Ubc9deletion in adipocytes causes lipoatrophy in mice

Abstract

Objective: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. WAT absence or loss occurring through lipodystrophy and lipoatrophy contributes to the development of dyslipidemia, hepatic steatosis, and insulin resistance. We previously demonstrated the sole small ubiquitin-like modifier (SUMO) E2- conjuguating enzyme Ubc9 represses human adipocyte differentiation. Germline and other tissue-specific deletions of Ubc9 frequently cause lethality in mice. As a result, the role of Ubc9 during WAT development remains unknown. Methods: To determine how Ubc9 impacts body composition and energy balance, we generated adipocyte-specific Ubc9 knockout mice (Ubc9a-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ubc9 locus. Subsequent genetic crosses to AdipoQ-Cre transgenic mice allowed deletion of Ubc9 in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ubc9a-KO and littermate controls during postnatal growth. Results: To our surprise, Ubc9a-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. Conclusions: Our results demonstrate that Ubc9 expression in mature adipocytes is essential for maintaining WAT expansion. Deletion of Ubc9 in fat cells compromised and diminished adipocyte function that provoked WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ubc9 during white adipocyte expansion and endocrine control of energy balance.

Waves of sumoylation support transcription dynamics during adipocyte differentiation

“…S1B), which was characterized by numerous small LDs (Fig. S1C-D), mirroring the recently reported phenotype of Ubc9 KO in mouse white adipose tissue (Cox et al, 2020). Given that sumoylation mostly targets nuclear proteins involved in chromatin and gene regulation (Cossec et al, 2018; Hendriks et al, 2018), we hypothesized that ML-792 treatment induces lipoatrophy due to abnormalities in adipogenic gene expression programs.…”

“…S1C), which was characterized by numerous small lipid droplets (Fig. S1D-E), mirroring the recently reported phenotype of loss of Ubc9 in mouse white adipose tissue (Cox et al, 2020). These data show that an active sumoylation pathway is required for efficient adipogenesis.…”

“…Evidence that the sumoylation pathway supports adipose tissue formation and function has been provided by previous studies (Chung et al, 2010;Cignarelli et al, 2010;Cox et al, 2020;Liu et al, 2014;Mikkonen et al, 2013;Zheng et al, 2018). The majority of these studies have concluded that sumoylation generally inhibits adipogenic transcription factors.…”

“…Therefore, there exists a need for a biologically relevant model to study sumoylome dynamics during differentiation. Interestingly, Sumo-1 but also Senp2 knockout (KO) mice are resistant to high fat diet (HFD)induced obesity (Mikkonen et al, 2013;Zheng et al, 2018) and white adipose tissue (WAT)-specific UBC9 KO triggers lipoatrophy (Cox et al, 2020). Consistently, loss of Sumo-1, Ubc9, Senp1 or Senp2 in cellular models impedes adipogenesis and the expression of genes under the control of PPARg, preprint (which was not certified by peer review) is the author/funder.…”

“…Therefore, there exists a need for a biologically relevant model to study sumoylome dynamics during differentiation. Interestingly, mouse knockout studies have revealed that animals lacking Sumo-1 or Senp2 are resistant to high fat diet (HFD)-induced obesity (Mikkonen et al, 2013;Zheng et al, 2018), whereas specific loss of UBC9 in white adipose tissue triggers lipoatrophy (Cox et al, 2020). Consistently, loss of Sumo-1, Ubc9, Senp1 or Senp2 in cellular models impedes adipogenesis and is associated with altered expression of genes under the control of PPARg, cEBPa, or cEBPd, as well as genes involved in lipid and energy metabolism (Chung et al, 2010;Cignarelli et al, 2010;Liu et al, 2014).…”