COP9 Signalosome is required for Brown Adipose Tissue Maintenance and Thermogenic Function

Brown adipose tissue (BAT) metabolizes lipids and glucose to produce heat through nonshivering thermogenesis, a vital process for thermoregulation, maintaining systemic energy balance, and combating obesity. The COP9 (constitutive photomorphogenesis mutant 9) signalosome (CSN), composed of eight subunits (CSN1–CSN8), is crucial for the activity of cullin-RING-ubiquitin (Ub) E3 ligases (CRLs), which target cellular proteins for degradation via ubiquitination. However, its role in BAT function remains largely unknown. Our goal was to explore the role of CSN8, the smallest subunit of the CSN complex, in BAT maintenance, thermogenesis, and obesity. We first examined the BAT phenotype in mice with adipocyte-specific deletion of Csn8 (Csn8f/f; AdipoqCre+, i.e., Csn8AKO). Csn8AKO mice showed BAT atrophy and severe cold intolerance. Bulk RNA-seq of BAT identified 790 upregulated and 1,550 downregulated genes. KEGG analysis revealed increased inflammatory and cell death pathways and decreased metabolic pathways in Csn8AKO BAT. To specifically study CSN8’s role in brown adipocytes, we created mice with brown adipocyte-specific deletion of Csn8 (Csn8f/f; Ucp1-Cre+, i.e., Csn8BKO). Csn8BKO mice showed no differences in body weight, total fat, or lean mass compared to wild-type Csn8f/f mice. However, they displayed BAT atrophy, with approximately 70% reduction in BAT mass by 10 weeks of age in both males and females, and were completely sensitive to cold. Histological analysis showed a lack of multilobular lipid droplets and infiltration by numerous immune cells in Csn8BKO BAT, which were confirmed by lower triglyceride levels, significantly higher expression of inflammatory marker genes, and increased staining for the macrophage marker (MAC2). Furthermore, increased expression of apoptotic and phagocytic genes and proteins in Csn8BKO BAT indicates the occurrence of apoptosis and phagocytosis after CSN8 deletion, which was linked to heightened ubiquitination in Csn8BKO BAT. Surprisingly, Csn8BKO mice did not exhibit worsening of high-fat diet-induced obesity. Instead, their BAT mass was restored and showed a similar degree of whitening as wild-type mice. In conclusion, our findings highlight CSN8 as a crucial player for brown adipocyte survival, BAT maintenance, and thermogenesis. A high-fat diet may affect CSN8's role in brown fat fate and obesity-induced whitening, underscoring its unique function in brown fat. This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases R01DK135657A1 and the National Heart, Lung and Blood Institute 2R01HL132182. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.