SUMO-1 Regulates Body Weight and Adipogenesis via PPARγ in Male and Female Mice

Abstract

Properly functioning adipose tissue is essential for normal insulin sensitivity of the body. When mice are kept on high-fat diet (HFD), adipose tissue expands, adipocytes increase in size and number, and the mice become obese. Many of these changes are mediated by the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), the activity of which is regulated by multiple posttranslational modifications, including SUMOylation. To address the role of small ubiquitin-like modifier-1 (SUMO-1) in PPARγ function in vivo, particularly in fat cell biology, we subjected Sumo1-knockout mice to HFD. Sumo1-null mice gained less weight and had smaller and fewer adipocytes in their gonadal fat tissue on HFD, but their glucose tolerance was similar to that of wild-type littermates. Adipogenesis was impaired in Sumo1-null cells, and expression of PPARγ target genes was attenuated. In addition, both Sumo1-null cells and Sumo1-null mice responded less efficiently to rosiglitazone, a PPARγ agonist. These findings indicate that SUMO-1 is important also for transcriptional activation by the PPARγ signaling pathway and not only for trans-repressive functions of PPARγ as previously reported.

Functional Regulation of PPARs through Post-Translational Modifications

“…While many details of the exact mechanisms and pathways governing SUMO-mediated PPARγ regulation remain open to future research, work from Mikkonen et al, has highlighted its physiological importance, as they showed that SUMO1 knockout mice exhibited a metabolic phenotype and decreased PPARγ target gene expression [ 69 ].…”

SUMOylation in brain ischemia: Patterns, targets, and translational implications

“…7,8 A more detailed analysis of SUMO1 knockout mice, however, has revealed differences in body weight, adipogenesis, and inflammatory responses. 9,10 This suggests that while SUMO2/3 may be able to compensate for many of the developmental roles of SUMO1, there are subtler isoform-specific functions which require SUMO1. 11 Of note, the existence of a fourth isoform (SUMO4), which possesses 86% homology with SUMO2, has been confirmed; however, its functional role remains unclear.…”

Ginkgolic acid, a sumoylation inhibitor, promotes adipocyte commitment but suppresses adipocyte terminal differentiation of mouse bone marrow stromal cells

“…Some evidence suggests that sumoylation promotes adipogenesis. For example, i) Sumo1 -null mice on a high-fat diet gained less weight, had fewer and smaller adipocytes, and had decreased PPARγ target gene expression 12 ; ii) a reduced level of UBC9 in 3T3-L1 adipocytes caused a significant delay in PPARγ and C/EBPα expression; and iii) UBC9 has been found to regulate glucose transporter 4 (GLUT4) turnover in adipocytes 13 . On the other hand, some studies suggest that sumoylation pathways suppress adipogenesis.…”