Leptin Signaling and Obesity Cardiovascular Consequences

 Figure 1. Leptin receptor signaling. The binding of leptin to its receptor leads to formation of the Ob-R/JAK2 complex that results in cross-phosphorylation. Tyr1138 on Ob-Rb is crucial for STAT3 activation, which stimulates SOCS3 expression that negatively inhibits leptin signaling via Tyr985 and additional sites on JAK2. Protein tyrosine phosphatase 1B (PTP1B) is also capable of inhibition of leptin signaling. JAK2 phosphorylation can lead to activation of MAPK and insulin receptor substrate/PI3K signaling pathways. See text. GRB2 indicates growth factor receptor–bound protein 2.

 Figure 2. Systemic leptin function. Chronic hyperleptinemia impairs the centrally mediated metabolic actions of the hormone, alyhough its activation of sympathetic outflow is preserved. Selective central leptin resistance results in obesity and adverse effects on the cardiovascular system including hypertension, atherosclerosis, and LVH. Although leptin can protect against ectopic lipid deposition in nonadipose tissue, whether this effect is abolished because of (selective) peripheral leptin resistance requires further examination.

Figure 3. Leptin and myocardial contractility. Leptin directly depresses cardiomyocyte contractility. The signaling pathways implicated in this process include the NO-cGMP pathway and pathways that lead to increased ROS production. Changes that occur in a chronic leptin-deficient state are also illustrated. TG indicates triacylglycerol; iNOS, inducible NO synthase; nNOS, neuronal NO synthase; AC, adenylate cyclase; PKA, protein kinase A; XOR, xanthine oxidoreductase; SR, sarcoplasmic reticulum.