The small molecule phenamil is a modulator of adipocyte differentiation and PPARγ expression

Abstract

We previously described the use of a cell-based screening approach to identify small molecules that regulate adipocyte differentiation. Here we identify the amiloride derivative phenamil as an adipogenic compound. Phenamil acutely induces expression of the key transcription factor of adipogenesis, peroxisome proliferator-activated receptor γ (PPARγ) and, consequently, promotes the differentiation of multiple preadipocyte cell lines, including 3T3-L1 and F442A. Interestingly, the adipogenic action of phenamil is distinct from and additive with both PPARγ ligands and the previously identified adipogenic small molecule harmine. To identify signaling pathways mediating phenamil's effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. ETS variant 4 (ETV4) was identified as a gene rapidly phenamil adipogenic small molecules PPARγ expression of the expression of of promotes expression of PPARγ and and differentiation. of PPARγ expression the of phenamil adipocyte differentiation and gene phenamil of that of PPARγ differentiation identify a phenamil as small molecule the of adipocyte differentiation that of We previously described the use of a cell-based screening approach to identify small molecules that regulate adipocyte differentiation. Here we identify the amiloride derivative phenamil as an adipogenic compound. Phenamil acutely induces expression of the key transcription factor of adipogenesis, peroxisome proliferator-activated receptor γ (PPARγ) and, consequently, promotes the differentiation of multiple preadipocyte cell lines, including 3T3-L1 and F442A. Interestingly, the adipogenic action of phenamil is distinct from and additive with both PPARγ ligands and the previously identified adipogenic small molecule harmine. To identify signaling pathways mediating phenamil's effects, we performed transcriptional profiling of 3T3-F442A preadipocytes. ETS variant 4 (ETV4) was identified as a gene rapidly phenamil adipogenic small molecules PPARγ expression of the expression of of promotes expression of PPARγ and and differentiation. of PPARγ expression the of phenamil adipocyte differentiation and gene phenamil of that of PPARγ differentiation identify a phenamil as small molecule the of adipocyte differentiation that of proliferator-activated receptor γ (PPARγ) is a of the receptor that as the transcriptional of of a transcription PPARγ with receptor and adipogenic gene PPARγ a of and as and transcriptional pathways that expression of PPARγ to that to PPARγ expression and expression of induces and of transcription transcription factor is a key of adipocyte of factor transcriptional of and factor peroxisome expression and and of transcription factor a of with to and factor transcription regulate adipocyte and adipocyte differentiation with and of multiple to PPARγ expression a of that the of multiple signaling and cell-based screening the of small molecules that We previously approach to the small molecule as an of PPARγ expression and that small molecule is an of Interestingly, of action the of signaling preadipocytes. profiling the of preadipocyte gene we identified the transcription factor as a of action of is a small of peroxisome proliferator-activated expression and adipocyte We adipogenic small molecules an to identify with of action distinct from that of and PPARγ the of the small molecule phenamil as a of adipocyte differentiation. Interestingly, phenamil PPARγ expression a distinct from harmine. 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