Metabolic characterization of a mouse deficient in all known leptin receptor isoforms

We have characterized a newly generated mouse model of obesity, a mouse strain deficient in all five previously described leptin receptor isoforms. These transgenic mice, named the db ₃₃₃/db ₃₃₃ mice, were identified from an ENU mutagenesis screen and carry a point mutation in the seventh exon of the db gene encoding the leptin receptor, resulting in a premature stop codon (Y₃₃₃Stop) and gene product that lacks STAT signaling domains. db ₃₃₃/db ₃₃₃ mice have a morbidly obese phenotype, with body weights diverging from wild type as early as 4 weeks of age (P < 0.05). To determine the contribution of the short isoforms of the leptin receptor in this metabolic phenotype, we performed an extensive metabolic characterization of the db ₃₃₃/db ₃₃₃ mouse in relation to the well-characterized db/db mouse lacking only the long form of the leptin receptor. db ₃₃₃/db ₃₃₃ mice have similar endocrine and metabolic parameters as previously described in other leptin receptor transgenic mice including db/db mice that lack only the long isoform of the leptin receptor. However, db ₃₃₃/db ₃₃₃ mice show a subtle trend toward higher body weight and insulin levels, lower oxygen, carbon dioxide production, respiratory exchange ratio (RER), and temperature than db/db mice suggesting the short isoforms may play an additional role in energy homeostasis.