Leptin Signaling in Cardiovascular Health

Leptin, a hormone produced chiefly by adipose tissue, plays a central role in coordinating energy balance, immune responses and vascular homeostasis. Beyond its well-characterised functions in appetite regulation, leptin influences cardiac structure and function via peripheral and central pathways. In the myocardium and vascular smooth muscle, leptin binds to its receptor and activates intracellular cascades, notably the JAK/STAT3 axis, as well as MAPK and PI3K signalling. These pathways modulate cardiomyocyte hypertrophy, fibroblast activity, endothelial function and inflammatory status. Physiological leptin levels maintain vascular tone and promote angiogenesis, while leptin resistance or impaired receptor signalling can precipitate adverse remodelling, fibrosis and hypertension. Central actions of leptin through hypothalamic circuits further affect sympathetic outflow, heart rate and cardiac output. In conditions of obesity, type 2 diabetes or hypoxia, chronic hyperleptinaemia and disrupted leptin signalling are implicated in atherosclerosis and heart failure. Experimental models reveal that intact leptin pathways confer cardioprotection, whereas attenuated signalling enhances oxidative stress and maladaptive hypertrophy, highlighting leptin’s pivotal interface between metabolic status and cardiovascular health.

Research from Nature Portfolio

Recent studies under hypobaric hypoxia conditions have illustrated the significance of leptin in preserving cardiac performance at high altitude. In human expeditioners exposed to prolonged hypoxia and in corresponding animal models, reduced plasma leptin levels were closely associated with deteriorations in left ventricular systolic and diastolic function. At the tissue level, chronic hypoxia diminished expression of key leptin signalling proteins in myocardial samples, coinciding with increased myocyte hypertrophy, fibrosis and mitochondrial dysfunction. Transcriptomic profiling further linked downregulation of leptin-related genes to alterations in ion transport and cytoskeletal components. These findings underscore a crucial adaptive role for leptin in the hypoxic heart, suggesting that maintenance of leptin signalling may mitigate altitude-induced cardiovascular impairment.

Leptin Signaling in Cardiovascular Health publication trend

The graph below shows the total number of articles in leptin signaling in cardiovascular health across all publications each year (not limited to Nature Index journals).

Technical terms

Adipokine: A bioactive peptide or protein secreted by adipose tissue that modulates metabolic and inflammatory processes.

Leptin resistance: A state in which elevated leptin levels fail to elicit normal receptor-mediated responses, often seen in obesity.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen that can damage cellular structures if overproduced.

Signal transducer and activator of transcription 3 (STAT3): A transcription factor activated downstream of leptin receptors that regulates gene expression related to cell survival and growth.

PPARβ/δ: A nuclear receptor that modulates lipid metabolism and energy homeostasis, instrumental in leptin-mediated cardiac effects.

References

1. Smooth Muscle Cells from a Rat Model of Obesity and Hyperleptinemia Are Partially Resistant to Leptin-Induced Reactive Oxygen Species Generation. Antioxidants (2023).
2. Role of Leptin in Obesity, Cardiovascular Disease, and Type 2 Diabetes. International Journal of Molecular Sciences (2024).
3. Central Actions of Leptin Induce an Atrophic Pattern and Improves Heart Function in Lean Normoleptinemic Rats via PPARβ/δ Activation. Biomolecules (2024).
4. Association of attenuated leptin signaling pathways with impaired cardiac function under prolonged high-altitude hypoxia. Scientific Reports (2024).