Lepr Knockin mouse models

Lepr, ortholog of human LEPR, encodes the leptin receptor, a class I cytokine receptor expressed as several splice isoforms of which only the long form carries the full intracellular Box1 and Box2 motifs needed to activate Jak2 and the downstream tyrosines that recruit SHP2 and ERK, STAT5, and STAT3 to drive Pomc and Agrp transcription in hypothalamic neurons. This isoform structure is the crux of allele design, since the classic db mutation is a splicing defect that eliminates the signaling isoform while leaving short forms intact, and single tyrosine knockins that block STAT3 recruitment reproduce obesity without the full null phenotype, cleanly separating individual signaling arms. Conditional deletion with neuron-subtype Cre drivers assigns energy balance and glucose control to defined populations, and Lepr-Cre is itself a knockin requiring dosage controls. Match alleles to endpoints spanning body composition, food intake, hepatic glucose production, and phosphorylated STAT3 immunostaining.

Lepr knockin models place a defined sequence at the endogenous locus. Expression stays under native regulation, which matters for reporters, tags, and precise allele swaps.