Effect Of Exogenous Leptin On Thrombotic And Metabolic Profiles Of Fvb/b6 Lipodystrophic Mice

Lipodystrophy caused by fat deficiency contributes to metabolic disease for which several treatment modalities have been implemented, with leptin therapy being the most effective to date. In addition to playing a role in energy homeostasis and metabolism, leptin was also shown to play a pro-thrombotic role in mice. This role was not examined in fatless mice, neither was thrombosis measured. The AZIP/F-1 (FVB) lipodystrophic mouse appeared to have a prolonged arterial occlusion time (p〈0.05) in a trial done in our lab, with clotting factors being normal. The present study was designed to observe the thrombotic and metabolic characteristics of fatless mice and examine the effect of leptin therapy on these traits. 16 FVB/B6 mice were produced in-house for the study, to receive recombinant mouse leptin or saline via osmotic pumps over 12 days. Transgenic (TG) mice were randomly divided into two groups: Treatment (Tx, n=4) and control (C, n=3); and their wild-type (WT) littermates were similarly divided into Tx (n=4) and C (n=5). TG mice had a prolonged time to formation of occlusive thrombus compared to WT mice (p〈0.05). Leptin treatment did not have an effect on arterial thrombosis in our mice. At baseline/control, TG mice were heavier than WT mice (p〈0.05), had larger livers (p〈0.0001), larger kidneys (p=0.01), higher serum insulin (p〈0.01), higher plasma and liver triglyceride (p〈0.01 and p〈0.05, respectively) and less leptin (p〈0.0001). TG-Tx mice decreased in weight (p〈0.05) and had smaller livers than those of TG-C mice (p〈0.05) while having higher levels of circulating leptin (p=0.01) and reduced levels of serum insulin (p〈0.05) and plasma cholesterol (p〈0.05). TG C mice had higher HOMA-IR scores (p〈0.05) than all other groups verifying insulin resistance that is ameliorated by leptin therapy. These findings confirm the hepatomegaly, hyperinsulinemia/ insulin resistance and hyperlipidemia seen in fatless mice and the effectiveness of leptin therapy while also suggesting that lipodystrophy, at least in the AZIP/F-1 mouse, is associated with delayed thrombosis independent of the lack of leptin. Lipodystrophic mice remain a useful model to study current epidemic metabolic disorders