Leptin system loss of function in the absence of obesity in zebrafish

The leptin system plays a crucial role in the regulation of appetite and energy homeostasis in vertebrates. While the phenotype of morbid obesity due to leptin or leptin receptor (lepr) loss of function is well established in mammals, evidence in fish is controversial, questioning the role of leptin as the vertebrate adipostat. Here we report on 3 lepr loss of function (lof) and one leptin loss of function allele in zebrafish. In order to demonstrate that the lepr lof alleles cannot transduce a leptin signal, we measured socs3a transcription after intraperitoneal leptin which is abolished by lepr lof. None of the lepr/lepa lof alleles lead to obesity / a body growth phenotype. We explore possible reasons leading to the difference in published results and find that even slight changes in background genetics such as inbreeding siblings and cousins can lead to significant variance in growth.

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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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Glycogenic induction of thyroid hormone conversion and leptin system activation in the liver of postpartum dairy cows

Acta Veterinaria Hungarica ◽

10.1556/avet.57.2009.1.14 ◽

2009 ◽

Vol 57 (1) ◽

pp. 139-146

Author(s):

Andrea Győrffy ◽

Mónika Keresztes ◽

Vera Faigl ◽

Vilmos Frenyó ◽

Margit Kulcsár ◽

...

Keyword(s):

Thyroid Hormone ◽

Energy Balance ◽

Dairy Cows ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Energy Content ◽

Short Form ◽

Negative Energy ◽

Type I ◽

Leptin System

In the regulation of energy metabolism, the liver plays an important role in the reinforcement of energy production. In periparturient cows the energy homeostasis turns into a negative energy balance that may shift the physiological regulation of energy balance towards pathological processes. Propylene glycol (PG), as a complementary source of energy used in the nutrition of dairy cows, alters systemic thyroid hormone economy; however, the exact mechanism through which highly glycogenic feed supplements impact liver metabolism is little known. Previous studies showed that only leptin receptors are expressed in the liver of cows, and now we report that leptin mRNA is expressed in the liver of cows as well. The present results show that the mRNA of leptin and its receptors are differentially modulated by the increased energy content of the feed consumed. Simultaneous changes in hepatic type I deiodinase activity suggest that hepatic modulation of the leptin system by PG supplementation may be mediated by an increased local thyroxine-triiodothyronine conversion. Since PG supplementation with simultaneous T4–T3 turnover and increased hepatic leptin- and short-form leptin receptor mRNA were not associated with a significant change in hepatic total lipid levels, it is suggested that the leptin system, directly or indirectly modulated by thyroid hormones, may represent a local defence mechanism to prevent fatty liver formation.

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Mice With Monoallelic GNAO1 Loss Exhibit Reduced Inhibitory Synaptic Input To Cerebellar Purkinje Cells

10.1101/2021.09.23.461583 ◽

2021 ◽

Author(s):

Huijie Feng ◽

Yukun Yuan ◽

Michael R Williams ◽

Alex Roy ◽

Jeffrey Leipprandt ◽

...

Keyword(s):

Synaptic Transmission ◽

Purkinje Cells ◽

Gabab Receptor ◽

Molecular Layer ◽

Loss Of Function ◽

Whole Cell Patch Clamp ◽

The Difference ◽

G Protein Alpha Subunit ◽

Cerebellar Purkinje Cells

GNAO1 encodes Gαo, a heterotrimeric G protein alpha subunit in the Gi/o family. In this report, we used a Gnao1 mouse model G203R previously described as a gain-of-function Gnao1 mutant with movement abnormalities and enhanced seizure susceptibility. Here, we report an unexpected second mutation resulting in a loss-of-function Gαo protein and describe alterations in central synaptic transmission. Whole cell patch clamp recordings from Purkinje cells (PCs) in acute cerebellar slices from Gnao1 mutant mice showed significantly lower frequencies of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) compared to WT mice. There was no significant change in sEPSCs or mEPSCs. Whereas mIPSC frequency was reduced, mIPSC amplitudes were not affected, suggesting a presynaptic mechanism of action. A modest decrease in the number of molecular layer interneurons was insufficient to explain the magnitude of IPSC suppression. Paradoxically, Gi/o inhibitors (pertussis toxin), enhanced the mutant-suppressed mIPSC frequency and eliminated the difference between WT and Gnao1 mice. While GABAB receptor regulates mIPSCs, neither agonists nor antagonists of this receptor altered function in the mutant mouse PCs. This study is the first electrophysiological investigation of the role of Gi/o protein in cerebellar synaptic transmission using an animal model with a loss-of-function Gi/o protein.

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Variations in Adipokine GenesAdipoQ,Lep, andLepRAre Associated with Risk for Obesity-Related Metabolic Disease: The Modulatory Role of Gene-Nutrient Interactions

Journal of Obesity ◽

10.1155/2011/168659 ◽

2011 ◽

Vol 2011 ◽

pp. 1-17 ◽

Cited By ~ 31

Author(s):

Jennifer Emily Enns ◽

Carla G. Taylor ◽

Peter Zahradka

Keyword(s):

Metabolic Disease ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Disease Risk ◽

Critical Role ◽

Nucleotide Polymorphisms ◽

Nutrient Interactions ◽

The Metabolic Syndrome ◽

Susceptible Populations

Obesity rates are rapidly increasing worldwide and facilitate the development of many related disease states, such as cardiovascular disease, the metabolic syndrome, type 2 diabetes mellitus, and various types of cancer. Variation in metabolically important genes can have a great impact on a population's susceptibility to becoming obese and/or developing related complications. The adipokines adiponectin and leptin, as well as the leptin receptor, are major players in the regulation of body energy homeostasis and fat storage. This paper summarizes the findings of single nucleotide polymorphisms in these three genes and their effect on obesity and metabolic disease risk. Additionally, studies of gene-nutrient interactions involving adiponectin, leptin, and the leptin receptor are highlighted to emphasize the critical role of diet in susceptible populations.

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Loss of Mrap2 is associated with Sim1 deficiency and increased circulating cholesterol

Journal of Endocrinology ◽

10.1530/joe-16-0057 ◽

2016 ◽

Vol 230 (1) ◽

pp. 13-26 ◽

Cited By ~ 23

Author(s):

T V Novoselova ◽

R Larder ◽

D Rimmington ◽

C Lelliott ◽

E H Wynn ◽

...

Keyword(s):

Lipid Metabolism ◽

Metabolic Regulation ◽

Energy Homeostasis ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Melanocortin Receptor ◽

Accessory Protein ◽

Loss Of Function ◽

Deficient Mice

Melanocortin receptor accessory protein 2 (MRAP2) is a transmembrane accessory protein predominantly expressed in the brain. Both global and brain-specific deletion of Mrap2 in mice results in severe obesity. Loss-of-function MRAP2 mutations have also been associated with obesity in humans. Although MRAP2 has been shown to interact with MC4R, a G protein-coupled receptor with an established role in energy homeostasis, appetite regulation and lipid metabolism, the mechanisms through which loss of MRAP2 causes obesity remains uncertain. In this study, we used two independently derived lines of Mrap2 deficient mice (Mrap2tm1a/tm1a) to further study the role of Mrap2 in the regulation of energy balance and peripheral lipid metabolism. Mrap2tm1a/tm1a mice have a significant increase in body weight, with increased fat and lean mass, but without detectable changes in food intake or energy expenditure. Transcriptomic analysis showed significantly decreased expression of Sim1, Trh, Oxt and Crh within the hypothalamic paraventricular nucleus of Mrap2tm1a/tm1a mice. Circulating levels of both high-density lipoprotein and low-density lipoprotein were significantly increased in Mrap2 deficient mice. Taken together, these data corroborate the role of MRAP2 in metabolic regulation and indicate that, at least in part, this may be due to defective central melanocortin signalling.

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Abstract 14729: Weight Loss Reduces Atrial Fibrillation Inducibility and Burden in Severe Obesity Induced by Either High-Fat Diet or Genetic Hyperphagia in Mice

Circulation ◽

10.1161/circ.132.suppl_3.14729 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Eleonora Savio-Galimberti ◽

Prince Kannankeril ◽

David Wasserman ◽

Dawood Darbar

Keyword(s):

Atrial Fibrillation ◽

Morbid Obesity ◽

Weight Loss ◽

High Fat Diet ◽

Energy Homeostasis ◽

Loss Of Function ◽

High Fat ◽

Knock Out ◽

Mc4r Gene ◽

Melanocortin 4 Receptor

Introduction: Atrial fibrillation (AF), the most common sustained arrhythmia worldwide, is associated with increased morbidity and mortality. Obesity is increasingly recognized as an important risk factor to develop AF and heart disease with a diet rich in fats leading to morbid obesity. Melanocortin-4 receptor (MC4R) gene is a critical regulator of energy homeostasis, and homozygous loss-of-function mutations cause hyperphagia and morbid obesity. Hypothesis: We hypothesized that obesity and its comorbidities can create a profibrillatory substrate for AF in high fat diet-induced obese (DIO) and MC4R knock-out (MC4R-KO) mice, and that this substrate can be reversed by weight loss. Methods: Transesophageal rapid pacing was performed using atrial burst pacing (cycle length: 50-15 ms, for 15 s) to determine AF inducibility (% of mice that develop AF) and AF burden (number of AF episodes and total AF duration/mouse) in lightly anesthesized normotensive mice (C57bl6 mice [LEAN], DIO, and MC4R-KO), with continuous ECG monitoring. Transthoracic echocardiography was performed to assess right (R) and left (L) atrial appendage (AA) sizes. Results: Atrial burst pacing induced AF in 91% of DIO and 100% of MC4R-KO vs. 50% of LEAN (P<0.01, N=8 mice/group). Compared to LEAN, both DIO and MC4R-KO exhibited greater number of inducible AF episodes (0.7±0.2 vs. 1.8±0.2 vs. 1.8±0.1, P<0.01, N=15 mice/group) with longer duration (17.9±3 vs. 196±22 vs. 244±34 s, P<0.0001, N=15 mice/group; Figure). Both DIO and MC4R-KO had greater LAA volumes as compared with LEAN (5.2±0.2 vs. 6.7±0.4 vs. 4.1±0.1 μl, P<0.01, N=8 mice/group). RAA volume was similar across groups. After 20% weight loss, both AF burden and LAA volumes were significantly reduced to those seen in LEAN (22±5 s, 4.5±0.1 μl, P<0.001, N=8 mice/group). Conclusions: High-fat diet or genetic hyperphagia-induced obesity increases LAA volume and creates a profibrillatory substrate for AF that can be reversed with weight loss.

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When Richard met CG: reference-point and English copy-raising

Language and Cognition ◽

10.1017/langcog.2016.25 ◽

2016 ◽

Vol 9 (3) ◽

pp. 473-500 ◽

Cited By ~ 1

Author(s):

CHONGWON PARK ◽

DANIEL TURNER

Keyword(s):

Reference Point ◽

Crucial Role ◽

Cognitive Grammar ◽

Point Property ◽

The Matrix ◽

The Difference ◽

Embedded Clause ◽

Copy Raising ◽

Matrix Subject

abstractThe aim of this paper is to develop a Cognitive Grammar-based analysis of English Copy-raising (CR) constructions such as Richard seems like he is dancing. We argue that the notion of reference-point plays a crucial role in licensing the matrix-subject of the construction. In CR, with the epistemic verbs seem and appear, the matrix-subject functions as a reference-point in relation to the pronominal copy (if a copy exists) in the embedded clause. The aboutness topicality of the matrix-subject in CR is expected, owing to its reference-point property. The epistemic CR construction is acceptable without a pronominal copy if the matrix-subject functions as a reference-point in relation to the complement clause. The same type of analysis is applied to the CR construction with perceptual resemblance (PR) verbs – sound, look, feel, and smell – leading to the conclusion that the strong dichotomy between epistemic and PR verbs is illusory. It is further demonstrated that expletive there-raising in CR is motivated by the same reference-point phenomenon. The difference between there-raising and other CR examples stems from the role of there as a setting subject. Our reference-point-based analysis predicts a metonymic interpretation of the matrix-subject, which we attribute to the connection between reference-point and metonymy.

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Loss of CTRP4 alters adiposity and food intake behaviors in obese mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00448.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. E1084-E1100

Author(s):

Dylan C. Sarver ◽

Ashley N. Stewart ◽

Susana Rodriguez ◽

Hannah C. Little ◽

Susan Aja ◽

...

Keyword(s):

Weight Gain ◽

Food Intake ◽

Energy Homeostasis ◽

Physiological Role ◽

Central Administration ◽

Loss Of Function ◽

Low Fat Diet ◽

Obesogenic Diet ◽

Food Intake Patterns

Central and peripheral mechanisms are both required for proper control of energy homeostasis. Among circulating plasma proteins, C1q/TNF-related proteins (CTRPs) have recently emerged as important regulators of sugar and fat metabolism. CTRP4, expressed in brain and adipose tissue, is unique among the family members in having two tandem globular C1q domains. We previously showed that central administration of recombinant CTRP4 suppresses food intake, suggesting a central nervous system role in regulating ingestive physiology. Whether this effect is pharmacological or physiological remains unclear. We used a loss-of-function knockout (KO) mouse model to clarify the physiological role of CTRP4. Under basal conditions, CTRP4 deficiency increased serum cholesterol levels and impaired glucose tolerance in male but not female mice fed a control low-fat diet. When challenged with a high-fat diet, male and female KO mice responded differently to weight gain and had different food intake patterns. On an obesogenic diet, male KO mice had similar weight gain as wild-type littermates. When fed ad libitum, KO male mice had greater meal number, shorter intermeal interval, and reduced satiety ratio. Female KO mice, in contrast, had lower body weight and adiposity. In the refeeding period following food deprivation, female KO mice had significantly higher food intake due to longer meal duration and reduced satiety ratio. Collectively, our data provide genetic evidence for a sex-dependent physiological role of CTRP4 in modulating food intake patterns and systemic energy metabolism.

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Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome

Endocrinology ◽

10.1210/en.2007-1200 ◽

2008 ◽

Vol 149 (5) ◽

pp. 2138-2148 ◽

Cited By ~ 142

Author(s):

Nathan C. Bingham ◽

Kimberly K. Anderson ◽

Anne L. Reuter ◽

Nancy R. Stallings ◽

Keith L. Parker

Keyword(s):

Metabolic Syndrome ◽

Energy Homeostasis ◽

Arcuate Nucleus ◽

Leptin Receptor ◽

Artificial Chromosome ◽

Hypothalamic Nucleus ◽

Steroidogenic Factor 1 ◽

Low Fat Diet ◽

Ventromedial Hypothalamic Nucleus

Leptin, an adipocyte-derived hormone, has emerged as a critical regulator of energy homeostasis. The leptin receptor (Lepr) is expressed in discrete regions of the brain; among the sites of highest expression are several mediobasal hypothalamic nuclei known to play a role in energy homeostasis, including the arcuate nucleus, the ventromedial hypothalamic nucleus (VMH), and the dorsomedial hypothalamic nucleus. Although most studies have focused on leptin’s actions in the arcuate nucleus, the role of Lepr in these other sites has received less attention. To explore the role of leptin signaling in the VMH, we used bacterial artificial chromosome transgenesis to target Cre recombinase to VMH neurons expressing steroidogenic factor 1, thereby inactivating a conditional Lepr allele specifically in steroidogenic factor 1 neurons of the VMH. These knockout (KO) mice, designated Lepr KOVMH, exhibited obesity, particularly when challenged with a high-fat diet. On a low-fat diet, Lepr KOVMH mice exhibited significantly increased adipose mass even when their weights were comparable to wild-type littermates. Furthermore, these mice exhibited a metabolic syndrome including hepatic steatosis, dyslipidemia, and hyperleptinemia. Lepr KOVMH mice were hyperinsulinemic from the age of weaning and eventually developed overt glucose intolerance. These data define nonredundant roles of the Lepr in VMH neurons in energy homeostasis and provide a model system for studying other actions of leptin in the VMH.

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