Review
Leptin receptor modulation of adiposity and fertility

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The leptin receptor was discovered as a leptin binding protein, which is highly expressed in the choroid plexus. Mapping of the gene's chromosomal locations in rodents revealed that mutations in Lepr were the basis of obesity/diabetes mutations in rodents and humans. Genetic manipulations that target Lepr expression in specific neurons or hypothalamic areas have generated insights into the modes by which body composition and reproductive function are modulated by the leptin receptor. These animal models have also been instrumental in identifying diabetes susceptibility genes. In this review we discuss the evidence that supports the concept of networked functions of leptin receptor as it pertains to feeding, substrate utilization and reproduction.

Section snippets

Obesity of leptin receptor deficiency caused by multiple mechanisms

The diabetes [1] and fatty [2] rodent models were established due to their extreme obesity, characterized by hyperphagia and elevated feed efficiency. Along with these traits the mutant rodents showed a constellation of endocrine disturbances: infertility due to hypothalamic hypogonadism, hyperinsulinemia associated with insulin resistance, hypercorticosteronemia, mild hypothyroidism and reduced levels of circulating growth hormone [3]. These models of obesity caused by mutations of the leptin

Leptin receptor signaling involves multiple signal transduction pathways

Leptin receptor isoforms, including several membrane bound receptors and a soluble receptor, are transcriptionally encoded or derived by proteolysis of membrane-bound isoforms 14, 15. However, inactivation of the membrane-bound isoform, LEPR-B, is sufficient to replicate the full phenotype of complete leptin or leptin receptor deficiency 16, 17. The LEPR-B isoform is the only leptin receptor isoform that contains both a janus kinase 2 (JAK2) binding domain and a signal transducer and activator

The development of obesity and leptin resistance

The initial discovery of leptin initiated a burst of activity examining the connection between leptin and adiposity in humans, leading to the observation that the amount of body fat is proportional to circulating leptin concentrations [27]. Thus, the concept of leptin resistance was put forth as an explanation for the inefficacy of leptin in reducing body fat in obese individuals without mutations in the leptin signaling axis [28]. Nevertheless, experiments increasing leptin concentrations in

Identified neurons modulating food intake and substrate utilization

The observation that the leptin receptor induces the phosphorylation of STAT3 [34] has made it relatively easy to identify leptin-activated neurons. One caveat is that some of these neurons might be activated indirectly because it is conceivable that STAT3 could become phosphorylated by activation from leptin sensitive neurons or that basal pSTAT3 is high in certain neurons. Nevertheless, this finding was of inordinate utility because highly sensitive anti-pSTAT3 antisera were available, but no

Insulin resistance and diabetes susceptibility – potential species differences

It has been difficult to define the neural pathways and contributing neurons that mediate leptin's effects on insulin sensitivity. Nevertheless, it is clear that descending projections [40], most likely from the hypothalamus, have a major impact on hepatic glucose production. Some of the specific neurons that are involved reside within the arcuate nucleus, with contributions from POMC 41, 42 and AGRP/NPY [43] neurons. Contributions from other types of neurons await further definition. As type 2

Hypothalamic hypogonadism and infertility of LEPR deficiency

Rodents and humans with leptin receptor deficiency have hypothalamic hypogonadism, resulting in delayed pubertal development and infertility. Female rodents and humans [6] with deficient leptin receptor signaling have atrophic uterine and ovarian size, abnormal estrous cyclicity and impaired mammary gland morphology and function [53]. Male mice with deficient leptin signaling have atrophic testicles and impaired spermatogenesis and behavioral responses to normal receptive females [54]. While

Summary

We have provided a view of a leptin-regulated network of neurons that provides a coordinated response to control feeding behavior, substrate oxidation and reproductive function. More neuron types remain to be identified to complete the cast of players in this network. An even greater task will be to define the interconnectivity of these separate neuron types and the coordination of their outputs. A similar puzzle, of defining the interactions between various hormonal and nutrient signaling

Acknowledgements

This work was supported by grants DK057621, 1U54HD058155 and PO1DK26687 to S.C.

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