response to Retinol Deficiency

“…liver and lungs) to the eye (27), possibly in conjunction with the recently identified RBPR2, another RBP4 receptor (4). Ablation of Stra6 can also protect animals from the insulin-resistant state induced by feeding a high fat, high sucrose diet (28), which may be a result of impaired Jak/Stat signaling (29). Why humans with certain mutations in STRA6 exhibit a more severe morphological phenotype (25)(26)(27) than the Stra6 knock-out mice is currently not understood.…”

Is retinol binding protein 4 a link between adiposity and cancer?

“…Further attesting to the central role of the RBP4/STRA6 pathway in suppressing insulin signaling, STRA6-null mice were found to be protected from insulin resistance brought about by ectopic administration of RBP4, as well as from insulin resistance brought about by feeding a high fat diet [64]. Moreover, even partial reduction of STRA6 expression restricted to adipocytes led to improved insulin sensitivity in obese mice [76]. …”