Fat remodeling has been extensively explored through protein deacetylation, but not yet acetylation, as a viable therapeutic approach in the management of obesity and related metabolic disorders. Here, we investigated the functions of key acetyltransferases CBP/p300 in adipose remodeling and their physiological effects by generating adipose-specific deletion of CBP (Cbp-AKO), p300 (p300-AKO) and double-knockout (Cbp/p300-AKO) models. We demonstrated that Cbp-AKO exhibited marked brown remodeling of inguinal WAT (iWAT) but not epididymal WAT (eWAT) after cold exposure and that this pattern was exaggerated in diet-induced obesity (DIO). Despite this striking browning phenotype, loss of Cbp was insufficient to impact body weight or glucose tolerance. In contrast, ablation of p300 in adipose tissues had minimal effects on fat remodeling and adiposity. Surprisingly, double-knockout mice (Cbp/p300-AKO) developed severe lipodystrophy along with marked hepatic steatosis, hyperglycemia and hyperlipidemia. Furthermore, we demonstrated that pharmacological inhibition of Cbp and p300 activity suppressed adipogenesis. Collectively, these data suggest that (i) CBP, but not p300, has distinct functions in regulating fat remodeling and that this occurs in a depot-selective manner; (ii) brown remodeling occurs independently of the improvements in glucose metabolism and obesity and (iii) the combined roles of CBP and p300 are indispensable for normal adipose development.
Figure S1. cDNA sequencing validation of Cbp-AKO and p300-AKO mice. (A) Cloning Cbp cDNA from fat of control mice and Cbp-AKO mice; (B) sequencing of Cbp WT or KO allele, showing Exon 9 which encodes the catalytic domain and deleted region in the KO allele. (C) Cloning p300 cDNA from fat of control mice and p300-AKO mice; (B) sequencing of p300 WT or KO allele, showing Exon 9 which encodes the catalytic domain and deleted region in the KO allele. The WT bands in Cbp-AKO and p300-AKO arose from non-adipocytes in adipose tissues. These cells don’t express Adipoq-Cre and account for ~50% of total adipose tissue cells.
Figure S2. (A-C) qPCR analysis of gene expression in BAT of Cbp-AKO and control mice on HFD feeding. n=6, 6, *: p<0.05.
Figure S3.FPLC fractionation of lipoprotein cholesterol in pooled sera from Cbp/p300 double knockouts and control mice fed on chow diet.
Supplemental Table 1.Expected and observed Mendelian ratios at weaning from an intercrosses between (A) CbpF/F, p300F/F and CbpF/+ p300F/+ Adipoq-Cre+ breeding pairs to generate Cbp/p300-AKO (double knockout) mice (Chi square =19.11, Degrees of Freedom =7, p = 0.0078); (B) CbpF/F, p300F/F and CbpF/+ p300F/F Adipoq-Cre+ breeding pairs to generate Cbp/p300-AKO (double knockout) mice (Chi square =19.37, Degrees of Freedom =3, p =0.0002); (C) CbpF/F, p300F/F and CbpF/F p300F/+ Adipoq-Cre+ breeding pairs to generate Cbp/p300-AKO (double knockout) mice (Chi square =13.48 , Degrees of Freedom =3, p =0.0037).