Abstract
Brown and beige adipocytes are specialized to dissipate energy as heat. Sgk2, encoding a serine/threonine kinase, has been identified as a brown and beige adipocyte-specific gene in rodents and humans; however, its function in brown/beige adipocytes remains unraveled. Here, we examined the regulation and role of Sgk2 in brown/beige adipose tissue thermogenesis. We found that transcriptional coactivators PGC-1α and NT-PGC-1α activated by the β3 adrenergic receptor-cAMP-PKA pathway are recruited to the Sgk2 promoter, triggering Sgk2 transcription in response to cold. SGK2 elevation was closely associated with increased serine/threonine phosphorylation of proteins carrying the consensus RxRxxS/T phosphorylation site. However, despite cold-dependent activation of SGK2, mice lacking Sgk2 exhibited normal cold tolerance at 4°C. In addition, Sgk2+/+ and Sgk2−/− mice induced comparable increases in energy expenditure during pharmacological activation of brown and beige adipose tissue with a β3AR agonist. In vitro loss- and gain-of-function studies further demonstrated that Sgk2 ablation or activation does not alter thermogenic gene expression and mitochondrial respiration in brown adipocytes. Collectively, our results reveal a new signaling component SGK2, although dispensable for cold-induced thermogenesis that adds an additional layer of complexity to the β3AR signaling network in brown/beige adipose tissue.
Highlights
While white adipocytes store energy as triglycerides, brown adipocytes located in interscapular brown adipose tissue (BAT) transform the nutrient-derived chemical energy into heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1) in the mitochondria (Golozoubova et al, 2001; Nedergaard et al, 2001; Cannon and Nedergaard, 2004)
Sgk2 gene expression is markedly elevated by cold in murine brown and beige adipocytes compared to white adipocytes (Rosell et al, 2014; Perdikari et al, 2018) and its transcripts are enriched in human supraclavicular BAT compared to subcutaneous white adipose tissue (WAT) (Perdikari et al, 2018; Toth et al, 2020)
To further confirm the direct effect of βAR signaling on Sgk2 gene expression in brown and beige adipocytes, we differentiated brown preadipocytes (Uldry et al, 2006; Jun et al, 2014) into brown adipocytes and treated with a βAR agonist isoproterenol or a cell-permeable cAMP analog dibutyryl cAMP, which mimics the main intracellular regulatory mechanism activated by βAR stimulation
Summary
While white adipocytes store energy as triglycerides, brown adipocytes located in interscapular brown adipose tissue (BAT) transform the nutrient-derived chemical energy into heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1) in the mitochondria (Golozoubova et al, 2001; Nedergaard et al, 2001; Cannon and Nedergaard, 2004). Both SGK and AKT are activated by signals stimulating phosphatidylinositol 3-kinase (PI3K) and phosphorylate serine and threonine residues that lie within the consensus RxRxxS/T motifs (Alessi et al, 1996; Kobayashi et al, 1999; Manning and Cantley, 2007; Hemmings and Restuccia, 2012) They have overlapping substrates (Brunet et al, 2001; Sakoda et al, 2003; Lee et al, 2007), a growing body of evidence indicates that SGK and AKT are activated under distinct physiological cues, phosphorylate distinct proteins, and have different functions (Sakoda et al, 2003; Lang et al, 2006; Toker and Marmiroli, 2014). Despite selective expression of SGK2 in brown and beige adipocytes compared to white adipocytes, its function in brown and beige adipocyte thermogenesis has not been examined to date
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