alitretinoin and Diabetes-Mellitus--Type-2

To elucidate the effects of retinoic acids (RAs) on adipogenesis and insulin sensitivity, we treated mature adipocytes with two different kinds of RA, 9-cis-RA and all-trans-RA. Both 9-cis- and all-trans-RA inhibited the secretion of leptin. However, the inhibition was significantly decreased at a higher dose of each RA. The inhibitory effect of 9-cis-RA was synergistically enhanced by the addition of rosiglitazone, a synthetic ligand for peroxisome proliferator-activated receptor (PPAR) gamma. 9-cis-RA also leads to adipogenesis in a dose-dependent manner. On the contrary, all-trans-RA does not increase adipogenesis in a dose-dependent manner. To clarify the antidiabetic effects of RA, glucose uptake was assessed by estimating glucose concentrations in the medium. 9-cis-RA reduced glucose levels in the culture media, but all-trans-RA did not. In conclusion, all-trans-RA does not alter adipogenesis and glucose uptake but does inhibit leptin secretion. 9-cis-RA, however, seems to increase both adipogenesis and glucose uptake through activation of the retinoid X receptor/PPARgamma heterodimer.

Topics: Adipocytes; Alitretinoin; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Synergism; Gene Expression Regulation; Glycerol; Isomerism; Leptin; Male; PPAR gamma; Rats; Rats, Sprague-Dawley; Retinoid X Receptors; Rosiglitazone; Thiazolidinediones; Tretinoin

The nuclear receptor PPARgamma/RXRalpha heterodimer regulates glucose and lipid homeostasis and is the target for the antidiabetic drugs GI262570 and the thiazolidinediones (TZDs). We report the crystal structures of the PPARgamma and RXRalpha LBDs complexed to the RXR ligand 9-cis-retinoic acid (9cRA), the PPARgamma agonist rosiglitazone or GI262570, and coactivator peptides. The PPARgamma/RXRalpha heterodimer is asymmetric, with each LBD deviated approximately 10 degrees from the C2 symmetry, allowing the PPARgamma AF-2 helix to interact with helices 7 and 10 of RXRalpha. The heterodimer interface is composed of conserved motifs in PPARgamma and RXRalpha that form a coiled coil along helix 10 with additional charge interactions from helices 7 and 9. The structures provide a molecular understanding of the ability of RXR to heterodimerize with many nuclear receptors and of the permissive activation of the PPARgamma/RXRbeta heterodimer by 9cRA.

Topics: Alitretinoin; Amino Acid Sequence; Binding Sites; Crystallography; Diabetes Mellitus, Type 2; Dimerization; Drug Design; Histone Acetyltransferases; Humans; Ligands; Models, Molecular; Molecular Sequence Data; Nuclear Proteins; Nuclear Receptor Coactivator 1; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Rosiglitazone; Sequence Homology, Amino Acid; Surface Properties; Thiazoles; Thiazolidinediones; Transcription Factors; Tretinoin