Phenotypic consequences of a nonsense mutation in the leptin receptor gene(fa(k)) in obese spontaneously hypertensive Koletsky rats (SHROB)

The genetically obese Koletsky rat (SHROB, fa(k)) has a novel point mutatio n of the leptin receptor at amino acid +763, resulting in a premature stop codon in the leptin receptor extracellular domain. This implies that all le ptin receptor isoforms should be absent in this model. We examined the phen otypic consequences of this mutation on leptin and leptin receptor mRNA in hypothalamus and peripheral tissues from SHROB and their lean SHR littermat es. Despite the mutation, mRNA for both the long (ObRa) and the short (ObRb ) form were expressed at comparable levels in SHROB and SHR in brain and th roughout peripheral tissues. Adipose tissue mRNA for leptin was two to thre e times greater in SHROB compared to SHR (P < 0.01), while circulating lept in concentration was 170 times greater than SHR littermates (P < 0.01), sug gesting extreme leptin resistance in SHROB. Leptin was also detected in the cerebrospinal fluid (CSF) of SHR and SHROB (13.8 and 27.2 pmol/L, respecti vely); however, the CSF/plasma ratio for leptin was 32-fold greater in SHR than in SHROB. To assess the putative action of leptin and leptin receptors on insulin-mediated glucose transport, muscles from SHR and SHROB were inc ubated in vitro with recombinant human leptin. Leptin directly suppressed i nsulin-mediated glucose transport by 50% in skeletal muscle from SHR but no t in obese SHROB rats lacking all forms of the leptin receptor. These resul ts suggest that the natural leptin receptor knockout in the SHROB represent s a unique rat model to define the functional role(s) of leptin in central and peripheral energy metabolism.