Research

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13 pages, 2832 KiB

Open AccessArticle

Caloric Restriction and Hypothalamic Leptin Gene Therapy Have Differential Effects on Energy Partitioning in Adult Female Rats

by Russell T. Turner, Carmen P. Wong, Kristina M. Fosse, Adam J. Branscum and Urszula T. Iwaniec

Int. J. Mol. Sci. 2021, 22(13), 6789; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136789 - 24 Jun 2021

Cited by 3 | Viewed by 2017

Abstract

Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of [...] Read more.

Dieting is a common but often ineffective long-term strategy for preventing weight gain. Similar to humans, adult rats exhibit progressive weight gain. The adipokine leptin regulates appetite and energy expenditure but hyperleptinemia is associated with leptin resistance. Here, we compared the effects of increasing leptin levels in the hypothalamus using gene therapy with conventional caloric restriction on weight gain, food consumption, serum leptin and adiponectin levels, white adipose tissue, marrow adipose tissue, and bone in nine-month-old female Sprague-Dawley rats. Rats (n = 16) were implanted with a cannula in the 3rd ventricle of the hypothalamus and injected with a recombinant adeno-associated virus, encoding the rat gene for leptin (rAAV-Lep), and maintained on standard rat chow for 18 weeks. A second group (n = 15) was calorically-restricted to match the weight of the rAAV-Lep group. Both approaches prevented weight gain, and no differences in bone were detected. However, calorically-restricted rats consumed 15% less food and had lower brown adipose tissue Ucp-1 mRNA expression than rAAV-Lep rats. Additionally, calorically-restricted rats had higher abdominal white adipose tissue mass, higher serum leptin and adiponectin levels, and higher marrow adiposity. Caloric restriction and hypothalamic leptin gene therapy, while equally effective in preventing weight gain, differ in their effects on energy intake, energy expenditure, adipokine levels, and body composition. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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12 pages, 1315 KiB

Open AccessArticle

Is LRP2 Involved in Leptin Transport over the Blood-Brain Barrier and Development of Obesity?

by Elvira S. Sandin, Julica Folberth, Helge Müller-Fielitz, Claus U. Pietrzik, Elisabeth Herold, Thomas E. Willnow, Paul T. Pfluger, Ruben Nogueiras, Vincent Prevot, Thomas Krey and Markus Schwaninger

Int. J. Mol. Sci. 2021, 22(9), 4998; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094998 - 08 May 2021

Cited by 3 | Viewed by 3167

Abstract

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin [...] Read more.

The mechanisms underlying the transport of leptin into the brain are still largely unclear. While the leptin receptor has been implicated in the transport process, recent evidence has suggested an additional role of LRP2 (megalin). To evaluate the function of LRP2 for leptin transport across the blood-brain barrier (BBB), we developed a novel leptin-luciferase fusion protein (pLG), which stimulated leptin signaling and was transported in an in vitro BBB model based on porcine endothelial cells. The LRP inhibitor RAP did not affect leptin transport, arguing against a role of LRP2. In line with this, the selective deletion of LRP2 in brain endothelial cells and epithelial cells of the choroid plexus did not influence bodyweight, body composition, food intake, or energy expenditure of mice. These findings suggest that LRP2 at the BBB is not involved in the transport of leptin into the brain, nor in the development of obesity as has previously been described. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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12 pages, 1848 KiB

Open AccessArticle

The Role of Nonshivering Thermogenesis Genes on Leptin Levels Regulation in Residents of the Coldest Region of Siberia

by Alena A. Nikanorova, Nikolay A. Barashkov, Vera G. Pshennikova, Sergey S. Nakhodkin, Nyurgun N. Gotovtsev, Georgii P. Romanov, Aisen V. Solovyev, Sargylana S. Kuzmina, Nikolay N. Sazonov and Sardana A. Fedorova

Int. J. Mol. Sci. 2021, 22(9), 4657; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094657 - 28 Apr 2021

Cited by 6 | Viewed by 2529

Abstract

Leptin plays an important role in thermoregulation and is possibly associated with the microevolutionary processes of human adaptation to a cold climate. In this study, based on the Yakut population (n = 281 individuals) living in the coldest region of Siberia (t°minimum [...] Read more.

Leptin plays an important role in thermoregulation and is possibly associated with the microevolutionary processes of human adaptation to a cold climate. In this study, based on the Yakut population (n = 281 individuals) living in the coldest region of Siberia (t°minimum −71.2 °C), we analyze the serum leptin levels and data of 14 single nucleotide polymorphisms (SNPs) of 10 genes (UCP1, UCP2, UCP3, FNDC5, PPARGC1A, CIDEA, PTGS2, TRPV1, LEPR, BDNF) that are possibly involved in nonshivering thermogenesis processes. Our results demonstrate that from 14 studied SNPs of 10 genes, 2 SNPs (the TT rs3811787 genotype of the UCP1 gene and the GG rs6265 genotype of the BDNF gene) were associated with the elevated leptin levels in Yakut females (p < 0.05). Furthermore, of these two SNPs, the rs3811787 of the UCP1 gene demonstrated more indications of natural selection for cold climate adaptation. The prevalence gradient of the T-allele (rs3811787) of UCP1 increased from the south to the north across Eurasia, along the shore of the Arctic Ocean. Thereby, our study suggests the potential involvement of the UCP1 gene in the leptin-mediated thermoregulation mechanism, while the distribution of its allelic variants is probably related to human adaptation to a cold climate. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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Review

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36 pages, 446 KiB

Open AccessReview

Human Milk Metabolic Hormones: Analytical Methods and Current Understanding

by Majed A. Suwaydi, Zoya Gridneva, Sharon L. Perrella, Mary E. Wlodek, Ching Tat Lai and Donna T. Geddes

Int. J. Mol. Sci. 2021, 22(16), 8708; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168708 - 13 Aug 2021

Cited by 13 | Viewed by 3124

Abstract

Human milk (HM) contains a wide array of peptide hormones including leptin and adiponectin, which are involved in the regulation of infant growth and development. These essential hormones might play an important role in the regulation of metabolic reprogramming of the new-born infant. [...] Read more.

Human milk (HM) contains a wide array of peptide hormones including leptin and adiponectin, which are involved in the regulation of infant growth and development. These essential hormones might play an important role in the regulation of metabolic reprogramming of the new-born infant. However, HM hormone studies are sparse and heterogeneous in regard to the study design, sample collection, preparation and analysis methods. This review discussed the limitations of HM hormone analysis highlighting the gaps in pre-analytical and analytical stages. The methods used to quantify HM metabolic hormones (leptin, adiponectin, ghrelin, insulin, obestatin, resistin and apelin) can be classified as immunoassay, immunosensor and chromatography. Immunoassay methods (ELISA and RIA) have been predominantly used in the measurement of these HM hormones. The relative validity parameters of HM hormones analysis are often overlooked in publications, despite the complexity and differences of HM matrix when compared to that of plasma and urine. Therefore, appropriate reports of validation parameters of methodology and instrumentation are crucial for accurate measurements and therefore better understanding of the HM metabolic hormones and their influences on infant outcomes. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

20 pages, 1103 KiB

Open AccessReview

Impaired Leptin Signalling in Obesity: Is Leptin a New Thermolipokine?

by Valentina Annamaria Genchi, Rossella D’Oria, Giuseppe Palma, Cristina Caccioppoli, Angelo Cignarelli, Annalisa Natalicchio, Luigi Laviola, Francesco Giorgino and Sebastio Perrini

Int. J. Mol. Sci. 2021, 22(12), 6445; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126445 - 16 Jun 2021

Cited by 21 | Viewed by 5064

Abstract

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. [...] Read more.

Leptin is a principal adipose-derived hormone mostly implicated in the regulation of energy balance through the activation of anorexigenic neuronal pathways. Comprehensive studies have established that the maintenance of certain concentrations of circulating leptin is essential to avoid an imbalance in nutrient intake. Indeed, genetic modifications of the leptin/leptin receptor axis and the obesogenic environment may induce changes in leptin levels or action in a manner that accelerates metabolic dysfunctions, resulting in a hyperphagic status and adipose tissue expansion. As a result, a vicious cycle begins wherein hyperleptinaemia and leptin resistance occur, in turn leading to increased food intake and fat enlargement, which is followed by leptin overproduction. In addition, in the context of obesity, a defective thermoregulatory response is associated with impaired leptin signalling overall within the ventromedial nucleus of the hypothalamus. These recent findings highlight the role of leptin in the regulation of adaptive thermogenesis, thus suggesting leptin to be potentially considered as a new thermolipokine. This review provides new insight into the link between obesity, hyperleptinaemia, leptin resistance and leptin deficiency, focusing on the ability to restore leptin sensitiveness by way of enhanced thermogenic responses and highlighting novel anti-obesity therapeutic strategies. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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19 pages, 1840 KiB

Open AccessReview

Leptin in Atherosclerosis: Focus on Macrophages, Endothelial and Smooth Muscle Cells

by Priya Raman and Saugat Khanal

Int. J. Mol. Sci. 2021, 22(11), 5446; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115446 - 21 May 2021

Cited by 34 | Viewed by 3829

Abstract

Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit [...] Read more.

Increasing adipose tissue mass in obesity directly correlates with elevated circulating leptin levels. Leptin is an adipokine known to play a role in numerous biological processes including regulation of energy homeostasis, inflammation, vascular function and angiogenesis. While physiological concentrations of leptin may exhibit multiple beneficial effects, chronically elevated pathophysiological levels or hyperleptinemia, characteristic of obesity and diabetes, is a major risk factor for development of atherosclerosis. Hyperleptinemia results in a state of selective leptin resistance such that while beneficial metabolic effects of leptin are dampened, deleterious vascular effects of leptin are conserved attributing to vascular dysfunction. Leptin exerts potent proatherogenic effects on multiple vascular cell types including macrophages, endothelial cells and smooth muscle cells; these effects are mediated via an interaction of leptin with the long form of leptin receptor, abundantly expressed in atherosclerotic plaques. This review provides a summary of recent in vivo and in vitro studies that highlight a role of leptin in the pathogenesis of atherosclerotic complications associated with obesity and diabetes. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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11 pages, 969 KiB

Open AccessReview

The Causes and Potential Injurious Effects of Elevated Serum Leptin Levels in Chronic Kidney Disease Patients

by Justyna Korczynska, Aleksandra Czumaj, Michal Chmielewski, Julian Swierczynski and Tomasz Sledzinski

Int. J. Mol. Sci. 2021, 22(9), 4685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094685 - 28 Apr 2021

Cited by 14 | Viewed by 2548

Abstract

Leptin is an adipokine that regulates appetite and body mass and has many other pleiotropic functions, including regulating kidney function. Increased evidence shows that chronic kidney disease (CKD) is associated with hyperleptinemia, but the reasons for this phenomenon are not fully understood. In [...] Read more.

Leptin is an adipokine that regulates appetite and body mass and has many other pleiotropic functions, including regulating kidney function. Increased evidence shows that chronic kidney disease (CKD) is associated with hyperleptinemia, but the reasons for this phenomenon are not fully understood. In this review, we focused on potential causes of hyperleptinemia in patients with CKD and the effects of elevated serum leptin levels on patient kidney function and cardiovascular risk. The available data indicate that the increased concentration of leptin in the blood of CKD patients may result from both decreased leptin elimination from the circulation by the kidneys (due to renal dysfunction) and increased leptin production by the adipose tissue. The overproduction of leptin by the adipose tissue could result from: (a) hyperinsulinemia; (b) chronic inflammation; and (c) significant lipid disturbances in CKD patients. Elevated leptin in CKD patients may further deteriorate kidney function and lead to increased cardiovascular risk. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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16 pages, 1532 KiB

Open AccessReview

The Role of Leptin in Fetal Growth during Pre-Eclampsia

by Victoria E. de Knegt, Paula L. Hedley, Jørgen K. Kanters, Ida N. Thagaard, Lone Krebs, Michael Christiansen and Ulrik Lausten-Thomsen

Int. J. Mol. Sci. 2021, 22(9), 4569; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094569 - 27 Apr 2021

Cited by 27 | Viewed by 3743

Abstract

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise [...] Read more.

Leptin is secreted by the placenta and has a multi-facetted role in the regulation of functions related to pregnancy. Metabolic disorders and insufficient homeostatic compensatory mechanisms involving leptin during pregnancy play a decisive role in the development of pre-eclampsia (PE) and give rise to compromised intrauterine growth conditions and aberrant birth weight of offspring. This review was compiled to elucidate the metabolic background of PE and its relationship with adverse intrauterine growth conditions through the examination of leptin as well as to describe possible mechanisms linking leptin to fetal growth restriction. This review illustrates that leptin in PE is dysregulated in maternal, fetal, and placental compartments. There is no single set of unifying mechanisms within the spectrum of PE, and regulatory mechanisms involving leptin are specific to each situation. We conclude that dysregulated leptin is involved in fetal growth at many levels through complex interactions with parallel pregnancy systems and probably throughout the entirety of pregnancy. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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11 pages, 878 KiB

Open AccessReview

Leptin Receptor Compound Heterozygosity in Humans and Animal Models

by Claudia Berger and Nora Klöting

Int. J. Mol. Sci. 2021, 22(9), 4475; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22094475 - 25 Apr 2021

Cited by 10 | Viewed by 5343

Abstract

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants [...] Read more.

Leptin and its receptor are essential for regulating food intake, energy expenditure, glucose homeostasis and fertility. Mutations within leptin or the leptin receptor cause early-onset obesity and hyperphagia, as described in human and animal models. The effect of both heterozygous and homozygous variants is much more investigated than compound heterozygous ones. Recently, we discovered a spontaneous compound heterozygous mutation within the leptin receptor, resulting in a considerably more obese phenotype than described for the homozygous leptin receptor deficient mice. Accordingly, we focus on compound heterozygous mutations of the leptin receptor and their effects on health, as well as possible therapy options in human and animal models in this review. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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16 pages, 1370 KiB

Open AccessReview

An Update on the Role of Leptin in the Immuno-Metabolism of Cartilage

by Alfonso Cordero-Barreal, María González-Rodríguez, Clara Ruiz-Fernández, Djedjiga Ait Eldjoudi, Yousof Ramadan Farrag AbdElHafez, Francisca Lago, Javier Conde, Rodolfo Gómez, Miguel Angel González-Gay, Ali Mobasheri, Jesus Pino and Oreste Gualillo

Int. J. Mol. Sci. 2021, 22(5), 2411; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052411 - 27 Feb 2021

Cited by 22 | Viewed by 5760

Abstract

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor [...] Read more.

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration. Full article

(This article belongs to the Special Issue Leptin–Metabolic Programming and Its Endocrine Signals)

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