Leptin receptor (LEP-R), also known as OB receptor (OB-R), HuB219, and CD295 is a receptor for the hormone leptin, which is involved in energy homeostasis and hunger/satiation cues.¹

LEP-R, encoded by the LEPR gene, is composed of 1165 amino acids with the extracellular domain consisting an N-terminal cytokine receptor homology domain (CRH-1), an immunoglobulin-like (Ig) domain, a second CRH domain (CRH-2) which is also known as the leptin-binding domain (LBD) and two Fibronectin type III (FNIII) domains. LEP-R forms a high-affinity 1:1 ratio complex with leptin in solution, but does not form the 2:1 ratio complex associated with the small cytokine receptors, such as growth hormone receptor (GHR). The 1:1 ratio interaction occurs at leptin’s binding site II and can be blocked by mutations in this region. Mutations within the Ig domain of LEP-R and binding site III of leptin have been shown to inhibit transduction without disrupting receptor binding, indicating that the leptin-signaling complex forms a crossover arrangement between two leptin-LEP-R complexes.¹

Leptin is produced in adipose tissue in proportion to triglyceride stores and serves as an indicator of long-term energy status. Leptin acts mainly in the brain, specifically the hypothalamus, where its action is integrated with that of other adipokines, gastrokines, and other signals to coordinate energy homeostasis. Once secreted into the circulation, leptin travels to the brain where it enters the CNS likely via the choroid plexus and circumventricular organs. In the brain, leptin acts by binding and activating LEP-R, which is primarily expressed on specialized subsets of neurons in certain hypothalamic and brainstem nuclei.²

Lack of leptin, such as in cases of starvation or genetic leptin deficiency, increases hunger while promoting an energy-sparing cascade of neuroendocrine and autonomic changes, including decreased sympathetic nervous system tone, thyroid function, growth, reproduction, and a variety of behavioral and physiological changes to respond appropriately to low stores of energy.²