Abstract
Previous reports suggested that low subcutaneous adiposity increases the risk of cardiovascular events and diabetes. Mechanisms of depot-specific differences are still unknown. During studying tissue-specific roles of ERK2 (MAPK1), we observed Fabp4Cre mediated adipocyte-specific ERK2 knockout mice (AE2KO) with HFHS diet showed diminished the size of adipocytes in an only subcutaneous depot and increased ectopic fat depot and fibrotic steatohepatitis. The male AE2KO was created by crossing the C57BL/6 background Fabp4-Cre with ERK2flox/flox mouse. ERK2flox/flox Cre- mouse was used as a control. ERK2KO was observed only in white adipose tissues. With a normal diet, AE2KO mice showed no phenotype. HFHS diet started at age 6 weeks for 18 weeks. AE2KO exhibited 18% increase in body weight (n=8 each, p<0.05). Whereas HFHS increased adipose weight, the distribution of adipocyte size showed a significant decrease in subcutaneous depot (30 vs. 60 µm in mode, p<0.05 by 2-way ANOVA, n=8 each), but not in gonadal. RNA-sequence analysis (n=4, each) revealed a significant increase in expression of lipolysis gene (Prkaca, Tshr, and Adcy) and of the genes reported to cause a defect in fat storage (L3mbtl3, Pik3r1). Fasting glucose was increased and the Insulin tolerance test showed no change in plasma glucose in AE2KO compared to control (105% vs. 75% at 60 min, p<0.05, n=8 each). Liver weight increased 1.8-fold (n=8, p<0.05). NAS score increased (6.2 vs. 4.4, p<0.05, n=6) with prominent fibrosis. The increased ectopic fat depot was also observed in skeletal muscle and kidney. Oxygen consumption and RER was not changed. ERK2 knockout in human subcutaneous preadipocyte by Crispr Cas9 decreased adipocyte differentiation by 50%, suggesting an involvement of ERK2 in adipogenesis. These results strongly indicated that ERK2 is involved in subcutaneous depot abnormality which causes ectopic fat depot and organ damage by a high caloric diet. Disclosure Y. Ishinoda: None. T. Adachi: None. H. Kumagai: None. Y. Ido: None. M. Noguchi: None. Y. Yumita: None. K. Kagami: None. A. Osaki: None. Y. Satoh: None. S. Endo: None. A. Kasuga: None.
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