Figure 2.

Leptin and LEPR signaling in the (dys-)regulation of the cardiovascular system. Leptin is mainly secreted from the adipose tissue and binds to the LEPR in the arcuate nucleus of the hypothalamus where it regulates food intake, energy expenditure and hormone release. The actions of leptin and insulin are interconnected and contribute to optimal metabolic control. Although leptin role in the cardiovascular system is still controversial, diabetic and obese animal models demonstrate that leptin has beneficial effects on cardiac metabolism. Under physiological condition, leptin signaling supports the balance between glucose metabolism and fatty acid oxidation in the heart, while the absence of leptin or LEPR results in the lack of the metabolic flexibility. The reduced dynamic between the energy substrates results in systemic metabolic disorders (insulin resistance, leptin resistance, metabolic dysfunction, and lipotoxicity), leading to decreased cardiac efficiency (impaired Ca²⁺ handling, contractile dysfunction, and fibrosis). In contrast, elevated leptin levels in obese patients contribute to the low-grade systemic inflammation, which increases the risk to develop cardiovascular diseases. Horizontal black line demarcates differences between the healthy heart and the heart in obesity/diabetes. LEPRb, leptin receptor b; MVO₂, myocardial oxygen consumption; ROS, reactive oxygen species; PPAR-α, peroxisome proliferator-activated receptor α; β-MHC, myosin heavy chain β; TNF-α, tumor necrosis factor-α; GLUT4, glucose transporter 4; IR, insulin receptor.