Evidence That the Diabetes Gene Encodes the Leptin Receptor: Identification of a Mutation in the Leptin Receptor Gene in db/db Mice

Abstract

OB-R is a high affinity receptor for leptin, an important circulating signal for the regulation of body weight. We identified an alternatively spliced transcript that encodes a form of mouse OB-R with a long intracellular domain. db/db mice also produce this alternatively spliced transcript, but with a 106 nt insertion that prematurely terminates the intracellular domain. We further identified G --> T point mutation in the genomic OB-R sequence in db/db mice. This mutation generates a donor splice site that converts the 106 nt region to a novel exon retained in the OB-R transcript. We predict that the long intracellular domain form of OB-R is crucial for initiating intracellular signal transduction, and as a corollary, the inability to produce this form of OB-R leads to the severe obese phenotype found in db/db mice.

The leptin hypothesis of depression: a potential link between mood disorders and obesity?

“…Studies on mouse models with mutations in the leptin gene (ob/ob) or the leptin receptor gene (db/db) have provided valuable information on the relationship between leptin and the HPA axis. Hypercorticosteronemia was observed in both ob/ob and db/db mice [42][43][44]. Chronic leptin administration can reverse the hypercorticosteronemia in ob/ob mice prior to significant weight loss [44], suggesting a role of leptin in HPA function independent of its effects on energy homeostasis.…”

Involvement of leptin signaling in the survival and maturation of bone marrow‐derived dendritic cells

“…Transcripts of DC from normal mice displayed a product of correct size (413 bp) for functional Ob-Rb, whereas those from db/db DC showed a larger product (519 bp) due to the gene targeting with an insertion [14][15][16]. The identities of these products were confirmed by sequencing, which showed an abnormal insertion (106 bp) with a stop codon within the coding region for the intracellular domain of Ob-Rb present in db/db DC, as previously reported for other tissues [14][15][16]. Furthermore, flow cytometric analysis confirmed the positive labeling of surface Ob-R on DC from normal control mice (Fig.…”

Global gene expression analysis in liver of obese diabetic db/db mice treated with metformin

“…Therefore, we performed a DNA microarray analysis experiment in order to study the global effect of metformin on gene expression in the livers of db/db mice [27]. We identified G6PC as a key enzyme in the liver in relation to the mechanism of action of metformin.…”