Trends in Endocrinology & Metabolism
ReviewLeptin receptor modulation of adiposity and fertility
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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Cited by (54)
Association analysis between novel variants in LEPR gene and litter size in Mongolia and ujimqin sheep breeds
2022, TheriogenologyCitation Excerpt :These mutations affecting ovulation rate and litter size have been well characterized in many different sheep populations globally; however, they might be present in as yet uncharacterized populations, and new mutations that are as yet undescribed might also exist [2]. LEPR, which is a receptor of leptin, can influence reproductive traits in sheep and cattle [3–6]. The expression of leptin and its receptors at the mRNA and/or protein level has been demonstrated in follicular cells from several species [7].
Leptin-mediated differential regulation of microsomal triglyceride transfer protein in the intestine and liver affects plasma lipids
2020, Journal of Biological ChemistryPuberty in the Female and Its Disorders
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and PrintLipid phosphate phosphatase 3 in vascular pathophysiology
2018, AtherosclerosisCould tea polyphenols be beneficial for preventing the precocious puberty?
2016, Medical HypothesesCitation Excerpt :The protein hormone leptin, which is produced and secreted by white adipose tissue, is encoded by the ob gene. It can regulate glucolipid metabolism and inhibit the secretion of insulin [16,17]. Leptin is recognized as a multi-functional hormone because its receptor was reported to be expressed in many organs, including hypothalamus, pituitary, ovary and uterus [18–20].