Molecular Mechanisms of Vaspin Action – From Adipose Tissue to Skin and Bone, from Blood Vessels to the Brain

ABSTRACTDifferent fasting regimens are known to promote health, mitigate chronic immunological disorders, and improve age-related pathophysiological parameters in animals and humans. Indeed, several clinical trials are currently ongoing using fasting as a potential therapy for a wide range of conditions. Fasting alters metabolism by acting as a reset for energy homeostasis. However, the molecular mechanisms underlying the beneficial effects of short-term fasting (STF) are still not well understood, particularly at the systems or multi-organ level. Here, we investigated the dynamic gene expression patterns associated with six periods of STF in nine different mouse organs. We cataloged the transcriptional dynamics within and between organs during STF and discovered differential temporal effects of STF among organs. Using gene ontology enrichment analysis, we identified an organ network sharing 37 common biological pathways perturbed by STF. This network incorporates the brain, liver, interscapular brown adipose tissue, and posterior-subcutaneous white adipose tissue, hence we named it the brain-liver-fats organ network. Using Reactome pathways analysis, we identified the immune system, dominated by T cell regulation processes, as a central and prominent target of systemic modulations during STF in this organ network. The changes we identified in specific immune components point to the priming of adaptive immunity and parallel the fine-tuning of innate immune signaling. Our study provides a comprehensive multi-organ transcriptomic profiling of mice subjected to multiple periods of STF, and adds new insights into the molecular modulators involved in the systemic immuno-transcriptomic changes that occur during short-term energy loss.

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Regulation of the Brain Neural Niche by Soluble Molecule Akhirin

Journal of Developmental Biology ◽

10.3390/jdb9030029 ◽

2021 ◽

Vol 9 (3) ◽

pp. 29

Author(s):

Mikiko Kudo ◽

Kunimasa Ohta

Keyword(s):

Spinal Cord ◽

Blood Vessels ◽

Molecular Mechanisms ◽

Neural Progenitor Cells ◽

Central Canal ◽

Neural Cells ◽

Neural Tissues ◽

The Central Nervous System ◽

The Brain

In the central nervous system (CNS), which comprises the eyes, spinal cord, and brain, neural cells are produced by the repeated division of neural stem cells (NSCs) during the development of the CNS. Contrary to the notion that the CNS is relatively static with a limited cell turnover, cells with stem cell-like properties have been isolated from most neural tissues. The microenvironment, also known as the NSC niche, consists of NSCs/neural progenitor cells, other neurons, glial cells, and blood vessels; this niche is thought to regulate neurogenesis and the differentiation of NSCs into neurons and glia. Although it has been established that neurons, glia, and blood vessels interact with each other in a complex manner to generate neural tissues in the NSC niche, the underlying molecular mechanisms in the CNS niche are unclear. Herein, we would like to introduce the extracellular secreted protein, Akhirin (AKH; Akhi is the Bengali translation for eye). AKH is specifically expressed in the CNS niche—the ciliary body epithelium in the retina, the central canal of the spinal cord, the subventricular zone, and the subgranular zone of the dentate gyrus of the hippocampus—and is supposedly involved in NSC niche regulation. In this review, we discuss the role of AKH as a niche molecule during mouse brain formation.

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Linking the brain and bone through fat

Journal of Mind and Medical Sciences ◽

10.22543/7674.81.p1726 ◽

2021 ◽

Vol 8 (1) ◽

pp. 17-26

Author(s):

Elisabeta Malinici ◽

Anca Sirbu ◽

Miruna Popa ◽

Simona Fica

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Molecular Mechanisms ◽

Lipocalin 2 ◽

Secreted Factors ◽

Tnf Α ◽

The Central Nervous System ◽

The Brain

Over the past years, bone and adipose tissue have gained interest from researchers in the light of their secretory profiles, being able to produce active molecules, with the final effect of regulating energy homeostasis. Both adipocytes and osteoblasts originate in the pluripotent mesenchymal stem cell and this common origin has been proposed as the core of the fat-bone relationship. The central nervous system might be the third player in this association, capable of integrating signals. Numerous adipose tissue secreted factors that influence energy homeostasis and bone have been described: leptin, adiponectin, lipocalin 2, and inflammatory cytokines (e.g. IL-1, IL-6 and TNF-α). Similarly, osteocalcin, the most abundant bone protein, has been shown to elicit numerous central and peripheral endocrine functions. In this paper, we provide a review of the current literature regarding the bone-adipose tissue-central nervous system axis and a brief description of the several underlying molecular mechanisms.

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Faculty Opinions recommendation of An Integrated Understanding of the Molecular Mechanisms How Adipose Tissue Metabolism Affects Long-Term Body Weight Maintenance.

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

10.3410/f.734356607.793555902 ◽

2019 ◽

Author(s):

Marleen van Baak

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Weight Maintenance ◽

Adipose Tissue Metabolism ◽

Tissue Metabolism

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Sublethal Exposure Effects of the Neonicotinoid Clothianidin Strongly Modify the Brain Transcriptome and Proteome in the Male Moth Agrotis ipsilon

Insects ◽

10.3390/insects12020152 ◽

2021 ◽

Vol 12 (2) ◽

pp. 152

Author(s):

Camille Meslin ◽

Françoise Bozzolan ◽

Virginie Braman ◽

Solenne Chardonnet ◽

Cédric Pionneau ◽

...

Keyword(s):

Sex Pheromone ◽

Molecular Mechanisms ◽

Insect Pest ◽

Agrotis Ipsilon ◽

Positive Effects ◽

Male Moth ◽

Hormetic Effect ◽

Pest Insects ◽

Neuronal Processes ◽

The Brain

Insect pest management relies mainly on neurotoxic insecticides, including neonicotinoids such as clothianidin. The residual accumulation of low concentrations of these insecticides can have positive effects on target pest insects by enhancing various life traits. Because pest insects often rely on sex pheromones for reproduction and olfactory synaptic transmission is cholinergic, neonicotinoid residues could indeed modify chemical communication. We recently showed that treatments with low doses of clothianidin could induce hormetic effects on behavioral and neuronal sex pheromone responses in the male moth, Agrotis ipsilon. In this study, we used high-throughput RNAseq and proteomic analyses from brains of A. ipsilon males that were intoxicated with a low dose of clothianidin to investigate the molecular mechanisms leading to the observed hormetic effect. Our results showed that clothianidin induced significant changes in transcript levels and protein quantity in the brain of treated moths: 1229 genes and 49 proteins were differentially expressed upon clothianidin exposure. In particular, our analyses highlighted a regulation in numerous enzymes as a possible detoxification response to the insecticide and also numerous changes in neuronal processes, which could act as a form of acclimatization to the insecticide-contaminated environment, both leading to enhanced neuronal and behavioral responses to sex pheromone.

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DNA Methylation Profiles of Tph1A and BDNF in Gut and Brain of L. Rhamnosus-Treated Zebrafish

Biomolecules ◽

10.3390/biom11020142 ◽

2021 ◽

Vol 11 (2) ◽

pp. 142

Author(s):

Mariella Cuomo ◽

Luca Borrelli ◽

Rosa Della Monica ◽

Lorena Coretti ◽

Giulia De Riso ◽

...

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

The Past ◽

Targeted Analysis ◽

Lack Of Information ◽

High Resolution Power ◽

Resolution Level ◽

Health And Disease ◽

High Doses ◽

The Brain

The bidirectional microbiota–gut–brain axis has raised increasing interest over the past years in the context of health and disease, but there is a lack of information on molecular mechanisms underlying this connection. We hypothesized that change in microbiota composition may affect brain epigenetics leading to long-lasting effects on specific brain gene regulation. To test this hypothesis, we used Zebrafish (Danio Rerio) as a model system. As previously shown, treatment with high doses of probiotics can modulate behavior in Zebrafish, causing significant changes in the expression of some brain-relevant genes, such as BDNF and Tph1A. Using an ultra-deep targeted analysis, we investigated the methylation state of the BDNF and Tph1A promoter region in the brain and gut of probiotic-treated and untreated Zebrafishes. Thanks to the high resolution power of our analysis, we evaluated cell-to-cell methylation differences. At this resolution level, we found slight DNA methylation changes in probiotic-treated samples, likely related to a subgroup of brain and gut cells, and that specific DNA methylation signatures significantly correlated with specific behavioral scores.

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Molecular mechanisms of metabotropic GABAB receptor function

Science Advances ◽

10.1126/sciadv.abg3362 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabg3362

Author(s):

Hamidreza Shaye ◽

Benjamin Stauch ◽

Cornelius Gati ◽

Vadim Cherezov

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Gabab Receptor ◽

Neurological Diseases ◽

Activation Mechanism ◽

Allosteric Modulators ◽

Inhibitory Neurotransmitter ◽

Therapeutic Drugs ◽

G Protein Coupled ◽

The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

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Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue

Scientific Reports ◽

10.1038/s41598-021-92711-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jie Qu ◽

Sarah Fourman ◽

Maureen Fitzgerald ◽

Min Liu ◽

Supna Nair ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Uptake ◽

Molecular Mechanisms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Receptor ◽

Dependent Manner ◽

Related Protein ◽

Density Lipoprotein Receptor ◽

Lipoprotein Receptor Related Protein

AbstractApolipoprotein A4 (APOA4) is one of the most abundant and versatile apolipoproteins facilitating lipid transport and metabolism. APOA4 is synthesized in the small intestine, packaged onto chylomicrons, secreted into intestinal lymph and transported via circulation to several tissues, including adipose. Since its discovery nearly 4 decades ago, to date, only platelet integrin αIIbβ3 has been identified as APOA4 receptor in the plasma. Using co-immunoprecipitation coupled with mass spectrometry, we probed the APOA4 interactome in mouse gonadal fat tissue, where ApoA4 gene is not transcribed but APOA4 protein is abundant. We demonstrate that lipoprotein receptor-related protein 1 (LRP1) is the cognate receptor for APOA4 in adipose tissue. LRP1 colocalized with APOA4 in adipocytes; it interacted with APOA4 under fasting condition and their interaction was enhanced during lipid feeding concomitant with increased APOA4 levels in plasma. In 3T3-L1 mature adipocytes, APOA4 promoted glucose uptake both in absence and presence of insulin in a dose-dependent manner. Knockdown of LRP1 abrogated APOA4-induced glucose uptake as well as activation of phosphatidylinositol 3 kinase (PI3K)-mediated protein kinase B (AKT). Taken together, we identified LRP1 as a novel receptor for APOA4 in promoting glucose uptake. Considering both APOA4 and LRP1 are multifunctional players in lipid and glucose metabolism, our finding opens up a door to better understand the molecular mechanisms along APOA4-LRP1 axis, whose dysregulation leads to obesity, cardiovascular disease, and diabetes.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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Effects of Brain Size on Adult Neurogenesis in Shrews

International Journal of Molecular Sciences ◽

10.3390/ijms22147664 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7664

Author(s):

Katarzyna Bartkowska ◽

Krzysztof Turlejski ◽

Beata Tepper ◽

Leszek Rychlik ◽

Peter Vogel ◽

...

Keyword(s):

Adult Neurogenesis ◽

Subventricular Zone ◽

Molecular Mechanisms ◽

Brain Size ◽

Hippocampal Formation ◽

Small Animals ◽

Suncus Murinus ◽

The Brain ◽

Neomys Fodiens ◽

Migratory Stream

Shrews are small animals found in many different habitats. Like other mammals, adult neurogenesis occurs in the subventricular zone of the lateral ventricle (SVZ) and the dentate gyrus (DG) of the hippocampal formation. We asked whether the number of new generated cells in shrews depends on their brain size. We examined Crocidura russula and Neomys fodiens, weighing 10–22 g, and Crocidura olivieri and Suncus murinus that weigh three times more. We found that the density of proliferated cells in the SVZ was approximately at the same level in all species. These cells migrated from the SVZ through the rostral migratory stream to the olfactory bulb (OB). In this pathway, a low level of neurogenesis occurred in C. olivieri compared to three other species of shrews. In the DG, the rate of adult neurogenesis was regulated differently. Specifically, the lowest density of newly generated neurons was observed in C. russula, which had a substantial number of new neurons in the OB compared with C. olivieri. We suggest that the number of newly generated neurons in an adult shrew’s brain is independent of the brain size, and molecular mechanisms of neurogenesis appeared to be different in two neurogenic structures.

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