7623 Transcriptional control of biogenesis and maintenance of adipocytes
Authors: Patel Sanil , Ganbold Khatanzul , Hwan Cho Chung , Siddiqui Juwairriyyah , Sparman Njeri , Sadeh Shani , Yildiz Ramazan , Nyugen Christy , Wang Jeixin , Whitelegge Julian , Fried Susan K , Hironori Waki , Villanueva Claudio J , Seldin Marcus , Sakaguchi Shinya , Ellmeier Wilfried , John Tontonoz Peter , Rajbhandari Prashant 
Published: October 2024

Abstract
Disclosure: S. Patel: None. K. Ganbold: None. C. Cho: None. N. Sparman: None. S. Sadeh: None. R. Yildiz: None. C. Nyugen: None. J. Wang: None. J. Whitelegge: None. S.K. Fried: None. W. Hironori: None. C.J. Villanueva: None. M. Seldin: None. S. Sakaguchi: None. W. Ellmeier: None. P.J. Tontonoz: None. P. Rajbhandari: None.
In caloric excess, the lack of functional adipocytes can cause lipid mishandling and altered adipokine production, leading to lipid accumulation in non-adipose organs (lipotoxicity) and insulin resistance. Proper adipocyte function is vital for metabolic health, as healthy adipocytes can mitigate the adverse effects of obesity; therefore, identifying factors involved in adipocyte formation and maintenance holds immense promise for combating the global epidemics of obesity and diabetes. Adipogenesis, a highly orchestrated program involving commitment and terminal differentiation phases, is driven by complex transcriptional events triggered by several transcription factors that drive the CEBPβ-PPARγ-CEBPα feed-forward circuitry. Through an unbiased high-throughput cDNA screen, we have identified the zinc finger protein PATZ1 as a novel transcription factor crucial for adipogenesis. In vitro studies have validated PATZ1's role in promoting both early and late differentiation phases of adipogenesis via its DNA binding ability. Genome-wide DNA binding analyses have uncovered PATZ1's interactions with the promoter regulatory regions of crucial adipogenic factors and histone modifiers, including CEBPβ, MED1, and p300, to maintain the CEBPβ-PPARγ and CEBPβ-PPARγ-CEBPα feed-forward circuitry for adipogenesis and maintenance of adipocytes, respectively. In vivo, analysis using three distinct mouse models has demonstrated that PATZ1 knockdown in adipocyte precursor cells leads to decreased fat mass and impaired expression of early adipogenesis factors, while PATZ1 knockdown in mature adipocytes results in reduced fat mass and a lipodystrophic-like phenotype. Intriguingly, the deletion of PATZ1 in brown adipose tissue precursors shows no significant differences compared to controls. Moreover, we have identified General Transcription Factor 2I (GTF2I) as a binding partner of PATZ1, which potentially forms a repressive complex that regulates PATZ1's adipogenic function. Notably, the knockdown of GTF2I enhances adipogenic programming, suggesting its role in limiting adipogenesis. These exciting findings position PATZ1 as a pivotal regulator of adipocyte differentiation and metabolic programs. By unveiling the intricate interplay between transcriptional programs and adipocyte-specific phenotypes, our study could inform future therapeutic interventions in adipose tissue to address obesity and its associated comorbidities.
Presentation: 6/1/2024