Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2^+/Akita:apoE^-/- mice

Aims: The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D. Methods and results: The present study has employed Ins2^+/Akita:apoE^-/- mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2^+/Akita:apoE^-/- mice showed leptin deficiency by ∼92% compared with nondiabetic Ins2^+/+:apoE^-/- mice. From 13 weeks to 25 weeks of age, diabetic Ins2^+/Akita:apoE^-/- mice were treated with low-dose leptin (at 0.4 μg/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ∼41%, especially in LDL fractions, in diabetic Ins2^+/Akita:apoE^-/- mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ∼62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling. Conclusions: The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D.