Inhibition of Preproinsulin Gene Expression by Leptin Induction of Suppressor of Cytokine Signaling 3 in Pancreatic β-Cells

Abstract

T he hormone leptin is the product of the obese (ob) gene, primarily produced by white adipose tissue (1) and typically circulates in proportion to body fat mass (2). Leptin acts on specific regions in the hypothalamus to inhibit food intake and raise energy expenditure. Elevated leptin levels in obese subjects are believed to be indicative of resistance to leptin. Leptin has also been shown to inhibit insulin secretion and preproinsulin gene expression in pancreatic ␤-cells (3-6), thereby establishing an adipoinsular feedback loop in concert with stimulatory action of insulin on leptin secretion from the adipose tissue (7,8). Dysregulation of this adipoinsular axis with the establishment of leptin resistance in pancreatic ␤-cells may lead to hyperinsulinemia, which could contribute to obesity and insulin resistance.Leptin signal transduction occurs through a distinct receptor of the class 1 cytokine superfamily of receptors (9), which is intracellularly coupled to the janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway (10). Several leptin receptor (ObR) isoforms are known, but the majority of physiological effects appear to be mediated via the longest form (ObRb) (11,12). In previous experiments, we and others have demonstrated that ObR isoforms, including ObRb, are expressed and functional in pancreatic ␤-cell lines and primary pancreatic islets (3,13). Binding of leptin to ObRb activates the receptor-associated kinase JAK2 via transphosphorylation and phosphorylates tyrosine residues on ObRb. Subsequently, transcription factors of the STAT family are recruited to the receptor and also phosphorylated. Phosphorylated STATs dimerize and translocate to the nucleus to regulate gene transcription (14). STATs have mainly been shown to transcriptionally enhance gene expression. However, we previously determined that leptin increases binding of STAT5b to the upstream sequences of the rat preproinsulin 1 promoter (6) and inhibits insulin biosynthesis via transcriptional repression (5). In this study, we sought to characterize this apparent contradiction at the molecular level.Suppressors of cytokine signaling (SOCS) belong to a family of molecules that inhibit cytokine signaling by inhibiting JAK-STAT signal transduction. These molecules contain a central Src-homology 2 domain and a conserved COOH-terminal SOCS box. Through the Src-homology 2 domain, they bind directly to tyrosine-phosphorylated residues on the cytokine receptor-associated kinase JAK2, which blocks the access of STATs to receptor binding sites and leads to inactivation of the JAKs (15). Expression of SOCS proteins is induced by various cytokines and hormones, including interleukin-6, leukemia inhibitory factor, erythropoietin, growth hormone, and leptin (16 -18). Accumulating evidence suggests that SOCS3 is a leptininduced negative feedback regulator of leptin receptor GFP, green fluorescent protein; JAK, janus kinase; ␣PY, anti-phosphotyrosine; SOCS, suppressor of cytokine signaling; STAT, signal transducer an...

Leptin promotes K ATP channel trafficking by AMPK signaling in pancreatic β-cells

“…Parallel increases in STAT3 phosphorylation levels ( Fig. S4A) ensured proper leptin signaling under our experimental conditions (20). In contrast, the surface levels of Kir2.1, another inwardly rectifying K + channel in pancreatic β-cells, were not affected by leptin (Fig.…”

Downregulating SOCS3 with siRNA ameliorates insulin signaling and glucose metabolism in hepatocytes of IUGR rats with catch-up growth

“…It can bind the insulin receptor (IR), impair the phosphorylation of the insulin receptor substrate (IRS)1 and 2 without inhibiting IR phosphorylation, and reduce the expression of IRS1 and IRS2 via a ubiquitin-mediated degradation (9). Furthermore, the overexpression of SOCS3 can also inhibit preproinsulin gene transcription in pancreatic β-cells, which directly reduces insulin secretion (10). Heterozygous SOCS3-deficient mice do not develop insulin resistance when exposed to a high-fat diet (11), whereas a SOCS3 deletion causes embryonic lethality on days 12-16 (12).…”

Role of leptin in the pancreatic β-cell: effects and signaling pathways

“…Thus, SOCS3 has another function in the pancreatic b-cell different from the well-known role as a negative regulator of the JAK/STAT pathway (Fruhbeck 2006). Given that leptin also increases SOCS3 expression in isolated human pancreatic islets and in islets from ob/ob mice treated in vivo, it seems that this mechanism may be general for various species (Laubner et al 2005). Consistent with these findings, SOCS3 mRNA is decreased and proinsulin mRNA is increased in KO mice with a pancreas-specific disruption of the leptin receptor (Morioka et al 2007).…”

“…Although STAT1, -3, -5b, and -6 are present in INS-1 cells, it seems that leptin-mediated activation of JAK2 recruits basically STAT3 and -5b. Interestingly, it was shown that the inhibitory effect of leptin on insulin gene expression was not mediated by direct interaction of STAT3 or -5b with the proinsulin promoter (Laubner et al 2005). By contrast, leptininduced suppressor of cytokine signaling 3 (SOCS3) expression by STAT-dependent mechanisms was found to be responsible for the inhibition of the rat insulin I gene promoter activity (Laubner et al 2005; Fig.…”

“…In INS-1 cells, it was reported that STAT5b was involved in leptin-mediated repression of the rat insulin I gene promoter (Seufert et al 1999a). More recently, this signaling pathway has been further characterized (Laubner et al 2005). Although STAT1, -3, -5b, and -6 are present in INS-1 cells, it seems that leptin-mediated activation of JAK2 recruits basically STAT3 and -5b.…”