Leptin modulates gene expression in the heart, cardiomyocytes and the adipose tissue mitigating LPS-induced inflammatory and oxidative damage

Background: Leptin is an adipokine of pleiotropic effects linked to energy metabolism, inflammation, and cardiac function. We have recently shown that leptin conferred resistance to myocardial infarction-induced damage in long-lived transgenic aMUPA mice overexpressing leptin (~8 folds increase in mRNA levels, p<0.0001) compared to wild-type (WT) mice and in cardiomyocytes following ischemia, as assessed by measuring fractional shortening and infarct size in the absence and presence of leptin inhibitors.

Aim and methods: We aimed to investigate if leptin can counteract the inflammatory and oxidative response triggered after LPS administration in vivo and cultured cardiomyocytes. Gene expression was analyzed using RT-PCR. ROS production in vitro was measured using DCF-DA staining.

Results: LPS upregulated pro-inflammatory and antioxidant genes, as well as the leptin gene both in vivo and in vitro. However, in the aMUPA mice treated with LPS the increase in this pro-inflammatory gene was attenuated (p<0.05). Pretreating mice with leptin neutralizing antibodies further upregulated the expression of TNFa and IL-1b in the adipose (p<0.05) and cardiac (p<0.001) tissues. Blocking the leptin signaling also increased the levels of serum markers for cell toxicity (GOT, GPT, and LDH). These results indicate that under LPS, leptin reduced the levels of these inflammatory-related parameters. In addition, pretreatment with leptin antibodies reduced the levels of HIF-1a and VEGF mRNAs in the heart, indicating that under LPS, leptin increased the levels of these genes. In cardiomyocytes, pretreatment with exogenous leptin prior to LPS reduced the expression of pro-inflammatory genes, and importantly enhanced the expression of the antioxidant genes HO-1, SOD2, and HIF-1a (p<0.05), and reduced ROS production (p<0.05).

Conclusion: These results indicate that under LPS, leptin concomitantly downregulated pro-inflammatory genes, upregulated antioxidant genes, and lowered ROS levels. These results suggest that leptin counteracts inflammation and oxidative stress in the heart and adipose tissue triggered by sepsis.