COP9 signalosome is required for adipose tissue maintenance and metabolic health.

Constitutive photomorphogenesis mutant 9 (COP9) signalosome (CSN) is composed of eight subunits (CSN1 through CSN8). It acts as an essential regulator of Cullin-RING-ubiquitin ligases (CRLs), which target critical cellular regulators for degradation via the ubiquitin (Ub) proteasome pathway. The role of CSN in adipose tissue development and function has not yet been studied. We sought to determine the role of CSN8, the smallest subunit of the CSN complex, in adipogenesis, adipose tissue maintenance, and metabolic balance. We first found that CSN8 level remained constant during adipogenesis and knocking down CSN8 by CRISPR/Cas9 did not impair adipocyte differentiation. Notably, mice with adipocyte-specific Csn8 gene deletion (Csn8AKO) showed disrupted CSN holo-complex formation and Cullin deneddylation, leading to the loss of white and brown adipose tissue. Csn8AKO mice displayed insulin resistance while maintaining glucose tolerance. They showed increased food intake and a trend toward higher energy expenditure but were cold-intolerant. Bulk RNA sequencing revealed that CSN deficiency caused significant remodeling of white and brown adipose tissues, characterized by adipocyte death and inflammation. Specifically, white and brown adipose tissues lacking CSN8 exhibited marked upregulation of apoptotic and pyroptotic cell death, which was associated with alterations in ubiquitination and proteasome activity. In addition, Csn8AKO mice were protected from high-fat diet-induced adipose tissue expansion but developed notable hepatomegaly, steatosis, and insulin resistance. Taken together, our data highlights that CSN8/CSN is crucial for maintaining protein homeostasis in adipose tissue, promoting adipocyte survival, supporting adipose tissue maintenance, and overall metabolic health.