Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistantob/obmice

Abstract

Decreased clearance of serum retinol-binding protein and elevated levels of transthyretin in insulin-resistant ob/ob mice. Am J Physiol Endocrinol Metab 294: E785-E793, 2008. First published February 19, 2008 doi:10.1152/ajpendo.00521.2007.-Serum retinol-binding protein (RBP4) is secreted by liver and adipocytes and is implicated in systemic insulin resistance in rodents and humans. RBP4 normally binds to the larger transthyretin (TTR) homotetramer, forming a protein complex that reduces renal clearance of RBP4. To determine whether alterations in RBP4-TTR binding contribute to elevated plasma RBP4 levels in insulin-resistant states, we investigated RBP4-TTR interactions in leptin-deficient ob/ob mice and high-fat-fed obese mice (HFD). Gel filtration chromatography of plasma showed that 88 -94% of RBP4 is contained within the RBP4-TTR complex in ob/ob and lean mice. Coimmunoprecipitation with an RBP4 antibody brought down stoichiometrically equal amounts of TTR and RBP4, indicating that TTR was not more saturated with RBP4 in ob/ob mice than in controls. However, plasma TTR levels were elevated approximately fourfold in ob/ob mice vs. controls. RBP4 injected intravenously in lean mice cleared rapidly, whereas the t 1/2 for disappearance was approximately twofold longer in ob/ob plasma. Urinary fractional excretion of RBP4 was reduced in ob/ob mice, consistent with increased retention. In HFD mice, plasma TTR levels and clearance of injected RBP4 were similar to chow-fed controls. Hepatic TTR mRNA levels were elevated approximately twofold in ob/ob but not in HFD mice. Since elevated circulating RBP4 causes insulin resistance and glucose intolerance in mice, these findings suggest that increased TTR or alterations in RBP4-TTR binding may contribute to insulin resistance by stabilizing RBP4 at higher steady-state concentrations in circulation. Lowering TTR levels or interfering with RBP4-TTR binding may enhance insulin sensitivity in obesity and type 2 diabetes. obesity; adipose; high-fat diet RESISTANCE TO INSULIN ACTION is a major risk factor for type 2 diabetes, cardiovascular disease, and early mortality (16, 39). Multiple factors secreted by adipocytes contribute to regulation of systemic insulin sensitivity, fuel metabolism, energy balance, cardiovascular function, and immune function (27, 41). Serum retinol-binding protein (RBP4) is secreted from liver and adipocytes. Previously, its only known function was to deliver retinol (vitamin A) to tissues (46). We recently discovered that RBP4 is elevated in serum in insulin-resistant rodents and humans (23, 59). Serum levels correlate highly with the magnitude of insulin resistance and with many other features of the "metabolic syndrome" (2,9,20,23,28,32,49,50,56,59), a constellation of insulin resistance and cardiovascular risk factors. Experimentally elevating serum RBP4 levels in mice causes insulin resistance, whereas lowering serum RBP4 in normal mice or in mice on a high-fat diet (HFD) enhances insulin sensitivity (59). A few studies have not found a corre...

Susceptibility to diet-induced obesity and glucose intolerance in the APP SWE/PSEN1 A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein

“…However, brain RBP4 protein levels tended to be higher in APP/PSEN1 mice on chow diet and significantly higher in PSEN1 and APP/PSEN1 mice on HFD, suggesting that increased RBP4 levels may be another mechanism by which Alzheimer's disease genotype predisposes to diet-induced glucose intolerance. RBP4 is an adipokine that was recently found to be elevated in insulin-resistant states as well as in obesity in mice [23,39,40] and humans [41][42][43][44], although not all studies have reported this [24,45]. These data suggest that there are early markers of insulin resistance already present with the APP genotype, making these mice more susceptible to the effects of HFD feeding and associated insulin resistance.…”

Genetic deficiency of apolipoprotein D in the mouse is associated with nonfasting hypertriglyceridemia and hyperinsulinemia

“…The lipocalin retinol-binding protein 4 (RBP4) and lipocalin-2 are elevated in obese humans, correlating with lower insulin sensitivity [25,26]. Likewise, circulating concentrations of RBP4 and lipocalin-2 are elevated in obese mice [26,27]. Transgenic overexpression of RBP4 in normal mice decreases insulin sensitivity, whereas genetic ablation of RBP4 improved insulin sensitivity [28].…”

RBP4: a controversial adipokine

“…These studies are supported by the fact that patients with end-stage kidney failure have significantly higher circulating RBP4 levels than healthy controls and that serum creatinine levels independently predict RBP4 concentrations in both controls and patients with kidney failure (81). There is an ongoing debate on the possible influence of transthyretin on circulating RBP4 levels via RBP4's decreased renal clearance (24,25). It is also proposed that imbalance between RBP4 and retinol might be the underlying cause for the observed association between RBP4 levels and systemic insulin resistance (22).…”

“…Formation of a complex with transthyretina carrier of thyroid hormone and retinol -prevents glomerular filtration of RBP4 and its subsequent excretion through the kidney (23). It is debatable whether increased transthyretin levels and/or enhanced RBP4 to transthyretin interaction can result in decreased renal clearance of RBP4 and consequently its increased circulating levels (24,25). Circulating RBP4 levels are also influenced by iron and ferritin status as discussed later in the text (26).…”