Adipogenesis is orchestrated by a highly ordered network of transcription factors including peroxisome-proliferator activated receptor-gamma (PPARy) and CCAAT-enhancer binding protein (C/EBP) family proteins. High mobility group protein AT-hook 2 (HMGA2), an architectural transcription factor, has been reported to play an essential role in preadipocyte proliferation, and its overexpression has been implicated in obesity in mice and humans. However, the direct role of HMGA2 in regulating the gene expression program during adipogenesis is not known. Here, we demonstrate that HMGA2 is required for C/EBP beta-mediated expression of PPARy, and thus promotes adipogenic differentiation. We observed a transient but marked increase of Hmga2 transcript at an early phase of differentiation of mouse 3T3-L1 preadipocytes. Importantly, Hmga2 knockdown greatly impaired adipocyte formation, while its over expression promoted the formation of mature adipocytes. We found that HMGA2 colocalized with C/EBP beta in the nucleus and was required for the recruitment of C/EBP beta to its binding element at the Ppar gamma 2 promoter. Accordingly, HMGA2 and C/EBP beta cooperatively enhanced the Ppar gamma 2 promoter activity. Our results indicate that HMGA2 is an essential constituent of the adipogenic transcription factor network, and thus its function may be affected during the course of obesity. (C) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license.