Métabolisme des rétinoïdes et facteurs d’influence dans l’obésité, la résistance à l’insuline et le diabète de type 2 : 
études chez l’animal et chez l’homme

Introduction: Vitamin A and its active metabolites (all-trans and 9-cis retinoic acid), which activate nuclear receptors (RARs and RXRs), are essential for cell differentiation, embryogenesis, growth and disease prevention such as cancer and diabetes. Differentiation of adipocytes is largely dependent on retinoid. Serum retinol (ROL) transporter, the RBP4, is also an adipokine inversely correlated with insulin sensitivity. Obesity and type 2 diabetes (T2DM) are diseases that have reached epidemic proportion worldwide. Many studies have tried to find a solution, but a clear cut treatment still strives to be found. Metabolic syndrome and T2DM are correlated with a higher proportion of visceral versus subcutaneous fat and disrupt retinoid homeostasis. The link between visceral fat, insulin resistance (IRe) and T2DM has been clearly established. Retinoid and related molecules (RBP4, TTR), may serve as metabolic targets in the study and treatment of these disorders. There is much to be done in this area, the links between these molecules and these pathologies being emergent. Hypothesis: In this context, we postulate that retinoid metabolism differs between subcutaneous and visceral fat and the levels of circulating ROL, RBP4, and TTR correlates with clinical descriptors of obesity, IRe and T2DM, as early physiological indicators of these conditions. Goals: The global goal of this study is to investigate retinoid homeostasis in visceral and subcutaneous fat and to establish the relationships between retinoid and related molecules with obesity, IRe and T2DM in a fundamental and in a clinical study. Our specific goals are: (1.1). The characterization of RALDHs 1-4 enzymes involved in RA formation in visceral and subcutaneous fat of C57BL/6 mice; (1.2) The identification and quantification of ROL isomers in visceral and subcutaneous fat of C57BL/6 mice; (1.3) A parallel in the expression levels (mRNA) for retinoid metabolism genes, in subcutaneous and visceral fat. Second step: (2.1) A clinical study, to evaluate serum ROL, RBP4, ROL/RBP4 and other retinoid-related molecules regarding their potential as physiological markers predicting IRe and (2.2) to assess the eventual correlations between these markers and clinical descriptors of IRe and T2DM. Methodology: Experimental approaches used to reach these goals are: 1. Identification and measurement of RALDH activity by enzymatic assays; 2. Measurement of ROL isomers by HPLC; 3. Evaluation of retinoid metabolism gene expressions by RT-q-PCR; 4. Clinical pilot study in humans using four groups of subjects: group A, normal weight and healthy controls; group B, obese diabetics with poorly-controlled diabetes; group C, well-controlled obese diabetics; and group D, non-diabetic obese. In this study we did anthropometric and biochemical measurements: BMI, waist circumference (WC), blood pressure, blood complete formula, lipids profile, general biochemistry, albumin-creatinine ratio, TSH, HbA1c, fasting glucose, insulinemia, TTR, vitamins E and D, serum ROL by HPLC, serum RBP4 by Western Blot/ImageQuant; 5.Evaluation of RBP4, ROL and ratio correlations with traditional IRe and T2DM markers. Conclusions: Our study shows a direct relationship of fat topography with retinoid homeostasis and correlations between RBP4 level and obesity, IRe, and T2DM, as well as between ROL, glucose intolerance and T2DM. In healthy and normal weight mice, higher levels of adipokine RBP4 (mRNA) are present in visceral versus subcutaneous fat, suggesting an early contribution of the visceral fat to future insulin resistance, which sets up with obesity. Overall it can be concluded that RBP4 is involved in the development of IRe and diabetes and that its circulating level influences and is influenced by IRe, whereas ROL only increases under conditions of pancreatic failure with glucose intolerance. High serum RBP4 contributes to decrease of HDL cholesterol and may also reflect early renal dysfunction. These molecules (RBP4 and ROL), originating from retinoid metabolism, can be proposed as early biological markers of insulin resistance and glucose intolerance respectively. Our findings highlight the retinoid innovative role in the study of obesity and T2DM. Several studies across larger cohorts are needed to determine the precise role of RBP4 and ROL in obesity, IRe and T2DM, as well as to explore targeted therapeutic pathways.

Keyphrases: RBP4, TTR, vitamin A, adipose tissue, obesity, insulin resistance, diabetes