scholarly journals Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity

2021 ◽  
Author(s):  
Marzia Savini ◽  
Jonathon Daniel Duffy ◽  
Andrew Folick ◽  
Yi-Tang Lee ◽  
Pei-Wen Hu ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Signaling Pathway ◽  
Nuclear Hormone Receptor ◽  
Lipid Signaling ◽  
Storage Tissue ◽  
Fat Storage ◽  
Signaling Mechanism ◽  
Chaperone Protein ◽  
Autonomous Regulation ◽  
Cellular Organelles

Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in aging-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate aging remains unclear. Here, we report a fat-to-neuron lipid signaling pathway induced by lysosomal metabolism and its longevity promoting role in Caenorhabditis elegans. We discovered that lysosomal lipolysis in peripheral fat storage tissue up-regulates the neuropeptide signaling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation requires the secretion from the fat storage tissue of a lipid chaperone protein LBP-3 and polyunsaturated fatty acids (PUFAs). LBP-3 binds to specific PUFAs, and acts through a nuclear hormone receptor NHR-49 and neuropeptide NLP-11 in neurons to extend lifespan. Together, these results reveal lysosomes as a signaling hub to coordinate metabolism and aging, and a lysosomal signaling mechanism that mediates inter-tissue communication to promote longevity.

scholarly journals Lysosome Lipid Signaling from the Periphery to Neurons Regulates Longevity

2021 ◽  
Author(s):  
Marzia Savini ◽  
Jonathon Duffy ◽  
Andrew Folick ◽  
Yi-Tang Lee ◽  
Pei-Wen Hu ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Nervous System ◽  
Signaling Pathway ◽  
Nuclear Hormone Receptor ◽  
Lipid Signaling ◽  
Storage Tissue ◽  
Fat Storage ◽  
Chaperone Protein ◽  
Autonomous Regulation ◽  
Cellular Organelles

Abstract Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in aging-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate aging remains unclear. Here, we report a fat-to-neuron lipid signaling pathway induced by lysosomal metabolism and its longevity promoting role in Caenorhabditis elegans. We discovered that lysosomal lipolysis in peripheral fat storage tissue up-regulates the neuropeptide signaling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation requires the secretion from the fat storage tissue of a lipid chaperone protein LBP-3 and polyunsaturated fatty acids (PUFAs). LBP-3 binds to specific PUFAs, and acts through a nuclear hormone receptor NHR-49 and neuropeptide NLP-11 in neurons to extend lifespan. Together, these results reveal lysosomes as a signaling hub to coordinate metabolism and aging, and lysosomal signaling mediated inter-tissue communication in promoting longevity.

The Effects of Omega-3 Fatty Acids Supplementation on Gene Expression Involved in the Insulin and Lipid Signaling Pathway in Patients with Polycystic Ovary Syndrome

2017 ◽  
Vol 49 (06) ◽  
pp. 446-451 ◽  
Author(s):  
Khadijeh Nasri ◽  
Sedigheh Hantoushzadeh ◽  
Esmat Aghadavod ◽  
Mohsen Taghizadeh ◽  
Zatollah Asemi
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Signaling Pathway ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Lipid Signaling ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Peripheral Blood Mononuclear

AbstractLimited data are available evaluating the effects of omega-3 fatty acids supplementation on gene expression involved in the insulin and lipid-signaling pathway in women with polycystic ovary syndrome (PCOS). This study was conducted to evaluate the effects of omega-3 fatty acids supplementation on gene expression involved in the insulin and lipid signaling pathway in women with PCOS. This randomized double blind, placebo-controlled trial was done among 60 women aged 18–40 years old and diagnosed with PCOS according to the Rotterdam criteria. Participants were randomly assigned into 2 groups to receive either 1 000 mg omega-3 fatty acids from flaxseed oil containing 400 mg α-linolenic acid (n=30) or placebo (n=30) twice a day for 12 weeks. Gene expressions involved in the insulin and lipid-signaling pathway were quantified in blood samples of PCOS women with RT-PCR method. Quantitative results of RT-PCR demonstrated that compared with the placebo, omega-3 fatty acids supplementation upregulated peroxisome proliferator-activated receptor gamma (PPAR-γ) mRNA (p=0.005) in peripheral blood mononuclear cells of women with PCOS. In addition, compared to the placebo, omega-3 fatty acids supplementation downregulated expressed levels of oxidized low-density lipoprotein receptor (LDLR) mRNA (p=0.002) in peripheral blood mononuclear cells of women with PCOS. We did not observe any significant effect of omega-3 fatty acids supplementation on expressed levels of glucose transporter 1 (GLUT-1) and lipoprotein(a) [Lp(a)] genes in peripheral blood mononuclear cells. Overall, omega-3 fatty acids supplementation for 12 weeks in PCOS women significantly improved gene expression of PPAR-γ and LDLR.

scholarly journals Saturated Fatty Acids Promote GDF15 Expression in Human Macrophages through the PERK/eIF2/CHOP Signaling Pathway

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3771
Author(s):  
Laurent L’homme ◽  
Benan Pelin Sermikli ◽  
Bart Staels ◽  
Jacques Piette ◽  
Sylvie Legrand-Poels ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Fatty Acids ◽  
Er Stress ◽  
Signaling Pathway ◽  
Promoter Region ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Growth Differentiation Factor 15 ◽  
Human Macrophages ◽  
Primary Monocyte

Growth differentiation factor-15 (GDF-15) and its receptor GFRAL are both involved in the development of obesity and insulin resistance. Plasmatic GDF-15 level increases with obesity and is positively associated with disease progression. Despite macrophages have been recently suggested as a key source of GDF-15 in obesity, little is known about the regulation of GDF-15 in these cells. In the present work, we sought for potential pathophysiological activators of GDF15 expression in human macrophages and identified saturated fatty acids (SFAs) as strong inducers of GDF15 expression and secretion. SFAs increase GDF15 expression through the induction of an ER stress and the activation of the PERK/eIF2/CHOP signaling pathway in both PMA-differentiated THP-1 cells and in primary monocyte-derived macrophages. The transcription factor CHOP directly binds to the GDF15 promoter region and regulates GDF15 expression. Unlike SFAs, unsaturated fatty acids do not promote GDF15 expression and rather inhibit both SFA-induced GDF15 expression and ER stress. These results suggest that free fatty acids may be involved in the control of GDF-15 and provide new molecular insights about how diet and lipid metabolism may regulate the development of obesity and T2D.

scholarly journals Polymorphism and Human Health

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-15 ◽  
Author(s):  
Weimin He
Keyword(s):  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Unsaturated Fatty Acids ◽  
Polycystic Ovary ◽  
Human Subjects ◽  
Saturated Fatty Acids ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Pro12ala Polymorphism ◽  
Peroxisome Proliferator Activated Receptor

The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPAR) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPAR have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPAR, Pro12Ala of PPAR2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPAR2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPAR2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPAR2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies.

scholarly journals Dietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain

2018 ◽  
Author(s):  
Zhe Cao ◽  
Yan Hao ◽  
Yiu Yiu Lee ◽  
Pengfei Wang ◽  
Xuesong Li ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Lipid Droplet ◽  
Mammalian Cells ◽  
Dietary Fatty Acids ◽  
Fat Storage ◽  
Over Expression ◽  
C Elegans ◽  
Cyclopropane Fatty Acids ◽  
Host Metabolism

AbstractExogenous metabolites from microbial and dietary origins have profound effects on host metabolism. Here, we report that a sub-population of lipid droplets (LDs), which are conserved organelles for fat storage, is defined by metabolites-driven targeting of theC. elegansseipin ortholog, SEIP-1. Loss of SEIP-1 function reduced the size of a subset of LDs while over-expression of SEIP-1 had the opposite effect. Ultrastructural analysis revealed SEIP-1 enrichment in an endoplasmic reticulum (ER) subdomain, which co-purified with LDs. Analyses ofC. elegansand bacterial genetic mutants indicated a requirement of polyunsaturated fatty acids (PUFAs) and microbial cyclopropane fatty acids (CFAs) for SEIP-1 enrichment, as confirmed by dietary supplementation experiments. In mammalian cells, heterologous expression of SEIP-1 promoted lipid droplet expansion from ER subdomains in a conserved manner. Our results suggest that microbial and polyunsaturated fatty acids serve unexpected roles in regulating cellular fat storage by enforcing LD diversity.

scholarly journals Regulation of Transcription Factors and Repression of Sp1 by Prolactin Signaling Through the Short Isoform of Its Cognate Receptor

Endocrinology ◽  
2009 ◽  
Vol 150 (7) ◽  
pp. 3327-3335 ◽  
Author(s):  
Y. Sangeeta Devi ◽  
Aurora Shehu ◽  
Carlos Stocco ◽  
Julia Halperin ◽  
Jamie Le ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Short Form ◽  
Binding Activity ◽  
In Vivo Model ◽  
Regulation Of Transcription ◽  
Signaling Mechanism ◽  
Dna Binding Activity ◽  
And Function

Prolactin (PRL) affects the development and function of the reproductive system by binding to two types of receptors, which differ by the size of their intracellular domain in rodents. Whereas the signaling pathway through the long form of the receptor (PRL-RL) is well characterized, signaling through the short form (PRL-RS) remains obscure. In this investigation, we examined transcription factors regulated by PRL in the ovary and decidua of mice expressing only PRL-RS in a PRL receptor null background. These mice provide a powerful in vivo model to study the selective signaling mechanism of PRL through PRL-RS independent of PRL-RL. We also examined the regulation of transcription factors in ovarian and uterine cell lines stably transfected with PRL-RS or PRL-RL. We focused our investigation on transcription factors similarly regulated in both these tissues and clearly established that signaling through PRL-RS does not activate the JaK/Stat in vivo but leads to severe down-regulation of Sp1 expression, DNA binding activity, and nuclear localization, events that appear to involve the calmodulin-dependent protein kinase pathway. Our in vivo and in culture data demonstrate that the PRL-RS activates a signaling pathway distinct from that of the PRL-RL.

scholarly journals Spatiotemporal dynamics of triglyceride storage in unilocular adipocytes

2014 ◽  
Vol 25 (25) ◽  
pp. 4096-4105 ◽  
Author(s):  
Michael Chu ◽  
Harini Sampath ◽  
David Y. Cahana ◽  
Christoph A. Kahl ◽  
Romel Somwar ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Adipose Tissue ◽  
Free Fatty Acids ◽  
Lipid Droplets ◽  
Ex Vivo ◽  
Spatiotemporal Dynamics ◽  
Biological Features ◽  
Adipocyte Hypertrophy ◽  
Cellular Organelles

The spatiotemporal dynamics of triglyceride (TG) storage in unilocular adipocytes are not well understood. Here we applied ex vivo technology to study trafficking and metabolism of fluorescent fatty acids in adipose tissue explants. Live imaging revealed multiple cytoplasmic nodules surrounding the large central lipid droplet (cLD) of unilocular adipocytes. Each cytoplasmic nodule harbors a series of closely associated cellular organelles, including micro–lipid droplets (mLDs), mitochondria, and the endoplasmic reticulum. Exogenously added free fatty acids are rapidly adsorbed by mLDs and concurrently get esterified to TG. This process is greatly accelerated by insulin. mLDs transfer their content to the cLD, serving as intermediates that mediate packaging of newly synthesized TG in the large interior of a unilocular adipocyte. This study reveals novel cell biological features that may contribute to the mechanism of adipocyte hypertrophy.

scholarly journals A novel sphingolipid-TORC1 pathway critically promotes postembryonic development in Caenorhabditis elegans

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Huanhu Zhu ◽  
Huali Shen ◽  
Aileen K Sewell ◽  
Marina Kniazeva ◽  
Min Han
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Caenorhabditis Elegans ◽  
Signaling Pathway ◽  
Growth And Development ◽  
Postembryonic Development ◽  
Chain Fatty Acid ◽  
Metabolic Status ◽  
Animal Development ◽  
Branched Chain

Regulation of animal development in response to nutritional cues is an intensely studied problem related to disease and aging. While extensive studies indicated roles of the Target of Rapamycin (TOR) in sensing certain nutrients for controlling growth and metabolism, the roles of fatty acids and lipids in TOR-involved nutrient/food responses are obscure. Caenorhabditis elegans halts postembryonic growth and development shortly after hatching in response to monomethyl branched-chain fatty acid (mmBCFA) deficiency. Here, we report that an mmBCFA-derived sphingolipid, d17iso-glucosylceramide, is a critical metabolite in regulating growth and development. Further analysis indicated that this lipid function is mediated by TORC1 and antagonized by the NPRL-2/3 complex in the intestine. Strikingly, the essential lipid function is bypassed by activating TORC1 or inhibiting NPRL-2/3. Our findings uncover a novel lipid-TORC1 signaling pathway that coordinates nutrient and metabolic status with growth and development, advancing our understanding of the physiological roles of mmBCFAs, ceramides, and TOR.

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