MinireviewLeptin: From structural insights to the design of antagonists
Graphical abstract
Introduction
Leptin is best known for its dramatic effect as a satiety signal, since mouse strains lacking leptin signaling components are hyperphagic and obese [54]. The hormone is mainly, but not exclusively, produced by adipocytes and its serum levels positively correspond with the energy stored in the fat mass [23], [39], [54]. Leptin functions as a negative feedback adipostat or an efferent satiety signal by activation of the LR in the feeding centers of the hypothalamus [120]. Loss-of-function mutations in the leptin or LR genes [18], [20], [84], [139], or genetic ablation of leptin's central signaling [127], [131] results in obesity and increases the risk of obesity-related conditions like type 2 diabetes [57].
Ten years after its initial discovery, it became clear that leptin is more than a satiety signal, and rather acts as a ‘metabolic switch’ by connecting the body's energy stores to high energy demanding processes like immunity and reproduction [35], [77]. Indeed, leptin or LR deficiency not only causes severe obesity, but also abnormalities in lipid and glucose metabolism [40], hematopoiesis [6], innate and adaptive immunity [13], [34], [137], reproduction [17], angiogenesis [117], vascular remodeling [65], blood pressure [75], and bone formation [30]. Furthermore, being overweight or obese is a major risk factor for several types of cancer including prostate [42], breast [19], colorectal [95], renal cancer [70] and myeloma [47].
Section snippets
Leptin
The first obese mouse arose by chance in a colony at the Jackson Laboratory in 1949 [59]. A series of parabiosis experiments illustrated that these ob/ob mice are deficient for a blood-borne factor that regulates feeding and metabolism [21], [22]. It took over 40 years before Friedman and colleagues positionally cloned the ob gene and demonstrated that it encodes for a hormone that they called leptin (after the Greek ‘leptos’ for thin) [139]. Administration of recombinant leptin to ob/ob mice
Leptin receptor
The LR was first cloned from a mouse choroid plexus cDNA library using an expression cloning strategy by Tartaglia and colleagues [120]. The full-length receptor is 1162 residues long divided in three regions: an extracellular part, a single pass helix trans-membrane domain and an intracellular part. Up to now, six LR isoforms produced by alternative splicing or proteolytic ectodomain shedding [129] have been identified: LRa-f. All these isoforms, except LRe, have an identical extracellular and
LR signaling
Like all class I cytokine receptors, the LR has no intrinsic kinase activity, and uses cytoplasmic associated Janus (JAK) kinases for intracellular signaling. These kinases associate with a well-conserved membrane-proximal proline-rich box1 and a less well-defined box2 motif in the receptor [3], [64]. Short LR variants lack this box2 motif, which might explain the inefficient JAK activation by these receptors. The LR predominantly activates JAK2 [64], although JAK1 activation has also been
Leptin independent LR oligomerisation at the cell surface
The existence of signaling-inactive, pre-formed receptor complexes on the cellular surface in the absence of ligands has been shown for several cytokine receptors. Examples include the erythropoietin (Epo) receptor [24], [72], [102], the growth hormone (GH) receptor [12], [44], and the IL-6 receptor [111]. Two different experimental set-ups proved that this is likely also true for the leptin receptor: co-immunoprecipitation of differently tagged LRs [1], [130], [135] and the relatively high
Leptin and LR antagonists
Not only are profound insights in the LR activation mechanisms a prerequisite for the rational design of leptin and LR antagonists, the evaluation of these antagonists can help to further unravel these mechanisms. These agents could have therapeutic value in uncontrolled immune responses in autoimmune diseases, cancer, elevated blood pressure, and certain cardiovascular diseases. At present, four strategies are being used to antagonize leptin signaling: (i) leptin antagonistic mutants; (ii)
Future perspectives: uncoupling of leptin physiologic functions
Leptin is a pleoptropic hormone with both beneficial and undesired effects. In some physiological or pathological situations like uncontrolled immune responses in autoimmune diseases, tumorigenesis, elevated blood pressure, and certain cardiovascular diseases, it is desirable to selectively block leptin activity. The use of current leptin and LR antagonists is hampered by the unwanted weight-gain (10–15% per week in rodent models) upon treatment. An ideal leptin (or LR) antagonist would
Conclusions
The crystal structure of the leptin:LR complex has not been determined. However, detailed mutagenesis studies, homology modeling and low-resolution EM and SAXS leptin:LR structures already provided valuable insights in the mechanism of LR activation. This knowledge allowed the design of several types of leptin and LR antagonists with proven efficacy both in vitro and in vivo. However, several important aspects remain unclear: what is the function of the CRH1 or the NTD domains? What is the
Acknowledgments
We apologize to our colleagues that space limitations did not allow us to cite all the relevant literature. This work was funded by IUAP (P6/36) and Research Foundation-Flanders (FWO-V, Project G.0521.12N). JT is a recipient of an ERC Advanced Grant (No. 340941-CYRE).
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