OBRb

OBRb, or the leptin receptor long form, is the signaling-competent isoform of the leptin receptor encoded by the LEPR gene. The LEPR gene produces multiple receptor isoforms through alternative splicing, of which OB-Rb is the long extracellular domain-containing form capable of transducing leptin signals. OB-Rb is predominantly expressed in the hypothalamus but is also found in various peripheral tissues.

Function and signaling pathways: Binding of the hormone leptin to OB-Rb activates the associated JAK2 tyrosine kinase. This leads to phosphorylation of tyrosine residues on the receptor’s cytoplasmic tail, recruitment and activation of STAT3, and transcriptional regulation of target genes involved in energy balance and neuroendocrine functions. Additional signaling pathways linked to OB-Rb include PI3K-Akt and MAPK/ERK. SOCS3 provides negative feedback to dampen signaling, contributing to the regulation of leptin sensitivity.

Physiological role: OB-Rb signaling is central to the control of appetite, energy expenditure, and reproductive function, with critical activity in hypothalamic nuclei such as the arcuate and paraventricular areas. Leptin signaling via OB-Rb informs the brain about adiposity levels, helping to coordinate food intake and metabolic rate.

Clinical significance: Mutations or defects in LEPR that impair OB-Rb signaling cause congenital leptin receptor deficiency, characterized by severe early-onset obesity, hyperphagia, and hypogonadism. Disturbances in OB-Rb signaling are also associated with leptin resistance in obesity, contributing to impaired energy homeostasis and metabolic complications. Treatment considerations depend on the underlying cause, with leptin therapy not effective for receptor defects.