A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction

The remarkable development and refinement of the Cre-loxP system coupled with the nonstop production of new mouse models and virus vectors have impelled the growth of various fields of investigation. In this article, I will discuss the data collected using these genetic tools in our area of interest, giving specific emphasis to the identification of the neuronal populations that relay leptin action in reproductive physiology. A series of mouse models that allow manipulation of the leptin receptor gene have been generated. Of those, I will discuss the use of two models of leptin receptor gene reexpression ( LepR neo/neo and LepR loxTB/loxTB) and one model of leptin signaling blockade ( LepR flox/flox). I will also highlight the differences of using stereotaxic delivery of virus vectors expressing DNA-recombinases (Flp and Cre) and mouse models expressing Cre-recombinase. Our findings indicate that leptin action in the ventral premammillary nucleus is sufficient, but not required, for leptin action in reproduction and that leptin action in Kiss1 neurons arises after pubertal maturation; therefore, direct leptin signaling in Kiss1 neurons is neither required nor sufficient for the permissive action of leptin in pubertal development. It also became evident that the full action of leptin in the reproductive neuroendocrine axis requires the engagement of an integrated circuitry, yet to be fully unveiled.

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Leptin Action in the Ventromedial Hypothalamic Nucleus Is Sufficient, But Not Necessary, to Normalize Diabetic Hyperglycemia

Endocrinology ◽

10.1210/en.2013-1328 ◽

2013 ◽

Vol 154 (9) ◽

pp. 3067-3076 ◽

Cited By ~ 28

Author(s):

Thomas H. Meek ◽

Miles E. Matsen ◽

Mauricio D. Dorfman ◽

Stephan J. Guyenet ◽

Vincent Damian ◽

...

Keyword(s):

Glucose Homeostasis ◽

Leptin Receptor ◽

Brain Area ◽

Receptor Gene ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Hypothalamic Nucleus ◽

Leptin Signaling ◽

Brown Adipose ◽

Tracer Dilution

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

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Severe Early-Onset Obesity in Three Adult Patients Harboring Inactivating Mutations of the Leptin Receptor Gene

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.072 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A37-A37

Author(s):

Carolina Marques Chaves ◽

Teresa Kay ◽

Joao Anselmo

Keyword(s):

Early Onset ◽

Leptin Receptor ◽

Reference Range ◽

Receptor Gene ◽

Pubertal Development ◽

Genetic Diagnosis ◽

The Body ◽

Homozygous Mutation ◽

Genetic Sequencing ◽

Lepr Gene

Abstract Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (> +3SD), and at 10 years old, it was over 40 kg/m2 (> +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T> C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.

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Phenotypic variation in constitutional delay of growth and puberty: relationship to specific leptin and leptin receptor gene polymorphisms

Acta Endocrinologica ◽

10.1530/eje.1.02184 ◽

2006 ◽

Vol 155 (1) ◽

pp. 121-126 ◽

Cited By ~ 23

Author(s):

Indraneel Banerjee ◽

Julie A Trueman ◽

Catherine M Hall ◽

David A Price ◽

Leena Patel ◽

...

Keyword(s):

Gene Polymorphisms ◽

Leptin Receptor ◽

Receptor Gene ◽

Pubertal Development ◽

Bone Age ◽

Short Allele ◽

Pubertal Delay ◽

The Us ◽

Constitutional Delay ◽

Bone Age Delay

Objectives: Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress, often with dominant inheritance. It is likely that one or more genes will be associated with CDGP. Possible candidates are the leptin (L) and the leptin receptor (LR) genes, as the leptin axis links nutritional status to pubertal development. This study has assessed whether a) L or LR gene polymorphisms were associated with CDGP and b) the CDGP phenotype was influenced by these polymorphisms. Design: Case–control and transmission disequilibrium tests were used to test genetic association of L and LR polymorphisms with CDGP. Methods: We genotyped L (3′CTTT repeat) and LR polymorphisms (Gln>Arg substitution, exon 6) in 81 CDGP children and 94 controls in the UK and 88 CDGP children from the US and assessed the effect of genotype on their anthropometric characteristics. Results: There was no association of these L or LR gene polymorphisms with CDGP. There was no difference in height or bone age delay within L or LR genotypes. However, UK CDGP children homozygous for the L short allele were heavier than heterozygotes and long allele homozygotes, with a similar trend in the US cohort. UK CDGP children with severe pubertal delay, who were thin, had significantly greater bone age delay and an increased frequency of parental pubertal delay than other groups and were less likely to be L short allele homozygotes. Conclusions: There was no association of specific L or LR polymorphisms with CDGP, but L short allele carriage influenced the phenotype within CDGP.

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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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Faculty Opinions recommendation of Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3518957.3512057 ◽

2010 ◽

Author(s):

Nelson Chao

Keyword(s):

Gene Therapy ◽

T Cell ◽

T Cell Receptor ◽

Mouse Models ◽

Graft Versus Host Disease ◽

Receptor Gene ◽

Cell Receptor ◽

Graft Versus Host ◽

T Cell Receptor Gene ◽

Cell Receptor Gene

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Faculty Opinions recommendation of Lethal graft-versus-host disease in mouse models of T cell receptor gene therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3518957.3216055 ◽

2010 ◽

Author(s):

David Kranz

Keyword(s):

Gene Therapy ◽

T Cell ◽

T Cell Receptor ◽

Mouse Models ◽

Graft Versus Host Disease ◽

Receptor Gene ◽

Cell Receptor ◽

Graft Versus Host ◽

T Cell Receptor Gene ◽

Cell Receptor Gene

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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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