BK_Ca channel participates in insulin‐induced lipid deposition in adipocytes by increasing intracellular calcium

Abstract

Storing energy in the form of triglyceride (TG) is one of the basic functions of adipose tissue. Large‐conductance calcium‐activated potassium channels (BKCa channels) are expressed in adipose tissue and adipocyte‐specific BKCa deficiency resists obesity in mice, but the role of BKCa channels in lipid deposition and the underlying mechanisms have not been elucidated. In the present study, we generated BKCa knockout (KO) rats and performed a transcriptome analysis of adipose tissue. We found that the phosphoinositide 3‐kinase (PI3K)–protein kinase B (Akt) signaling pathway, which is important for lipid deposition, exhibited the most notable reduction among various signaling pathways in BKCa KO rats compared to wild‐type rats. Insulin‐induced TG deposition, glucose uptake, and Akt (Ser473) phosphorylation were significantly reduced in cultured adipocytes differentiated from adipose‐derived stem cells of BKCa KO rats. Furthermore, we found that the insulin‐induced increase of intracellular calcium resulting from extracellular calcium influx was significantly impaired in BKCa KO adipocytes. Finally, insulin activated BKCa currents through PI3K, which was independent of Akt and intracellular calcium. The results of this study suggested that BKCa channels participate in the insulin signaling pathway and promote TG deposition by increasing extracellular calcium influx in adipocytes.

Regulatory effects of protein S-acylation on insulin secretion and insulin action

“…Moreover, both global Kcnma1 deletion in mice, as well as inducible conditional genetic deletion of Kcnma1 in adult mouse adipocytes, prevents excessive body weight gain and fat deposition in response to a high-fat diet, revealing an important role for adipocyte BK channels in controlling obesity [97]. Importantly, recent studies in rats with a global deletion of BK channels reveal that loss of BK channels attenuates insulin-induced calcium influx, glucose uptake and triglyceride deposition in adipocytes [94]. Importantly, insulin-induced activation of BK channels and subsequent calcium influx in adipocytes was PI3 K-dependent, as it was prevented by the PI3 K inhibitor LY294002 but independent of elevated calcium or PKB activity.…”

“…zDHHC17 was identified as the main enzyme responsible for S-acylation of ClipR-59, and depletion of zDHHC17 perturbed both the recruitment of activated PKB to the plasma membrane and insulin-stimulated GLUT4 plasma membrane translocation [93]. Intriguingly, zDHHC17 may also play a role in insulin signalling in adipocytes through control of STREX variant BK channels (discussed above), to regulate calcium homeostasis [94], which is important for adipocyte maturation and physiology [95]. In humans, genome-wide association studies have identified BK channels as a susceptibility locus for obesity with increased expression of mRNA encoding the pore-forming α-subunit (KCNMA1) in white adipose tissue and adipose tissue-derived cells [96].…”

“…Intriguingly, zDHHC17 may also play a role in insulin signalling in adipocytes through control of STREX variant BK channels (discussed above), to regulate calcium homeostasis [94], which is important for adipocyte maturation and physiology [95]. In humans, genome-wide association studies have identified BK channels as a susceptibility locus for obesity with increased expression of mRNA encoding the pore-forming α-subunit ( KCNMA1 ) in white adipose tissue and adipose tissue-derived cells [96].…”

“…Importantly, insulin-induced activation of BK channels and subsequent calcium influx in adipocytes was PI3 K-dependent, as it was prevented by the PI3 K inhibitor LY294002 but independent of elevated calcium or PKB activity. mRNA for both the ZERO and STREX variant of BK channels was expressed in mature rat adipocytes, however, in HEK293 cells only STREX variant channels were activated by insulin in a PI3 K-dependent mechanism [94]. Thus, insulin-induced activation of STREX is proposed to hyperpolarize adipocytes, that are non-excitable, and promote calcium influx most likely through members of the transient receptor family of voltage-independent calcium channels [94,97].…”

“…mRNA for both the ZERO and STREX variant of BK channels was expressed in mature rat adipocytes, however, in HEK293 cells only STREX variant channels were activated by insulin in a PI3 K-dependent mechanism [94]. Thus, insulin-induced activation of STREX is proposed to hyperpolarize adipocytes, that are non-excitable, and promote calcium influx most likely through members of the transient receptor family of voltage-independent calcium channels [94,97]. As STREX is S-acylated by zDHHC17 this reveals the interesting possibility that S-acylation of STREX variant BK channels controls insulin-dependent calcium influx and adipocyte physiology.…”