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RBP4 is produced mainly by hepatocytes. In type 2 diabetes and obesity, circulating RBP4 is increased and may act systemically to cause insulin resistance and glucose intolerance. Observations that adipocyte RBP4 mRNA increases in parallel with circulating RBP4 in these conditions, whereas liver RBP4 mRNA does not, led to a widely held hypothesis that elevated circulating RBP4 is a direct result of increased production by adipocytes. To test this, we generated mice with hepatocyte-specific deletion of RBP4 (liver RBP4 knockout or LRKO mice). Adipose tissue RBP4 expression and secretion remained intact in LRKO mice and increased as expected in the setting of diet-induced insulin resistance. However, circulating RBP4 was undetectable in LRKO mice. We conclude that adipocyte RBP4 is not a significant source of circulating RBP4, even in the setting of insulin resistance. Adipocyte RBP4, therefore, may have a more important autocrine or paracrine function that is confined within the adipose tissue compartment. [ABSTRACT FROM AUTHOR]

OBJECTIVE--We identified lipocalin 2 (Lcn2) as a gene induced by dexamethasone and tumor necrosis factor-α in cultured adipocytes. The purpose of this study was to determine how expression of Lcn2 is regulated in fat cells and to ascertain whether Lcn2 could be involved in metabolic dysregulation associated with obesity. RESEARCH DESIGN AND METHODS--We examined Lcn2 expression in murine tissues and in 3T3-L1 adipocytes in the presence and absence of various stimuli. We used quantitative Western blotting to observe Lcn2 serum levels in lean and obese mouse models. To assess effects on insulin action, we used retroviral delivery of short hairpin RNA to reduce Lcn2 levels in 3T3-L1 adipocytes. RESULTS--Lcn2 is highly expressed by fat cells in vivo and in vitro. Expression of Lcn2 is elevated by agents that promote insulin resistance and is reduced by thiazolidinediones. The expression of Lcn2 is induced during 3T3-L1 adipogenesis in a CCAAT/enhancer-binding protein-dependent manner. Lcn2 serum levels are elevated in multiple rodent models of obesity, and forced reduction of Lcn2 in 3T3-L1 adipocytes improves insulin action. Exogenous Lcn2 promotes insulin resistance in cultured hepatocytes. CONCLUSIONS--Lcn2 is an adipokine with potential importance in insulin resistance associated with obesity. Diabetes 56:2533-2540, 2007 [ABSTRACT FROM AUTHOR]

Serum levels of retinol binding protein 4 (RBP4) are increased in insulin resistant states. We measured RBP4 levels in 240 non-diabetic offspring of type 2 diabetic subjects. Offspring had the following measurements: oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), euglycemic hyperinsulinemic clamp, and CT scan to evaluate subcutaneous and intra-abdominal fat. Mean age was 36.5±6.4 years, mean BM126±5 kg/m². No statistically significant differences in serum RBP4 levels were found between subjects with normoglycemia (n=170, mean RBP4 25.6 µg/ml), impaired fasting glucose (n=47, RBP4 27.4 µg/ml) and impaired glucose tolerance (n=23, RBP4 26.7 µg/ml). RBP4 levels correlated positively with BMI (p=0.007), systolic (p=0.022) and diastolic (p=0.02 l) blood pressure, fasting glucose (p=0.004) and insulin (p=0.029), 1st phase insulin response in an IVGTT (p=0.009), plasma glucose (p<0.001) and insulin (p=0.005) area under the curve during OGTT, total and LDL cholesterol (p<0.001), total triglycerides (p<0.001), and intra-abdominal fat area (13<0.001). RBP4 levels correlated inversely with whole body glucose uptake (WBGU) (p=0.003) and HDL cholesterol (p=0.027). In multivariate linear regression analysis including RBP4 levels, age, BMI, WBGU, and 1st phase insulin response as independent variables and glucose AUC in OGTT as the dependent variable, RBP4 levels were associated with glucose AUC in OGTT (p=0.006) independently of other variables. Genetic analysis of 900 Caucasian nondiabetic offspring of type 2 diabetic subjects revealed that several SNPs in the RBP4 gene are associated with circulating glucose levels from 10 to 60 min during an IVGTT. In sum, high serum RBP4 levels are associated with components of the metabolic syndrome in nonobese, nondiabetic subjects. High RBP4 is also associated with hyperglycemia, evaluated by glucose AUC in OGTT, independently of age, BMI, insulin sensitivity and insulin secretion in offspring of type 2 diabetic patients. In conclusion, genetic and metabolic data suggest that RBP4 may regulate insulin action on hepatic glucose output. Furthermore, RBP4 is a convenient marker to assess risk of diabetes and cardiovascular disease in subjects in whom the risk might otherwise be overlooked. [ABSTRACT FROM AUTHOR]

The adipocyte-derived peptide retinol-binding protein 4 (RBP4) is associated with insulin resistance. Genetic deletion enhances insulin sensitivity and overexpression causes insulin resistance in mice. RBP4 is elevated in insulin resistant subjects. Metabolic syndrome markers (obesity, dyslipidemia, insulin resistance) improve with dietary carbohydrate restriction. Here, we test whether in RBP4 levels are also reduced by carbohydrate restriction. Overweight/obese nondiabetic subjects with atherogenic dyslipidemia were randomized to a very low carbohydrate ketogenic diet (n=20, VLCKD) (1504 kcal: %CHO:fat:protein = 12:59:28) or a low fat diet (n=19, LFD) (1478 kcal: %CHO:fat:protein = 56:24:20) for 12 wk. Compared to subjects consuming LFD, subjects on VLCKD reduced body weight and adiposity, and improved glycemic control, insulin sensitivity and atherogenic dyslipidemia (decreased triglyceride, increased HDL-C, and increased LDL particle size). Serum RBP4 levels were reduced more in subjects on VLCKD (-20.2%) compared to LFD (+5.1%) (p = 0.02). For all subjects, the change in amount of dietary carbohydrate intake correlated with the change in RBP4; the correlation was stronger in subjects on VLCKD (r=0.54). The absolute and percent changes in RBP4 correlated with weight loss, fat loss, and improvement in glucose, insulin, triglycerides, and the quantity of small LDL particles. These findings link the role of RBP4 in insulin resistance with studies showing a tight connection between carbohydrate restriction and features of metabolic syndrome. In addition to improvement in markers of metabolic syndrome, restriction of dietary carbohydrate is more effective than a low fat diet for reducing RBP4. [ABSTRACT FROM AUTHOR]

Increased intraabdominal fat is associated with insulin resistance and increased cardiovascular risk. Adipose tissue secretes proteins (adipokines) that regulate systemic insulin action. Adipokine production varies among fat depots. The adipokine, RBP4, is increased in obesity, impaired glucose tolerance, and type 2 diabetes and serum concentrations correlate highly with insulin resistance (measured by clamp), dyslipidemia, hypertension, and intraabdominal fat mass. We aimed to determine whether (1) RBP4 expression differs in visceral and subcutaneous fat depots, (2) is associated with increased intraabdominal fat mass, and (3) correlates with adipose GLUT4 expression. Serum RBP4 and RBP4 mRNA in paired visceral and subcutaneous adipose biopsies were measured in 196 subjects with a wide range of metabolic characteristics. RBP4 mRNA in visceral fat was increased ∼60-fold in subjects with visceral, and 12-fold with subcutaneous, obesity versus lean subjects, and ∼2-fold with Type 2 diabetes versus nondiabetic subjects. Serum RBP4 levels were increased 3-fold with visceral obesity and 2-fold with subcutaneous obesity. Serum RBP4 correlated with RBP4 mRNA in visceral (Fig A) and subcutaneous adipose tissue (R=0.80 and R=0.50, respectively, p<0.001), with intra-abdominal fat area measured by CT (R=0.42,p=0.004, Fig B), and inversely with insulin sensitivity (R=0.50, p<0.001), independently of age, gender and BMI. RBP4 mRNA correlated inversely with GLUT4 mRNA in visceral fat (R=0.47, p=0.001). Among many adipokines, RBP4 was the strongest predictor of insulin resistance (glucose disposal rate during clamp) and intraabdominal fat mass. In summary, RBP4 concentrations are linked to visceral adiposity. In conclusion, visceral fat with reduced expression of GLUT4 may be a major source of RBP4 in insulin-resistant states. RBP4 can be used as a marker for intraabdominal fat mass and associated abnormalities. [ABSTRACT FROM AUTHOR]

Serum RBP4 levels correlate highly with insulin resistance and associated metabolic abnormalities. RBP4 overexpression in mice causes insulin resistance. Chronic exercise training that improves insulin sensitivity in insulin resistant human subjects lowers serum RBP4. Liver is considered the primary source of circulating RBP4 but adipose tissue may also produce RBP4 in insulin resistance. RBP4 mRNA is detected in cardiac and skeletal muscle, but it is not known whether muscle contributes to circulating RBP4 levels. Our aims were to determine: (1) whether RBP4 expression is altered in muscle in subjects with impaired glucose tolerance (IGT) or type 2 diabetes (T2D) and (2) whether RBP4 is regulated by chronic or acute exercise. RBP4 mRNA in quadriceps biopsies from IGT or T2D subjects was increased ∼250-fold (p<0.0001) at baseline relative to normal glucose tolerant control subjects. Exercise training for 1 month improved insulin sensitivity (measured by clamp) and lowered muscle RBP4 mRNA in the majority of IGT/T2D subjects. These decreases in muscle RBP4 mRNA correlated highly with decreases in serum RBP4 (R=0.86, p<0.0001) and inversely with changes in insulin sensitivity (R= -0.65, p<0.0001). In contrast, 1 mo of exercise training in lean, normoglycemic control subjects increased serum RBP4 and muscle RBP4 mRNA∼2-fold and ∼30-fold, respectively (p<0.0001), although mRNA was still only ∼8% of IGT/T2D levels. After 6 mo of training, serum RBP4 levels returned to baseline in controls. Studies of acute exercise in untrained control subjects demonstrated that exercise for 180 min at ∼70% VO[sub 2]max increased muscle RBP4 mRNA 9-fold (p=0.001) and serum RBP4 levels by 70% (p<0.05). Similarly, acute treadmill exercise in rats increased muscle RBP4 mRNA ∼5-fold and serum RBP4 40% with no change in liver or adipose tissue RBP4 mRNA. The amount of RBP4 secreted from soleus muscle ex vivo was greater than from the same amount of fat. These results show: (1) In IGT/T2D subjects, exercise training-induced decreases in muscle RBP4 mRNA correlate inversely with changes in insulin sensitivity; (2) in normal subjects, exercise training increases muscle RBP4; and (3) acute exercise-induced increases of RBP4 in serum correspond to increased RBP4 mRNA in muscle but not in other tissues. These findings suggest that RBP4 may be a novel muscle-secreted signal regulating fuel homeostasis in exercise. [ABSTRACT FROM AUTHOR]