LEPR: A crucial component of the leptin signaling pathway.

• Gene Information: The leptin receptor (LEPR) is a single membrane-spanning receptor that plays a crucial role in mediating the effects of leptin—a peptide hormone best known for its involvement in energy homeostasis, appetite regulation, and neuroendocrine function.
• Protein Expression: LEPR is predominantly expressed in hypothalamic regions—including the arcuate nucleus (ARC) and the paraventricular nucleus (PVN)—which integrate hormonal signals to control hunger, satiety, and growth hormone (GH) release.
• Signaling Pathway: LEPR interacts with leptin through its extracellular domain, initiating a series of intracellular signaling pathways that are primarily mediated by Janus kinase 2 (JAK2) and signal transducer and activator of transcription (STAT) proteins.
• LEPR Agonists: LEPR agonists activate downstream signaling cascades that regulate multiple physiological processes, including appetite suppression, energy expenditure, and glucose metabolism.

LEPR

• The exons 3 17 of mouse Lepr gene that encode extracellular domain is replaced by human counterparts in B hLEPR, Lep KO mice.
• The genomic region of mouse Lepr gene that encodes signal peptide, cytoplasmic portion and transmembrane domain is retained.
• The promoter, 5’UTR and 3’UTR region of the mouse gene are also retained.
• The chimeric LEPR expression is driven by endogenous mouse Lepr promoter.

Leptin

• The exons 2 3 of the mouse Lep gene were knocked out in B hLEPR, Lep KO mice.
• As a result,the mouse Leptin protein is not expressed anymore.

B-hLEPR, Lep KO mice were obtained by mating B hLEPR mice (113250), and B ob/ob mice (110172).

Human LEPR and mouse Leptin expression analysis in wild-type C57BL/6JNifdc mice and homozygous B-hLEPR, Lep KO mice by ELISA. Serum was collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hLEPR, Lep KO mice (H/H, -/-) (male, n=5, 7-week-old). Expression levels of human LEPR and mouse LEP were analyzed by ELISA (anti-mouse LEP ELISA kit: Abcam, ab199082; anti-human LEPR ELISA kit: Abcam, ab282876). (A) Human LEPR was exclusively detectable in homozygous B-hLEPR, Lep KO mice. (B) Mouse Leptin was exclusively detectable in wild-type mice, but not detectable in homozygous B-hLEPR, Lep KO mice. Values are expressed as mean ± SEM.

The body weight and blood glucose of wild-type C57BL/6JNifdc mice (+/+), B-hLEPR mice (H/H) and homozygous B-hLEPR, Lep KO mice (H/H, -/-) (male, n=10) were monitored at different ages. (A) The body weight at different ages. (B) The blood glucose levels at different ages. Significance was determined by two-way ANOVA. *p<0.05, p<0.01, ***p<0.001. Values are expressed as mean ± SEM. Note: The B-hLEPR, Lep KO mouse model was developed on the C57BL/6 background. Although it functions as a spontaneous obesity model, the concomitant hyperglycemia is transient and typically improves as the animals age.