Loss of Leptin Receptors on Hypothalamic POMC Neurons Alters Synaptic Inhibition

Adaptive changes in hypothalamic neural circuitry occur in response to alterations in nutritional status. This plasticity at hypothalamic synapses contributes to the control of food intake and body weight. Here we show that genetic ablation of leptin receptor gene expression in pro-opiomelanocortin (POMC) neurons (POMC: Lepr−/− GFP) induces alterations at synapses on POMC neurons in the arcuate nucleus of the hypothalamus. Our studies reveal that POMC: Lepr−/− GFP mice have decreased frequency of spontaneous GABAergic, but not glutamatergic, postsynaptic currents at synapses on POMC neurons. The decay time course of GABAergic spontaneous inhibitory postsynaptic currents (sIPSCs) onto POMC neurons in POMC: Lepr−/− GFP mice is significantly slower than that of sIPSCs in control animals. While analysis of individual miniature IPSCs shows lowered baseline activity, this tonic decrease is associated with an increased amplitude and slow decay of mini-IPSCs onto POMC neurons in POMC: Lepr−/− GFP mice. Moreover, POMC neurons receive greater total ionic flux per GABAergic event in the absence of leptin receptor signaling. In addition, treatment with the alpha 3 subunit-containing GABAA receptor modulator SB-205384 enhances GABAergic transmission only onto POMC neurons in POMC: Lepr−/− GFP mice. Single-cell RT-PCR analysis further supports the expression of the alpha 3 subunit of the GABAA receptor on POMC neurons in POMC: Lepr−/− GFP mice. Finally, the responses to the GABAA receptor agonist isoguvacine of POMC neurons are significantly smaller in POMC: Lepr−/− GFP than in control animals. Therefore our present work demonstrates that loss of leptin signaling in POMC neurons induces synaptic alterations at POMC synapses that may play an essential role in energy homeostasis.

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Ontogeny of the long form of leptin receptor gene expression in the porcine ovarian follicles

Polish Journal of Veterinary Sciences ◽

10.2478/pjvs-2013-0014 ◽

2013 ◽

Vol 16 (1) ◽

pp. 101-105

Author(s):

N. Smolinska ◽

T. Kaminski ◽

G. Siawrys ◽

J. Przala

Keyword(s):

Energy Homeostasis ◽

Leptin Receptor ◽

Receptor Gene ◽

Follicular Development ◽

Ovarian Follicles ◽

Antral Follicles ◽

Long Form ◽

Rb Gene ◽

Receptor Gene Expression

Abstract Leptin is a polypeptide hormone produced predominantly in adipocytes. It has been found to be implicated in the regulation of satiety and energy homeostasis. A role for leptin in reproduction was later suggested by findings that this hormone may be involved in the regulation of the hypothalamic- pituitary-gonadal axis via endocrine, paracrine and/or autocrine pathways. The objective of the study was to investigate the ontogeny of the long isoform of leptin receptor (OB-Rb) gene in porcine ovarian follicles. The expression of OB-Rb gene was detected in porcine primordial, primary, secondary and antral follicles by in situ hybridization. In summary, our data suggest that leptin might have a direct effect on porcine follicles and plays an important role in the follicular development.

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Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion

Endocrinology ◽

10.1210/en.2007-1132 ◽

2007 ◽

Vol 149 (4) ◽

pp. 1773-1785 ◽

Cited By ~ 222

Author(s):

Esther van de Wall ◽

Rebecca Leshan ◽

Allison W. Xu ◽

Nina Balthasar ◽

Roberto Coppari ◽

...

Keyword(s):

Body Weight ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Receptor Gene ◽

Normal Glucose Tolerance ◽

Adult Mice ◽

Normal Glucose ◽

High Doses ◽

Agouti Gene

Two known types of leptin-responsive neurons reside within the arcuate nucleus: the agouti gene-related peptide (AgRP)/neuropeptide Y (NPY) neuron and the proopiomelanocortin (POMC) neuron. By deleting the leptin receptor gene (Lepr) specifically in AgRP/NPY and/or POMC neurons of mice, we examined the several and combined contributions of these neurons to leptin action. Body weight and adiposity were increased by Lepr deletion from AgRP and POMC neurons individually, and simultaneous deletion in both neurons (A+P LEPR-KO mice) further increased these measures. Young (periweaning) A+P LEPR-KO mice exhibit hyperphagia and decreased energy expenditure, with increased weight gain, oxidative sparing of triglycerides, and increased fat accumulation. Interestingly, however, many of these abnormalities were attenuated in adult animals, and high doses of leptin partially suppress food intake in the A+P LEPR-KO mice. Although mildly hyperinsulinemic, the A+P LEPR-KO mice displayed normal glucose tolerance and fertility. Thus, AgRP/NPY and POMC neurons each play mandatory roles in aspects of leptin-regulated energy homeostasis, high leptin levels in adult mice mitigate the importance of leptin-responsiveness in these neurons for components of energy balance, suggesting the presence of other leptin-regulated pathways that partially compensate for the lack of leptin action on the POMC and AgRP/NPY neurons.

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Expression of the long (OB-RB) and short (OB-RA) forms of the leptin receptor throughout the oestrous cycle in the mature rat ovary

Reproduction ◽

10.1530/rep.0.1230899 ◽

2002 ◽

pp. 899-905 ◽

Cited By ~ 32

Author(s):

PS Duggal ◽

SR Weitsman ◽

DA Magoffin ◽

RJ Norman

Keyword(s):

Gene Expression ◽

Leptin Receptor ◽

Short Form ◽

Receptor Gene ◽

Oestrous Cycle ◽

Pcr Analysis ◽

Short Isoforms ◽

Mrna Content ◽

Total Dna ◽

Rat Ovary

Leptin is secreted by adipocytes and exerts its effects by interacting with the long form of the leptin receptor, OB-RB. The leptin protein and leptin receptors have been localized in the ovary, and acute leptin treatment directly inhibits ovulation in the rat ovary. It was hypothesized that expression of the leptin receptor gene varies throughout the oestrous cycle to modulate the sensitivity of the ovary to leptin. In this study, expression of genes for the long and short isoforms of the leptin receptor in the adult ovary was investigated at different stages of the rat oestrous cycle. Vaginal cytology was used to determine the stage of the oestrous cycle. Ovaries were collected and RNA was extracted for real-time RT-PCR analysis of leptin receptor gene expression. OB-RB gene expression was low in pro-oestrus (3.13 +/- 0.18 fg RNA per microg total DNA) and dioestrus II (2.52 +/- 0.19 fg RNA per microg total DNA) of the oestrous cycle, whereas expression was high in oestrus (5.9 +/- 0.27 fg RNA per microg total DNA) and dioestrus I (4.6 +/- 0.24 fg RNA per microg total DNA) (P < 0.001). Expression of the gene for the short form of the leptin receptor (OB-RA) was at a maximum in dioestrus I (65.5 +/- 0.8 fg RNA per ng total DNA), high in oestrus (39.0 +/- 0.8 fg RNA per ng total DNA) and low at pro-oestrus (5.0 +/- 0.2 fg RNA per ng total DNA) and dioestrus II (1.1 +/- 0.09 fg RNA per ng total DNA) (P < 0.001). Plasma oestradiol concentrations (pg ml-1) were highest at pro-oestrus (19.38 +/- 1.3), and similar at the remaining three stages studied (oestrus: 13.7 +/- 1.9; dioestrus I: 12.4 +/- 1.0; dioestrus II: 10.3 +/- 0.9) (P < 0.05). Plasma progesterone concentrations (ng ml-1) were higher in the luteal phases of the oestrous cycle (dioestrus I: 18.6 +/- 2.3; dioestrus II: 14.7 +/- 2.5) than during pro-oestrus (5.12 +/- 0.6) and oestrus (5.9 +/- 0.8) (P < 0.05). Plasma leptin concentrations were detectable only in pro-oestrus (0.35 +/- 0.05 ng ml(-1)) and were below the detection limit of the assay at other stages of the oestrous cycle. In summary, mRNA content for the long and short isoforms of the leptin receptor is lower in pro-oestrus and dioestrus II than in oestrus and dioestrus I of the rat oestrous cycle. The fluctuations in leptin receptor mRNA content may be a response to the concentrations of circulating steroid hormones and leptin. This research supports the initial hypothesis and shows that ovarian leptin receptor concentrations vary throughout the oestrous cycle in response to the changing environment of the ovary.

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A fresh look to the phenotype in mono-allelic likely pathogenic variants of the leptin and the leptin receptor gene

Molecular and Cellular Pediatrics ◽

10.1186/s40348-021-00119-7 ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Ingrid Koerber-Rosso ◽

Stephanie Brandt ◽

Julia von Schnurbein ◽

Pamela Fischer-Posovszky ◽

Josef Hoegel ◽

...

Keyword(s):

Animal Studies ◽

Weight Status ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Receptor Gene ◽

Reproductive Function ◽

Pathogenic Variant ◽

Human Studies ◽

Fat Percentage ◽

Pathogenic Variants

AbstractLeptin (LEP) and leptin receptor (LEPR) play a major role in energy homeostasis, metabolism, and reproductive function. While effects of biallelic likely pathogenic variants (-/-) on the phenotype are well characterized, effects of mono-allelic likely pathogenic variants (wt/-) in the LEP and LEPR gene on the phenotype compared to wild-type homozygosity (wt/wt) have not been systematically investigated. We identified in our systematic review 44 animal studies (15 on Lep, 29 on Lepr) and 39 studies in humans reporting on 130 mono-allelic likely pathogenic variant carriers with 20 distinct LEP variants and 108 heterozygous mono-allelic likely pathogenic variant carriers with 35 distinct LEPR variants. We found indications for a higher weight status in carriers of mono-allelic likely pathogenic variant in the leptin and in the leptin receptor gene compared to wt/wt, in both animal and human studies. In addition, animal studies showed higher body fat percentage in Lep and Lepr wt/- vs wt/wt. Animal studies provided indications for lower leptin levels in Lep wt/- vs. wt/wt and indications for higher leptin levels in Lepr wt/- vs wt/wt. Data on leptin levels in human studies was limited. Evidence for an impaired metabolism in mono-allelic likely pathogenic variants of the leptin and in leptin receptor gene was not conclusive (animal and human studies). Mono-allelic likely pathogenic variants in the leptin and in leptin receptor gene have phenotypic effects disposing to increased body weight and fat accumulation.

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Association between leptin receptor gene polymorphism and quality of both meat and back fat in large white pigs of ukrainian breeding

Agricultural science and practice ◽

10.15407/agrisp3.02.042 ◽

2016 ◽

Vol 3 (2) ◽

pp. 42-48

Author(s):

V. Balatsky ◽

I. Bankovska ◽

A. Saienko

Keyword(s):

Gene Polymorphism ◽

Leptin Receptor ◽

Receptor Gene ◽

Intramuscular Fat ◽

Large White ◽

Pig Breeds ◽

Lepr Gene ◽

Large White Breed ◽

White Breed

Leptin receptor is one of the components of the system of regulating energy homeostasis of the organism. Leptin receptor gene (LEPR) polymorphism is associated with pig carcass index of the content of intramus- cular fat in its valuable parts, which is particularly important when assessing the quality of their carcasses for processing. Intramuscular fat is associated with meat fl avor characteristics and partly determines its tenderness, juiciness, and other parameters. Aim. To analyze LEPR gene (SNP NM001024587.1, p. 1987 C > T) polymor- phism in populations of various pig breeds and to establish its relationship with the quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. Methods. Genetic-population analysis of nine pig breeds, associative analysis on the search connection of LEPR gene polymorphism with quality of both meat and fat of pigs of Large White breed of Ukrainian breeding. LEPR locus genotyping was performed by High Resolution Melting (HRM). Results. All the studied breeds are characterized by polymorphism of the leptin receptor gene (SNP NM001024587.1, p. 1987 C > T), signifi cant breed specifi city in the distribution of frequencies of alleles was established. Statistically confi rmed effect (p < 0.05) of genotypes LEPR on the content of intramuscular fat, total dry matter and moisture in the meat, as well as the moisture content in the back fat of pigs of Ukrainian Large White breed was revealed. Higher content of intramuscular fat was found in the animals with genotype TT, while a smaller amount of intramuscular fat and more moisture in fat was revealed in heterozygotes. Conclusions. Genetic marker LEPR SNP NM001024587.1, p. 1987 C > T can be used in the marker-assisted selection to predict and improve the performance quality of the meat of pigs of Large White breed of the Ukrainian breeding. These results suggest that porcine leptin receptor gene controls the quality of fat comp- lex – inside muscles and in the dorsal part of the carcass.

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The Neuronal Actions of Leptin and the Implications for Treating Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph14010052 ◽

2021 ◽

Vol 14 (1) ◽

pp. 52

Author(s):

Kirsty Hamilton ◽

Jenni Harvey

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Hippocampal Formation ◽

Synaptic Function ◽

Receptor Expression ◽

Neuroprotective Actions ◽

Novel Target ◽

Leptin System

It is widely accepted that the endocrine hormone leptin controls food intake and energy homeostasis via activation of leptin receptors expressed on hypothalamic arcuate neurons. The hippocampal formation also displays raised levels of leptin receptor expression and accumulating evidence indicates that leptin has a significant impact on hippocampal synaptic function. Thus, cellular and behavioural studies support a cognitive enhancing role for leptin as excitatory synaptic transmission, synaptic plasticity and glutamate receptor trafficking at hippocampal Schaffer collateral (SC)-CA1 synapses are regulated by leptin, and treatment with leptin enhances performance in hippocampus-dependent memory tasks. Recent studies indicate that hippocampal temporoammonic (TA)-CA1 synapses are also a key target for leptin. The ability of leptin to regulate TA-CA1 synapses has important functional consequences as TA-CA1 synapses are implicated in spatial and episodic memory processes. Moreover, degeneration is initiated in the TA pathway at very early stages of Alzheimer’s disease, and recent clinical evidence has revealed links between plasma leptin levels and the incidence of Alzheimer’s disease (AD). Additionally, accumulating evidence indicates that leptin has neuroprotective actions in various AD models, whereas dysfunctions in the leptin system accelerate AD pathogenesis. Here, we review the data implicating the leptin system as a potential novel target for AD, and the evidence that boosting the hippocampal actions of leptin may be beneficial.

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Impact of leptin and leptin-receptor gene polymorphisms on serum lipids in Japanese obese children

Acta Paediatrica ◽

10.1111/j.1651-2227.2010.01778.x ◽

2010 ◽

Vol 99 (8) ◽

pp. 1213-1217 ◽

Cited By ~ 15

Author(s):

T Okada ◽

T Ohzeki ◽

Y Nakagawa ◽

S Sugihara ◽

O Arisaka ◽

...

Keyword(s):

Gene Polymorphisms ◽

Serum Lipids ◽

Leptin Receptor ◽

Receptor Gene ◽

Obese Children ◽

Receptor Gene Polymorphisms

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The Trend in Distribution of Q223R Mutation of Leptin Receptor Gene in Amoebic Liver Abscess Patients from North India: A Prospective Study

BioMed Research International ◽

10.1155/2014/847132 ◽

2014 ◽

Vol 2014 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Anil Kumar Verma ◽

Vineet Ahuja ◽

Jaishree Paul

Keyword(s):

Liver Abscess ◽

Leptin Receptor ◽

Receptor Gene ◽

Rflp Analysis ◽

North India ◽

Amoebic Liver Abscess ◽

Fisher Exact Test ◽

Exact Test ◽

Pcr Rflp ◽

A Prospective Study

Host genetic susceptibility is an important risk factor in infectious diseases. We explored the distribution of Q223R mutation in leptin receptor gene of amoebic liver abscess (ALA) patients of North India. A total of 55 ALA samples along with 102 controls were subjected to PCR-RFLP analysis. The frequency of allele “G” (coding for arginine) was in general high in Indian population irrespective of the disease. Our results of Fisher exact test shows that heterozygous mutant (QQ versus QR,P=0.049) and homozygous mutant (QQ versus RR,P=0.004) were significantly associated with amoebic liver abscess when compared with homozygous wild (QQ).

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