Leptin, represented here as the Leptin E-100 mutant, is the product of the obesity gene (OB) < discovered in 1994 by Zhang et al . Leptin is responsible for the ob/ob phenotype in obese mice. Although leptin is commonly present as its wild type, it can only be crystallized in the E-100 mutant form which substitutes glutamine for tryptophan at position 100 <
The signalling interaction between leptin and the hypothalamus is regulated by specific interactions between the protein and the leptin receptor Ob-Rb. Leptin receptors are expressed throughout the CNS, including the hypothalamus, and other body tissues. Ob-Rb and other leptin receptors that represent different splices of the same gene expressed throughout the body (Ob-Ra, Ob-Rc, Ob-Rd, Ob-Re, Ob-Rf), are part of the class I cytokine receptor family. The binding of leptin to Ob-Rb activates the signaling of transducer and activator of transcription (STAT) proteins that regulate the expression of neuronal genes affecting appetite. The hypothalamus is considered to be the main location for energy intake regulation; however, other parts of the brain can function similarly when exposed to leptin.
The continued study of leptin has focused on understanding obesity,
diabetes, and cardiovascular disease in humans. Most of the research unfortunately
can only use the mouse as a model which presents obstacles in understanding
the function of leptin in humans. While obesity in mice can be cured by artificially
increasing leptin levels in the blood stream, obese humans are resistant to
similar treatments. In other words, obesity in mice is the result of mutations
in the OB gene which render leptin inactive. However, obesity in humans, appears
to be the result of the inability to transport leptin into CNS cells. PLEASE ACTIVATE LEPTIN RESTORE MODE <
The obese gene codes for a leptin molecule that is 167 amino acids in length, and includes a secretory signal sequence that is 21 amino acids in length. Thus, the protein that circulates in the body and contacts the CNS along with other body tissues is 146 amino acids long and 16 kDa in weight. This is the protein displayed here. The secondary structure of leptin is most obviously characterized by a four helix bundle which adopts an unusual up-up-down-down fold <
Four loop structures join the helices. The AB loop < .
A large hydrophobic core of the protein runs through the center of the helix bundle and is maintained by the conserved regions of αA < .
Conserved residues from the CD loop which mostly reside in Helix E (Leu 104, Leu 107, Leu 110, Leu 114, and Val 113) < .
Leptin receptors are members of the class I cytokine receptor family. Class I cytokine receptors do not have activity inside the cell therefore we say they do not have endogenous kinase activity. These receptors instead have janus kinase (JAK) activity that phosphorylates the tyrosines within Ob-Rb . Furthermore, the binding of leptin to its receptor causes the phosphorylation of the STAT protein . The phosphorylation of the STAT proteins results in the activation of transcription of the neuronal genes associated with appetite and body weight management, and completes the JAK/STAT pathway. Studies have shown that the activation of the phosphatidulinositol 3-kinase and phosphodiesterase 3B are necessary prior to the activation of the STAT proteins. The five other Ob receptors found in other cells and tissues lack the STAT protein binding, thus they are unable to activate STAT signaling. These receptors intead activate the JAK 2 and the mitogen-activated kinase, however, little is known about the physiological significance of the activation of this kinase. The Ob-Ra is better understood and it has been demonstrated that this receptor's function is to transport leptin across the blood/cerebrospinal fluid barrier in the choroid plexus. Further studies have shown that the Ob-Re receptor acts as a leptin binding protein to activate a second protein binding, which prolongs the half-life of leptin.
The majority of knowledge we have about leptin receptor binding is derived from leptin's structural similarity to other long-chain helical cytokines. Though the sequences in this family of proteins differ significantly their structures are highly superimposible. Leptin receptor binding has been elucidated largely by this method of comparison because the complex of leptin and Ob-Rb has not yet been demonstrated. Within regions where other proteins of this family bind their receptors, key differences have been shown that are understood to be important in leptin binding of Ob-Rb. The first of these structural differences is the small kink in the last turn of helix D which is thought to accomodate the specific structure of leptin's receptors < < < < Finally, there is a section of the AB loop that is distorted in the crystal structure and that remains undefined structurally<
The study of leptin has revealed that this protein is involved in many different physiological processes besides its key role in weight homeostasis. Although many physiological pathways are controled by the CNS, the presence of leptin and its receptors throughout the entire body suggests that the protein is able to directly affect other cells and tissues. Ongoing studies have suggested that levels of leptin and proper leptin receptor expression control the possibilities for cardiovascular risk, platelet aggregation, hypertension, oxidative stress, anguigenesis, and thrombosis. Furthermore, leptin appears to have functions related to the immune system as it is present in many different immune system cells like macrophages and other bone marrow cells. Leptin works closely with insulin sensitivity to directly and indirectly affect energy intake. Just like leptin, insulin increases the activation of STAT3 and myogen-activated kinase activity explaining how leptin may influence insulin action on tissues. Other studies have shown how leptin stimulates lypolysis in white adipose tissues which results in the stimulation of the oxidation of fatty acids within the adipocytes. Although not fully understood, observations of the activity of leptin have suggested that leptin may have functions relating to reproduction. Leptin's ability to control energy intake may play a crucial role in fetal growth and development, ovarian steroidogenesis, and placental function.
Crystal Structure Information:
Zhang, Faming, et al. 1997. Crystal structure of the obese protein leptin-E100. Nature 387:206-209.
Physiological Background Information:
Prolo, Paolo, et al. 1998. Molecules in focus Leptin. The International Journal of Biochemistry & Cell Biology. 30: 1285-1290.
Considine, Robert V. 2005. Human Leptin: An Adipocyte Hormone with Weight-Regulatory and Endocrine Functions. Seminars in Vascular Medicine 5: 15-24.
Diamond, Frank B., et al. 1997. Demonstration of a Leptin Binding Factor in Human Serum. Biochemical and Biophysical research communications 233: 818-822.