The LEPR gene: A multifaceted regulator of energy homeostasis, obesity pathogenesis, and metabolic health

Background & Aim

This review examines the leptin-LEPR axis and its role in regulating energy balance and obesity. The LEPR gene provides the essential instructions for synthesizing the leptin receptor, a protein of paramount importance within the neuroendocrine system that orchestrates energy balance. Leptin, an adipokine secreted primarily by adipose tissue, functions as a critical signal reflecting the body's energy stores. It modulates appetite and energy expenditure by binding to its cognate receptor, which is predominantly expressed in the hypothalamus.

Materials & methods

The authors comprehensively examined a wide range of studies to detail the function of the LEPR gene and the complex intracellular signalling pathways it initiates. The focus was on understanding how dysfunctions, from rare genetic mutations to common acquired leptin resistance, disrupt these homeostatic mechanisms.

Results

The review confirms that when leptin binds to its receptor, it initiates a complex cascade of intracellular signalling pathways. These include the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) and phosphatidylinositol 3 kinase (PI3K)/Akt pathways. Dysfunction of the leptin-LEPR axis, whether stemming from rare genetic mutations leading to congenital leptin receptor deficiency or the more prevalent acquired leptin resistance observed in common obesity, severely disrupts these intricate homeostatic mechanisms. Such disruptions invariably manifest as profound hyperphagia (excessive hunger) and severe obesity.

Conclusion

A comprehensive understanding of the LEPR axis and its intricate signalling networks is therefore fundamental for elucidating the pathophysiology of obesity and for the development of effective therapeutic strategies.