1809-P: Comparing Male and Female Metabolic Phenotypes in Mouse Strains Deficient in Leptin Signaling

National Institutes of Health policy states that animal studies should account for sex as a biological variable by including males and females when possible. Male mice are mainly used in diabetes research involving mutations that inactivate the leptin hormone (Lep^ob) or its receptor (Lepr^db). We found that many metabolic phenotypes were similar in males and females from two C57BL/6J mutant strains with transient hyperglycemia (B6-ob and B6-db) and a C57BLKS/J strain with sustained hyperglycemia (BKS-db). In all strains, homozygous ob or db genotypes led to similar male and female weight gain despite sexual dimorphism in weights of control genotypes. In homozygous mutant mice at 8 and 16 weeks of age, the only significant weight differences between males and females were at 8 weeks in B6-db (males weighed 1.7 g more; P = 0.0037) and 16 weeks in B6-ob (females weighed 2.5 g more; P = 0.0017). BKS-db/db males had higher nonfasted blood glucose than females (415 mg/dL vs. 357 mg/dL; P < 0.0001) at 8 weeks, but no other differences were significant at 8 and 16 weeks. Male and female B6-ob/ob and B6-db/db mice reverted to normal blood glucose at similar rates. HbA1c levels were higher in males for all strains at 16 weeks (P < 0.05 for all 3 pairwise comparisons). Male and female mutants had similar body fat percentages, with the exception of higher adiposity in B6-ob/ob females at 16 weeks (6% greater; P = 0.0163). We assessed serum insulin and leptin in BKS-db mice. Insulin was significantly higher in male and female db/db mice relative to db/+ or +/+ controls at 8 weeks, but db/db levels did not differ by sex. Leptin was significantly higher in db/db mice relative to controls (P < 0.0001 for all pairwise comparisons). Leptin did not differ by sex in db/db mice at 8 weeks; leptin levels were significantly higher in females at 16 weeks of age (P = 0.0039). All data will be made publicly available from the Mouse Phenome Database to serve as reference values when considering the use of female ob and db mutant mice in diabetes research.