Fenretinide Ameliorates Insulin Resistance and Fatty Liver in Obese Mice

Abstract

Fenretinide (FEN), a ligand of retinol binding protein 4 (RBP4), has been suggested as a measure to reduce insulin resistance and its associated disorders such as obesity, and fatty liver by reducing serum RBP4. We investigated whether there is another possible mechanism by which fenretinide reduces insulin resistance and fatty liver in genetically obese (ob/ob) mice. Male obese mice fed a high-fat diet (45% of calories from fat) were divided into two groups (n 13 each). One (FEN) received fenretinide (20 mg/kg body weight, intraperitoneally) and the other (O) received vehicle three times weekly for 24 d. C57BL/6J mice fed a normal-fat diet (16% of calories from fat) were used as a control (C; n 13). No changes in fat weight and serum leptin level could be observed in FEN mice. Lower plasma RBP4 was observed in FEN mice compared with O mice. Fenretinide improved whole-body insulin sensitivity based on glucose and insulin tolerance tests and the homeostasis model assessment of insulin resistance. Fenretinide decreased the plasma lipid (triglyceride, cholesterol, and free-fatty acid) levels, hepatic TG level, and histological steatosis score. The mechanism by which fenretinide prevents fatty liver may be explained by an increased plasma adiponectin level, increased activation of hepatic AMP-activated protein kinase, and the expression of peroxisome proliferator-activated protein-α and peroxisomal acyl-CoA oxidase, which promote fat oxidation. FEN alleviated insulin resistance and fatty liver in obese mice and thus may act as an anti-lipidemic and anti-diabetic drug.Key words fenretinide; retinol binding protein-4; insulin resistance; fatty liver; fatty acid oxidation Obesity is a worldwide public health problem and is associated with hypertension, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and type 2 diabetes, with insulin resistance being a common factor. The pathogenesis of these conditions occurs in insulin-acting peripheral tissues, including skeletal muscle, liver, and adipose tissue. [1][2][3] In particular, insulin resistance-related adipose tissue dysfunction leads to the release of a high level of free-fatty acids and perturbs the levels of various adipokines, such as leptin, adiponectin, and retinol binding protein 4 (RBP4), which directly or indirectly affect insulin sensitivity by modulating insulin signaling and molecules involved in glucose and lipid metabolism in many tissues. [4][5][6] RBP4 is a compact, globular, 21-kDa protein and was known only as a retinol carrier synthesized and secreted by the liver, until recently. 6) Although serum RBP4 originates largely from the liver under physiological conditions, it is secreted considerably from fat tissues in an insulin-resistant state.7) Yang et al. showed that adipose tissue-specific ablation of glucose transporter 4 increased RBP4 mRNA expression in adipocytes and serum RBP4 levels in rats, and focused on the link between the serum RBP4 level and insulin sensitivity. 8)Despite some reports that RBP4 is not associated with insulin resis...

Pioglitazone Lowers Serum Retinol Binding Protein 4 by Suppressing its Expression in Adipose Tissue of Obese Rats

“…Many adipokines are implicated directly in the pathologies associated with obesity, particularly the metabolic syndromes [18]. RBP4 is a compact and globular protein that was first identified as a retinol carrier, and is mainly synthesized and secreted by the liver [19]. Recently, an increasing body of evidence has identified RBP4 as an adipokine and elevated RBP4 expression is closely related to insulin resistance and type 2 diabetes [20].…”

“…An increasing body of evidence from both clinical and experimental studies have corroborated that elevated serum RBP4 level contributes to systemic insulin resistance and is associated with metabolic disorders, including diabetes, dyslipidemia, and cardiovascular risk factors [4,5,6]. Suppression of serum RBP4 by fenretinide, which increases urinary excretion of RBP4, improves insulin resistance and glucose intolerance [7,8]. …”

The Effect of Acitretin Treatment on Insulin Resistance, Retinol-Binding Protein-4, Leptin, and Adiponectin in Psoriasis Vulgaris: A Noncontrolled Study

“…Fenretinide is a synthetic retinoid and anticancer agent that reduces serum RBP-4 levels by interfering with RBP-4 binding to transthyretin resulting in an improvement in insulin sensitivity [16,17]. In an experimental study, fenretinide, a ligand of RBP-4, was given to genetically obese (ob/ob) mice [18]. Plasma RBP-4 levels were decreased and adiponectin levels were increased significantly with fenretinide treatment.…”

Retinol-Binding Protein 4 Is an Independent Factor Associated With Triglycerides and a Determinant of Very Low-Density Lipoprotein–Apolipoprotein B100 Catabolism in Type 2 Diabetes Mellitus

“…This is in line with animal studies that have shown that reduction in plasma rbp4 level using RNA oligonucleotide against rbp4 in high-fat diet-fed mice or using a ligand of rbp4 in ob/ob mice induces a significant reduction in plasma triglycerides. 16,37 To precisely determine the association between plasma rbp4 and triglycerides and to explore a possible link between elevated plasma rbp4 levels and hypertriglyceridemia, in T2DM, we performed an in vivo kinetic study of apoB-containing lipoproteins (VLDL, IDL, LDL) with stable isotopes in a group of 14 patients with T2DM. The results of our kinetic study clearly show that rbp4 is negatively associated with the catabolism of VLDL-apoB100 and that this relationship is independent of triglycerides, age, sex, BMI, HbA1c, HDL-C, and markers of insulin resistance, such as homeostasis model assessment of insulin resistance or plasma adiponectin level.…”