Reversal of obesity development in Ceacam1-/- male mice by bone marrow transplantation or introduction of the human CEACAM1 gene.

OBJECTIVE: Although Ceacam1-/- male mice become obese on normal chow, the effect of bone marrow transplantation or introduction of the carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) gene has not been studied, to the knowledge of the authors. METHODS: This study analyzed Ceacam1-/- mice on normal diet or high-fat diet (HFD), including effects of bone marrow transplantation or introduction of the CEACAM1 gene. RESULTS: Male Ceacam1-/- mice on normal diet versus HFD for 24 weeks gained significantly more weight than controls, and Ceacam1-/- mice aged up to 2 years had a high frequency of liver cancer. Transplantation of wild-type bone marrow into Ceacam1-/- mice or introduction of the human CEACAM1 gene fully or partially reversed the obesity phenotype. Liver lipidomics on Ceacam1-/- versus wild-type controls on an HFD revealed a significant increase in diacyl glycerides. An increase in fatty acid transporter CD36 levels further suggests that loss of Ceacam1 leads to a major dysregulation of free fatty acid uptake. CONCLUSIONS: CEACAM1 expression in both the liver and immune cells regulates obesity and lipid storage pathways in the liver. Bone marrow reconstitution of the immune system or introduction of the human CEACAM1 gene can fully or partially reverse the phenotype.

Role of lncRNA LIPE-AS1 in adipogenesis.

Recent studies have identified long non-coding RNAs (lncRNAs) as potential regulators of adipogenesis. In this study, we have characterized a lncRNA, LIPE-AS1, that spans genes CEACAM1 to LIPE in man with conservation of genomic organization and tissue expression between mouse and man. Tissue-specific expression of isoforms of the murine lncRNA were found in liver and adipose tissue, one of which, designated mLas-V3, overlapped the Lipe gene encoding hormone-sensitive lipase in both mouse and man suggesting that it may have a functional role in adipose tissue. Knock down of expression of mLas-V3 using anti-sense oligos (ASOs) led to a significant decrease in the differentiation of the OP9 pre-adipocyte cell line through the down regulation of the major adipogenic transcription factors Pparg and Cebpa. Knock down of mLas-V3 induced apoptosis during the differentiation of OP9 cells as shown by expression of active caspase-3, a change in the localization of LIP/LAP isoforms of C/EBPß, and expression of the cellular stress induced factors CHOP, p53, PUMA, and NOXA. We conclude that mLas-V3 may play a role in protecting against stress associated with adipogenesis, and its absence leads to apoptosis.