The Leptin Receptor Complex: Heavier Than Expected?

Abstract

Under normal physiological conditions, leptin and the leptin receptor (ObR) regulate the body weight by balancing food intake and energy expenditure. However, this adipocyte-derived hormone also directs peripheral processes, including immunity, reproduction, and bone metabolism. Leptin, therefore, can act as a metabolic switch connecting the body’s nutritional status to high energy consuming processes. We provide an extensive overview of current structural insights on the leptin–ObR interface and ObR activation, coupling to signaling pathways and their negative regulation, and leptin functioning under normal and pathophysiological conditions (obesity, autoimmunity, cancer, … ). We also discuss possible cross-talk with other receptor systems on the receptor (extracellular) and signaling cascade (intracellular) levels.

Leptin action in normal and pathological pregnancies

“…Leptin or LepR deficiencies not only cause severe obesity but also abnormalities in haematopoiesis, immunity, angiogenesis, bone formation, blood pressure and reproduction. Mutations in the leptin gene, in human and/or mouse models, result in infertility or significant reproductive dysfunction . Leptin is required for the release of gonadotrophin‐releasing hormone (GnRH) from the pituitary, and as a consequence, female ob/ob mice (deficient in leptin) have reduced oestrogen levels and exhibit low uterine weight .…”

“…Therefore, leptin can act as metabolic switch connecting the nutritional status of the body to high energy consuming processes. The energy requirements of pregnancy are those desired for correct maternal gain to ensure the growth of the foetus, placenta and associated maternal tissues . Another key observation that built on the link between leptin and reproduction is the secretion of leptin from human placenta, further establishing an association between leptin and pregnancy .…”

Adipocytokines leptin and adiponectin function as mast cell activity modulators

“…The functional receptor for leptin has been identified. It is established that this adipocytokine acts through the membrane‐spanning receptor OB‐R, which belongs to the class I cytokine receptor family . It is also documented that leptin signaling occurs typically by way of the JAK/signal transducer and activator of transcription (STAT) pathway with the primary involvement of JAK2 molecule.…”

“…It is also documented that leptin signaling occurs typically by way of the JAK/signal transducer and activator of transcription (STAT) pathway with the primary involvement of JAK2 molecule. In leptin signaling, a crucial role of PI3K, ERK1/2, mitogen‐activated protein kinase (MAPK), and AMP‐activated protein kinase (AMPK) pathways is also suggested . Moreover, Zhou, et al .…”

“…In leptin signaling, a crucial role of PI3K, ERK1/2, mitogen-activated protein kinase (MAPK), and AMP-activated protein kinase (AMPK) pathways is also suggested. 48,49 Moreover, Zhou, et al 50 studied the involvement of JAK2, IjB, PI3K, ERK1/2, p38, JNK, and STAT5 molecules in leptin-induced cytokine production by bone-marrow-derived MCs and leptin-induced histamine release from these cells. OB-R is present in peripheral tissues and different immune cell populations, i.e.…”