The long and short isoforms of the leptin receptor (OBRl and OBRs) differ in their signaling capabilities. OBRl, with 302 cytoplasmic residues, is primarily responsible for leptin signaling, while OBRs, with 34 cytoplasmic residues, is thought to be involved in leptin transport or clearance. Studies show that OBRl undergoes tyrosine phosphorylation in response to leptin, which is enhanced by co-expression with JAK2. Both OBRs and OBRl can mediate leptin-dependent tyrosine phosphorylation of JAK2, but this is abolished when the Box 1 motif in OBRs is mutated. In cells expressing OBRs and OBRl along with JAK2 and IRS-1, leptin induces tyrosine phosphorylation of IRS-1 through both isoforms. In COS cells, OBRl increases ERK1 kinase activity, which is further enhanced by co-expression of JAK1 or JAK2. OBRs also contributes to ERK1 activation, though to a lesser extent. In stable CHO cell lines, leptin stimulates endogenous ERK2 phosphorylation. OBRl activates STAT3 tyrosine phosphorylation and induces a c-fos luciferase reporter plasmid, while OBRs does not. These findings suggest that OBRl can signal through JAK and activate STAT pathways, while OBRs, though less potent, can also mediate signal transduction via JAK. The results indicate that both isoforms have signaling capabilities, but OBRl is more effective. The study highlights the distinct roles of the long and short leptin receptor isoforms in leptin signaling.The long and short isoforms of the leptin receptor (OBRl and OBRs) differ in their signaling capabilities. OBRl, with 302 cytoplasmic residues, is primarily responsible for leptin signaling, while OBRs, with 34 cytoplasmic residues, is thought to be involved in leptin transport or clearance. Studies show that OBRl undergoes tyrosine phosphorylation in response to leptin, which is enhanced by co-expression with JAK2. Both OBRs and OBRl can mediate leptin-dependent tyrosine phosphorylation of JAK2, but this is abolished when the Box 1 motif in OBRs is mutated. In cells expressing OBRs and OBRl along with JAK2 and IRS-1, leptin induces tyrosine phosphorylation of IRS-1 through both isoforms. In COS cells, OBRl increases ERK1 kinase activity, which is further enhanced by co-expression of JAK1 or JAK2. OBRs also contributes to ERK1 activation, though to a lesser extent. In stable CHO cell lines, leptin stimulates endogenous ERK2 phosphorylation. OBRl activates STAT3 tyrosine phosphorylation and induces a c-fos luciferase reporter plasmid, while OBRs does not. These findings suggest that OBRl can signal through JAK and activate STAT pathways, while OBRs, though less potent, can also mediate signal transduction via JAK. The results indicate that both isoforms have signaling capabilities, but OBRl is more effective. The study highlights the distinct roles of the long and short leptin receptor isoforms in leptin signaling.