The glucoregulatory actions of leptin

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Abstract

Background

The hormone leptin is an important regulator of metabolic homeostasis, able to inhibit food intake and increase energy expenditure. Leptin can also independently lower blood glucose levels, particularly in hyperglycemic models of leptin or insulin deficiency. Despite significant efforts and relevance to diabetes, the mechanisms by which leptin acts to regulate blood glucose levels are not fully understood.

Scope of review

Here we assess literature relevant to the glucose lowering effects of leptin. Leptin receptors are widely expressed in multiple cell types, and we describe both peripheral and central effects of leptin that may be involved in lowering blood glucose. In addition, we summarize the potential clinical application of leptin in regulating glucose homeostasis.

Major conclusions

Leptin exerts a plethora of metabolic effects on various tissues including suppressing production of glucagon and corticosterone, increasing glucose uptake, and inhibiting hepatic glucose output. A more in-depth understanding of the mechanisms of the glucose-lowering actions of leptin may reveal new strategies to treat metabolic disorders.

Related collections

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The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.

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Mutations in the mouse diabetes (db) gene result in obesity and diabetes in a syndrome resembling morbid human obesity. Previous data suggest that the db gene encodes the receptor for the obese (ob) gene product, leptin. A leptin receptor was recently cloned from choroid plexus and shown to map to the same 6-cM interval on mouse chromosome 4 as db. This receptor maps to the same 300-kilobase interval as db, and has at least six alternatively spliced forms. One of these splice variants is expressed at a high level in the hypothalamus, and is abnormally spliced in C57BL/Ks db/db mice. The mutant protein is missing the cytoplasmic region, and is likely to be defective in signal transduction. This suggests that the weight-reducing effects of leptin may be mediated by signal transduction through a leptin receptor in the hypothalamus.

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Author and article information

Contributors

Anna M. D'souza

Ursula H. Neumann

Maria M. Glavas

Timothy J. Kieffer

Journal

Journal ID (nlm-ta): Mol Metab

Journal ID (iso-abbrev): Mol Metab

Title: Molecular Metabolism

Publisher: Elsevier

ISSN (Electronic): 2212-8778

Publication date PMC-release: 04 May 2017

Publication date Collection: September 2017

Publication date (Electronic): 04 May 2017

Volume: 6

Issue: 9

Pages: 1052-1065

Affiliations

[1 ]Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada

[2 ]Department of Surgery, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada

Author notes

[∗ ]Corresponding author. Department of Cellular and Physiological Sciences, 2350 Health Sciences Mall, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.Department of Cellular and Physiological SciencesUniversity of British Columbia2350 Health Sciences MallVancouverBritish ColumbiaV6T 1Z3Canada tim.kieffer@ 123456ubc.ca

[3]

Anna M. D'souza and Ursula H. Neumann contributed equally to this work.

Article

Publisher ID: S2212-8778(17)30175-8

DOI: 10.1016/j.molmet.2017.04.011

PMC ID: 5605734

PubMed ID: 28951828

SO-VID: 852229e8-6644-4022-b5b7-145f245c6c1b

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 6 March 2017

Date revision received : 18 April 2017

Date accepted : 24 April 2017

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