The role of the molecular circadian clock in human energy homeostasis

Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.

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The Role of Tanycytes in the Hypothalamus-Pituitary-Thyroid Axis and the Possibilities for Their Genetic Manipulation

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/a-1065-1855 ◽

2019 ◽

Vol 128 (06/07) ◽

pp. 388-394

Author(s):

Helge Müller-Fielitz ◽

Markus Schwaninger

Keyword(s):

Energy Homeostasis ◽

Genetic Manipulation ◽

Heart Function ◽

Feedback Regulation ◽

Target Organs ◽

Pituitary Thyroid Axis ◽

Thyroid Axis ◽

Hpt Axis ◽

The Brain

AbstractThyroid hormone (TH) regulation is important for development, energy homeostasis, heart function, and bone formation. To control the effects of TH in target organs, the hypothalamus-pituitary-thyroid (HPT) axis and the tissue-specific availability of TH are highly regulated by negative feedback. To exert a central feedback, TH must enter the brain via specific transport mechanisms and cross the blood-brain barrier. Here, tanycytes, which are located in the ventral walls of the 3rd ventricle in the mediobasal hypothalamus (MBH), function as gatekeepers. Tanycytes are able to transport, sense, and modify the release of hormones of the HPT axis and are involved in feedback regulation. In this review, we focus on the relevance of tanycytes in thyrotropin-releasing hormone (TRH) release and review available genetic tools to investigate the physiological functions of these cells.

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Circadian clock protein Rev-erbα regulates neuroinflammation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812405116 ◽

2019 ◽

Vol 116 (11) ◽

pp. 5102-5107 ◽

Cited By ~ 36

Author(s):

Percy Griffin ◽

Julie M. Dimitry ◽

Patrick W. Sheehan ◽

Brian V. Lananna ◽

Chun Guo ◽

...

Keyword(s):

Circadian Clock ◽

Microglial Activation ◽

Time Of Day ◽

Resting State Functional Connectivity ◽

Promoter Regions ◽

Clock Component ◽

Glial Cultures ◽

Inflammatory Phenotype

Circadian dysfunction is a common attribute of many neurodegenerative diseases, most of which are associated with neuroinflammation. Circadian rhythm dysfunction has been associated with inflammation in the periphery, but the role of the core clock in neuroinflammation remains poorly understood. Here we demonstrate that Rev-erbα, a nuclear receptor and circadian clock component, is a mediator of microglial activation and neuroinflammation. We observed time-of-day oscillation in microglial immunoreactivity in the hippocampus, which was disrupted in Rev-erbα−/− mice. Rev-erbα deletion caused spontaneous microglial activation in the hippocampus and increased expression of proinflammatory transcripts, as well as secondary astrogliosis. Transcriptomic analysis of hippocampus from Rev-erbα−/− mice revealed a predominant inflammatory phenotype and suggested dysregulated NF-κB signaling. Primary Rev-erbα−/− microglia exhibited proinflammatory phenotypes and increased basal NF-κB activation. Chromatin immunoprecipitation revealed that Rev-erbα physically interacts with the promoter regions of several NF-κB–related genes in primary microglia. Loss of Rev-erbα in primary astrocytes had no effect on basal activation but did potentiate the inflammatory response to lipopolysaccharide (LPS). In vivo, Rev-erbα−/− mice exhibited enhanced hippocampal neuroinflammatory responses to peripheral LPS injection, while pharmacologic activation of Rev-erbs with the small molecule agonist SR9009 suppressed LPS-induced hippocampal neuroinflammation. Rev-erbα deletion influenced neuronal health, as conditioned media from Rev-erbα–deficient primary glial cultures exacerbated oxidative damage in cultured neurons. Rev-erbα−/− mice also exhibited significantly altered cortical resting-state functional connectivity, similar to that observed in neurodegenerative models. Our results reveal Rev-erbα as a pharmacologically accessible link between the circadian clock and neuroinflammation.

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The melanocortin system

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00434.2002 ◽

2003 ◽

Vol 284 (3) ◽

pp. E468-E474 ◽

Cited By ~ 264

Author(s):

Ira Gantz ◽

Tung M. Fong

Keyword(s):

Sexual Function ◽

Energy Homeostasis ◽

Melanocortin Receptors ◽

Experimental Basis ◽

Melanocortin System ◽

Genetic Studies ◽

Melanocortin Peptides ◽

Selective Agonists ◽

Made In

The melanocortin system consists of melanocortin peptides derived from the proopiomelanocortin gene, five melanocortin receptors, two endogenous antagonists, and two ancillary proteins. This review provides an abbreviated account of the basic biochemistry, pharmacology, and physiology of the melanocortin system and highlights progress made in four areas. In particular, recent pharmacological and genetic studies have affirmed the role of melanocortins in pigmentation, inflammation, energy homeostasis, and sexual function. Development of selective agonists and antagonists is expected to further facilitate the investigation of these complex physiological functions and provide an experimental basis for new pharmacotherapies.

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Importance And Role Of Competence In Professional Career Of Product Develop Engineers

ACTA Universitatis Cibiniensis ◽

10.1515/aucts-2015-0038 ◽

2015 ◽

Vol 66 (1) ◽

pp. 114-118

Author(s):

Aleksandar Miltenović ◽

Milan Banić ◽

Vojislav Miltenović

Keyword(s):

Product Development ◽

New Product ◽

Production Costs ◽

Improve Product Quality ◽

Professional Career ◽

Material Resources ◽

Human Energy ◽

Optimum Utilization ◽

Fierce Competition

Abstract Product development is a creative task where is systematically created a new product, which makes possible to firms to offer attractive, innovative and market oriented products. In conditions of fierce competition and saturated markets, companies that do not innovate are stagnating and disappear from the market. Innovation is therefore every intervention which can reduce production costs, enables optimum utilization of available human, energy and material resources, improve product quality, improve the placement, which leads to an increase in competitiveness. A prerequisite for fulfillment of the above-mentioned tasks is that the companies have engineers with the appropriate competencies, which are able to, through creativity, innovation and fascinating technique of creating new or improving existing products and lunch it on the market. The paper discusses the role and importance of the competences that are necessary for a successful professional career of product development engineers.

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Evidence for a dysfunction and disease-promoting role of the circadian clock in the diabetic retina

Experimental Eye Research ◽

10.1016/j.exer.2021.108751 ◽

2021 ◽

Vol 211 ◽

pp. 108751

Author(s):

Patrick Vancura ◽

Laura Oebel ◽

Simon Spohn ◽

Ute Frederiksen ◽

Kristina Schäfer ◽

...

Keyword(s):

Circadian Clock ◽

Diabetic Retina

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L-Carnitine in Drosophila: A Review

Antioxidants ◽

10.3390/antiox9121310 ◽

2020 ◽

Vol 9 (12) ◽

pp. 1310

Author(s):

Maria Rosaria Carillo ◽

Carla Bertapelle ◽

Filippo Scialò ◽

Mario Siervo ◽

Gianrico Spagnuolo ◽

...

Keyword(s):

Transport System ◽

Essential Role ◽

Energy Homeostasis ◽

Current Knowledge ◽

Fatty Acyl ◽

Amino Acid Derivative ◽

Carnitine Transport ◽

Human Transport ◽

Drosophila Models

L-Carnitine is an amino acid derivative that plays a key role in the metabolism of fatty acids, including the shuttling of long-chain fatty acyl CoA to fuel mitochondrial β-oxidation. In addition, L-carnitine reduces oxidative damage and plays an essential role in the maintenance of cellular energy homeostasis. L-carnitine also plays an essential role in the control of cerebral functions, and the aberrant regulation of genes involved in carnitine biosynthesis and mitochondrial carnitine transport in Drosophila models has been linked to neurodegeneration. Drosophila models of neurodegenerative diseases provide a powerful platform to both unravel the molecular pathways that contribute to neurodegeneration and identify potential therapeutic targets. Drosophila can biosynthesize L-carnitine, and its carnitine transport system is similar to the human transport system; moreover, evidence from a defective Drosophila mutant for one of the carnitine shuttle genes supports the hypothesis of the occurrence of β-oxidation in glial cells. Hence, Drosophila models could advance the understanding of the links between L-carnitine and the development of neurodegenerative disorders. This review summarizes the current knowledge on L-carnitine in Drosophila and discusses the role of the L-carnitine pathway in fly models of neurodegeneration.

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