Lipostatic Effects Of Leptin Acting Through The Brain: Molecular Mechanisms In Liver And White Adipose Tissue. Effect Of Central Leptin Resistance

Leptin reduces food intake, adiposity and increases the whole-body insulin sensitivity. Dysregulations of leptin action result in obesity, insulin resistance and Type 2 diabetes. This thesis explores the molecular mechanisms responsible for the lipostatic and insulin-sensitizing effects of leptin acting only through the brain. Central leptin infusion elicits tissue-specific effects on liver and epididymal white adipose tissue (eWAT), that reduce triacylglycerol (TAG) and total fatty acids (free and acyl-CoA) in both tissues and TAG in plasma. Central leptin promotes b-oxidation of fatty acids (FA) in eWAT by increasing the mRNA levels of the transcription factors involved in lipid oxidation. Additionally, leptin increases the ATGL-mediated lipolysis in this tissue. The released free FA are taken up and oxidized mainly by the liver. Additionally, central leptin down-regulates the expression of lipogenic enzymes in the liver by reducing the mRNA levels of the lipogenic transcription factor SREBP-1c. In eWAT leptin also reduces the expression of lipogenic and glyceroneogenic enzymes, but controlling SREBP-1c post-transcriptionally, inhibiting its proteolytic maturation. Also, in eWAT leptin reduces lipogenesis by promoting insulin resistance from the early steps of the insulin signaling pathway (IR, IRS-1 and Akt2), which results in decreased glucose up-take by this tissue upon insulin stimulation. Additionally, by inhibiting de novo ceramide synthesis in eWAT, central leptin appears to protect this tissue from lipotoxicity. As a result, central leptin reduces plasmatic insulin levels and enhances the in vivo insulin ability to reduce plasmatic free FA. On the other hand, central leptin resistance (aged rats) is linked to increased contents of lipids in liver, eWAT and plasma. The increased lipogenesis in the liver, but not in eWAT, is the one responsible for the augmented adiposity of the aged rats, and explains their hypertriglyceridemia and hypercholesterolemia….