Selective interaction between leptin and insulin signaling pathways in a hepatic cell line

Abstract

Leptin is a 16-kDa hormone secreted by adipocytes and plays an important role in control of feeding behavior and energy expenditure. In obesity, circulating levels of leptin and insulin are high because of the presence of increased body fat mass and insulin resistance. Recent reports have suggested that leptin can act through some of the components of the insulin signaling cascade, such as insulin receptor substrates (IRS-1 and IRS-2), phosphatidylinositol 3-kinase (PI 3-kinase), and mitogen-activated protein kinase, and can modify insulin-induced changes in gene expression in vitro and in vivo. Well differentiated hepatoma cells (Fao) possess both the long and short forms of the leptin receptor and respond to leptin with a stimulation of c-fos gene expression. In Fao cells, leptin alone had no effects on the insulin signaling pathway, but leptin pretreatment transiently enhanced insulininduced tyrosine phosphorylation and PI 3-kinase binding to IRS-1, while producing an inhibition of tyrosine phosphorylation and PI 3-kinase binding to IRS-2. Leptin alone also induced serine phosphorylation of Akt and glycogen synthase kinase 3 but to a lesser extent than insulin, and the combination of these hormones was not additive. These results suggest complex interactions between the leptin and insulin signaling pathways that can potentially lead to differential modification of the metabolic and mitotic effects of insulin exerted through IRS-1 and IRS-2 and the downstream kinases that they activate.T he product of the ob gene is leptin, a 16-kDa peptide hormone produced by adipocytes that acts in the hypothalamus and plays a central role in regulation of feeding behavior and energy homeostasis (1-4). The leptin receptor (OB-R) occurs in several isoforms that differ in the length of their intracellular domains because of alternative splicing of the gene (5, 6). The long form is termed OB-Rb or OB-R L and is expressed abundantly in specific nuclei of the hypothalamus. The short forms, OB-Ra, c, d, and e (collectively referred to OB-R S ), have a wide tissue distribution. The long form of the OB-R belongs to the gp130 family of cytokine receptors that also includes the receptor for IL-6, leukocyte inhibitory factor, and granulocyte colony stimulating factor. These receptors act by activating cytoplasmic tyrosine kinases of the Janus kinase (JAK) family that in return phosphorylate specific transcription factors of the Stat (signal transducer and activator of transcription) family (7-10). On phosphorylation, the Stat proteins dimerize and translocate to the nucleus where they bind to specific nucleotide sequences and induce gene expression. Despite the abundance of the short forms of receptor, little is known about their physiological significance. Cells transfected with the short form of receptor may be capable of activating JAK kinases but fail to phosphorylate Stat proteins or activate gene expression (6,8).In vivo and in vitro evidence supports the hypothesis that leptin and insulin signaling networks may be connected at s...

Phosphoinositide 3-kinases as a common platform for multi-hormone signaling

“…Although many effects of leptin are mediated through the central nervous system (for PI3K-mediated effects of leptin on the brain refer to review; Plum et al 2005), this peptide can regulate metabolism through a direct action on tissues, such as pancreas and liver. In agreement with this finding, previous studies have shown that leptin activates PI3K in b-cells and hepatocytes , Harvey et al 2000, Szanto & Kahn 2000. Moreover, in primary rat hepatocytes, leptin induces PI3K-dependent activation of phosphodiesterase 3B, a cAMP-degrading enzyme, to suppress glucagon-induced cAMP elevation (Zhao et al 2000).…”

Suppressor of cytokine signaling-3 (SOCS-3) and a deficit of serine/threonine (Ser/Thr) phosphoproteins involved in leptin transduction mediate the effect of fructose on rat liver lipid metabolism

“…1E), reflecting the lack of activation of JAK-2 by leptin in these animals. 20,22,24 When phosphorylated at a Ser residue by the protein kinase B or Akt kinase, FoxO1 is inactivated and migrates from the nucleus to the cytosolic compartment. 25 Thus the excess nuclear activity of FoxO1 in the livers of fructose-fed animals is again related to a deficit in the leptin-signal pathway through JAK-2 activation.…”

Effect of pinealectomy on plasma levels of insulin and leptin and on hepatic lipids in type 2 diabetic rats

“…Mounting evidence shows that leptin can also regulate the metabolism of fat and glucose, including attenuation of insulin action and sensitivity in peripheral tissues [37], and that it can function through some of the components of the insulin signaling cascade, thereby modifying insulin-induced changes in gene expression [38]. Plasma leptin concentrations have been shown to be related to insulin sensitivity in diabetic subjects [39].…”