The brain leptin signaling system and its functional state in metabolic syndrome and type 2 diabetes mellitus

Abstract

The brain leptin signaling system plays a key role in the regulation of feeding behavior, peripheral metabolism, functions of the nervous and endocrine systems; its abnormalities lead to metabolic disorders, including metabolic syndrome (MS) and type 2 diabetes mellitus (DM2). This system is activated by leptin, which is produced by adipocytes and then penetrates into the brain through the blood–brain barrier, where leptin binds to leptin receptors OBRb. This leads to an activation of tyrosine kinase JAK2, which phosphorylates tyrosine-containing sites located in the cytoplasmic domain of the receptor, resulting in stimulation of phosphatidylinositol-3-kinase, transcription factors STAT3 and STAT5, phosphatase SHP2 and mitogen-activated protein kinases. Reduction in the number of functionally active leptin receptors and abnormalities in the downstream components of leptin cascades in nerve cells lead to leptin resistance. Since the leptin system in hypothalamic neurons is closely interrelated with the insulin, melanocortin, dopaminergic and other signaling systems, leptin resistance induces multiple functional disorders in the CNS and at the periphery. Restoring the brain leptin system functions is one of the promising approaches to treat and prevent metabolic disorders, including MS and DM2. This review addresses the structural-functional organization of the leptin signaling system, its functional interaction with other brain signaling systems, causes and consequences of central leptin resistance as well as approaches aimed at restoring leptin functions in hypothalamic neurons under MS and DM2.