Enrichment of Short-Chain Ceramides and Free Fatty Acids in the Skin Epidermis, Liver, and Kidneys of db/db Mice, a Type 2 Diabetes Mellitus Model

Patients with diabetes mellitus (DM) often suffer from diverse skin disorders, which might be attributable to skin barrier dysfunction. To explore the role of lipid alterations in the epidermis in DM skin disorders, we quantitated 49 lipids (34 ceramides, 14 free fatty acids (FFAs), and cholesterol) in the skin epidermis, liver, and kidneys of db/db mice, a Type 2 DM model, using UPLC-MS/MS. The expression of genes involved in lipid synthesis was also evaluated. With the full establishment of hyperglycemia at the age of 20 weeks, remarkable lipid enrichment was noted in the skin of the db/db mice, especially at the epidermis and subcutaneous fat bed. Prominent increases in the ceramides and FFAs (>3 fold) with short or medium chains (<C26) occurred in the skin epidermis (16NS, 18NS, 24NS, 16NDS, 18NDS, 20NDS, 22NDS, 24NDS, C16:1FA, C18:2FA, and C18:1FA) and the liver (16NS, 18NS, 20NS, 24:1NS, 18NDS, 20NDS, 22NDS, C16:1FA, C18:2FA, C18:1FA), whereas those with very long chains were not affected. In the kidney, only slight increases (<3 fold) were observed for 16NS, 18NS, 20NS, 26NDS, C26FA, and C22:1FA. Consistently, LXRα/β and PPARγ, nuclear receptors promoting lipid synthesis, lipid synthesis enzymes such as elongases 1, 4, and 6, and fatty acid synthase and stearoyl-CoA desaturase were highly expressed in the skin and livers of the db/db mice. Collectively, our study demonstrates an extensive alteration in the skin and systemic lipid profiles of db/db mice, which could contribute to the development of skin disorders in DM.