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24 pages, 2866 KiB

Open AccessArticle

Impact of a High-Fat Diet on the Metabolomics Profile of 129S6 and C57BL6 Mouse Strains

by Maria Piirsalu, Egon Taalberg, Mohan Jayaram, Kersti Lilleväli, Mihkel Zilmer and Eero Vasar

Int. J. Mol. Sci. 2022, 23(19), 11682; https://doi.org/10.3390/ijms231911682 - 2 Oct 2022

Viewed by 1936

Abstract

Different inbred mouse strains vary substantially in their behavior and metabolic phenotype under physiological and pathological conditions. The purpose of this study was to extend the knowledge of distinct coping strategies under challenging events in two differently adapting mouse strains: C57BL/6NTac (Bl6) and [...] Read more.

Different inbred mouse strains vary substantially in their behavior and metabolic phenotype under physiological and pathological conditions. The purpose of this study was to extend the knowledge of distinct coping strategies under challenging events in two differently adapting mouse strains: C57BL/6NTac (Bl6) and 129S6/SvEvTac (129Sv). Thus, we aimed to investigate possible similarities and differences in the body weight change, behavior, and several metabolic variables in Bl6 and 129Sv strains in response to high-fat diet (HFD) using the AbsoluteIDQ p180 kit. We found that 9 weeks of HFD induced a significant body weight gain in 129Sv, but not in Bl6 mice. Besides that, 129Sv mice displayed anxiety-like behavior in the open-field test. Metabolite profiling revealed that 129Sv mice had higher levels of circulating branched-chain amino acids, which were even more amplified by HFD. HFD also induced a decrease in glycine, spermidine, and t4-OH-proline levels in 129Sv mice. Although acylcarnitines (ACs) dominated in baseline conditions in 129Sv strain, this strain had a significantly stronger AC-reducing effect of HFD. Moreover, 129Sv mice had higher levels of lipids in baseline conditions, but HFD caused more pronounced alterations in lipid profile in Bl6 mice. Taken together, our results show that the Bl6 line is better adapted to abundant fat intake. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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15 pages, 2686 KiB

Open AccessArticle

Whole Body Ip6k1 Deletion Protects Mice from Age-Induced Weight Gain, Insulin Resistance and Metabolic Dysfunction

by Sarbani Ghoshal, Sandip Mukherjee, Molee Chakraborty, Eliwaza Naomi Msengi, Jake Haubner and Anutosh Chakraborty

Int. J. Mol. Sci. 2022, 23(4), 2059; https://doi.org/10.3390/ijms23042059 - 12 Feb 2022

Cited by 5 | Viewed by 3530

Abstract

(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this [...] Read more.

(1) Background: We previously demonstrated that disruption of IP6K1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis. Age-induced metabolic dysfunction is a major risk factor for metabolic diseases. The involvement of IP6K1 in this process is unknown. (2) Methods: Here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (aWT) and whole body Ip6k1 knockout (aKO) mice. (3) Results: IP6K1 was upregulated in the adipose tissue and liver of aWT mice compared to young WT mice. Moreover, Ip6k1 deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice. aKO mice oxidized carbohydrates more efficiently. The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids. Ip6k1 deletion partly protected age-induced decline of the thermogenic uncoupling protein UCP1 in inguinal white adipose tissue. Targets inhibited by IP6K1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase B (PKB/Akt) and AMP-activated protein kinase (AMPK), were activated in the adipose tissue and liver of aKO mice. (4) Conclusions: Ip6k1 deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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13 pages, 3402 KiB

Open AccessArticle

High Glucose Impairs Expression and Activation of MerTK in ARPE-19 Cells

by Alessandra Puddu, Silvia Ravera, Isabella Panfoli, Nadia Bertola and Davide Maggi

Int. J. Mol. Sci. 2022, 23(3), 1144; https://doi.org/10.3390/ijms23031144 - 20 Jan 2022

Cited by 5 | Viewed by 2804

Abstract

MerTK (Mer Tyrosine Kinase) is a cell surface receptor that regulates phagocytosis of photoreceptor outer segments (POS) in retinal pigment epithelial (RPE) cells. POS phagocytosis is impaired in several pathologies, including diabetes. In this study, we investigate whether hyperglycemic conditions may affect MerTK [...] Read more.

MerTK (Mer Tyrosine Kinase) is a cell surface receptor that regulates phagocytosis of photoreceptor outer segments (POS) in retinal pigment epithelial (RPE) cells. POS phagocytosis is impaired in several pathologies, including diabetes. In this study, we investigate whether hyperglycemic conditions may affect MerTK expression and activation in ARPE-19 cells, a retinal pigment epithelial cellular model. ARPE-19 cells were cultured in standard (CTR) or high-glucose (HG) medium for 24 h. Then, we analyzed: mRNA levels and protein expression of MerTK and ADAM9, a protease that cleaves the extracellular region of MerTK; the amount of cleaved Mer (sMer); and the ability of GAS6, a MerTK ligand, to induce MerTK phosphorylation. Since HG reduces miR-126 levels, and ADAM9 is a target of miR-126, ARPE-19 cells were transfected with miR-126 inhibitor or mimic; then, we evaluated ADAM9 expression, sMer, and POS phagocytosis. We found that HG reduced expression and activation of MerTK. Contextually, HG increased expression of ADAM9 and the amount of sMer. Overexpression of miR-126 reduced levels of sMer and improved phagocytosis in ARPE-19 cells cultured with HG. In this study, we demonstrate that HG compromises MerTK expression and activation in ARPE-19 cells. Our results suggest that HG up-regulates ADAM9 expression, leading to increased shedding of MerTK. The consequent rise in sMer coupled to reduced expression of MerTK impairs binding and internalization of POS in ARPE-19 cells. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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18 pages, 5240 KiB

Open AccessArticle

Cysteine Restriction in Murine L929 Fibroblasts as an Alternative Strategy to Methionine Restriction in Cancer Therapy

by Werner Schmitz, Elena Ries, Corinna Koderer, Maximilian Friedrich Völter, Anna Chiara Wünsch, Mohamed El-Mesery, Kyra Frackmann, Alexander Christian Kübler, Christian Linz and Axel Seher

Int. J. Mol. Sci. 2021, 22(21), 11630; https://doi.org/10.3390/ijms222111630 - 27 Oct 2021

Cited by 2 | Viewed by 2328

Abstract

Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since [...] Read more.

Methionine restriction (MetR) is an efficient method of amino acid restriction (AR) in cells and organisms that induces low energy metabolism (LEM) similar to caloric restriction (CR). The implementation of MetR as a therapy for cancer or other diseases is not simple since the elimination of a single amino acid in the diet is difficult. However, the in vivo turnover rate of cysteine is usually higher than the rate of intake through food. For this reason, every cell can enzymatically synthesize cysteine from methionine, which enables the use of specific enzymatic inhibitors. In this work, we analysed the potential of cysteine restriction (CysR) in the murine cell line L929. This study determined metabolic fingerprints using mass spectrometry (LC/MS). The profiles were compared with profiles created in an earlier work under MetR. The study was supplemented by proliferation studies using D-amino acid analogues and inhibitors of intracellular cysteine synthesis. CysR showed a proliferation inhibition potential comparable to that of MetR. However, the metabolic footprints differed significantly and showed that CysR does not induce classic LEM at the metabolic level. Nevertheless, CysR offers great potential as an alternative for decisive interventions in general and tumour metabolism at the metabolic level. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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12 pages, 2327 KiB

Open AccessArticle

A Lipidomics Atlas of Selected Sphingolipids in Multiple Mouse Nervous System Regions

by Chunyan Wang, Juan Pablo Palavicini and Xianlin Han

Int. J. Mol. Sci. 2021, 22(21), 11358; https://doi.org/10.3390/ijms222111358 - 21 Oct 2021

Cited by 4 | Viewed by 2663

Abstract

Many lipids, including sphingolipids, are essential components of the nervous system. Sphingolipids play critical roles in maintaining the membrane structure and integrity and in cell signaling. We used a multi-dimensional mass spectrometry-based shotgun lipidomics platform to selectively analyze the lipid species profiles of [...] Read more.

Many lipids, including sphingolipids, are essential components of the nervous system. Sphingolipids play critical roles in maintaining the membrane structure and integrity and in cell signaling. We used a multi-dimensional mass spectrometry-based shotgun lipidomics platform to selectively analyze the lipid species profiles of ceramide, sphingomyelin, cerebroside, and sulfatide; these four classes of sphingolipids are found in the central nervous system (CNS) (the cerebrum, brain stem, and spinal cord) and peripheral nervous system (PNS) (the sciatic nerve) tissues of young adult wild-type mice. Our results revealed that the lipid species profiles of the four sphingolipid classes in the different nervous tissues were highly distinct. In addition, the mRNA expression of sphingolipid metabolism genes—including the ceramidase synthases that specifically acylate the N-acyl chain of ceramide species and sphingomyelinases that cleave sphingomyelins generating ceramides—were analyzed in the mouse cerebrum and spinal cord tissue in order to better understand the sphingolipid profile differences observed between these nervous tissues. We found that the distinct profiles of the determined sphingolipids were consistent with the high selectivity of ceramide synthases and provided a potential mechanism to explain region-specific CNS ceramide and sphingomyelin levels. In conclusion, we portray for the first time a lipidomics atlas of select sphingolipids in multiple nervous system regions and believe that this type of knowledge could be very useful for better understanding the role of this lipid category in the nervous system. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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12 pages, 24573 KiB

Open AccessArticle

Gamma-Aminobutyric Acid (GABA) Promotes Growth in Zebrafish Larvae by Inducing IGF-1 Expression via GABA_A and GABA_B Receptors

by Athapaththu Mudiyanselage Gihan Kavinda Athapaththu, Ilandarage Menu Neelaka Molagoda, Rajapaksha Gedara Prasad Tharanga Jayasooriya, Yung Hyun Choi, You-Jin Jeon, Joung-Hyun Park, Bae-Jin Lee and Gi-Young Kim

Int. J. Mol. Sci. 2021, 22(20), 11254; https://doi.org/10.3390/ijms222011254 - 19 Oct 2021

Cited by 9 | Viewed by 3677

Abstract

Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish [...] Read more.

Insulin-like growth factor-1 (IGF-1) primarily increases the release of gamma-aminobutyric acid (GABA) in neurons; moreover, it is responsible for the promotion of longitudinal growth in children and adolescents. Therefore, in this study, we investigated whether exogenous GABA supplementation activates IGF-mediated growth performance. Zebrafish larvae treated with GABA at three days post fertilization (dpf) showed a significant increase in the total body length from 6 to 12 dpf through upregulation of growth-stimulating genes, including IGF-1, growth hormone-1 (GH-1), growth hormone receptor-1 (GHR-1), and cholecystokinin A (CCKA). In particular, at 9 dpf, GABA increased total body length from 3.60 ± 0.02 to 3.79 ± 0.03, 3.89 ± 0.02, and 3.92 ± 0.04 mm at concentrations of 6.25, 12.5, and 25 mM, and the effect of GABA at 25 mM was comparable to 4 mM β-glycerophosphate (GP)-treated larvae (3.98 ± 0.02 mm). Additionally, the highest concentration of GABA (50 mM) -induced death in 50% zebrafish larvae at 12 dpf. GABA also enhanced IGF-1 expression and secretion in preosteoblast MC3T3-E1 cells, concomitant with high levels of the IGF-1 receptor gene (IGF-1R). In zebrafish larvae, the GABA-induced growth rate was remarkably decreased in the presence of an IGF-1R inhibitor, picropodophyllin (PPP), which indicates that GABA-induced IGF-1 enhances growth rate via IGF-1R. Furthermore, we investigated the effect of GABA receptors on growth performance along with IGF-1 activation. Inhibitors of GABA_A and GABA_B receptors, namely bicuculline and CGP 46381, respectively, considerably inhibited GABA-induced growth rate in zebrafish larvae accompanied by a marked decrease in the expression of growth-stimulating genes, including IGF-1, GH-1, GHR-1, and CCKA, but not with an inhibitor of GABA_C receptor, TPMPA. Additionally, IGF-1 and IGF-1R expression was impaired in bicuculline and CGP 46381-treated MC3T3-E1 cells, but not in the cells treated with TPMPA. Furthermore, treatment with bicuculline and CGP 46381 significantly downregulated GABA-induced IGF-1 release in MC3T3-E1 cells. These data indicate that GABA stimulates IGF-1 release via GABA_A and GABA_B receptors and leads to growth promotion performance via IGF-1R. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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Review

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21 pages, 2156 KiB

Open AccessReview

The Inositol Phosphate System—A Coordinator of Metabolic Adaptability

by Becky Tu-Sekine and Sangwon F. Kim

Int. J. Mol. Sci. 2022, 23(12), 6747; https://doi.org/10.3390/ijms23126747 - 16 Jun 2022

Cited by 22 | Viewed by 6780

Abstract

All cells rely on nutrients to supply energy and carbon building blocks to support cellular processes. Over time, eukaryotes have developed increasingly complex systems to integrate information about available nutrients with the internal state of energy stores to activate the necessary processes to [...] Read more.

All cells rely on nutrients to supply energy and carbon building blocks to support cellular processes. Over time, eukaryotes have developed increasingly complex systems to integrate information about available nutrients with the internal state of energy stores to activate the necessary processes to meet the immediate and ongoing needs of the cell. One such system is the network of soluble and membrane-associated inositol phosphates that coordinate the cellular responses to nutrient uptake and utilization from growth factor signaling to energy homeostasis. In this review, we discuss the coordinated interactions of the inositol polyphosphates, inositol pyrophosphates, and phosphoinositides in major metabolic signaling pathways to illustrate the central importance of the inositol phosphate signaling network in nutrient responses. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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17 pages, 950 KiB

Open AccessReview

Deranged Myocardial Fatty Acid Metabolism in Heart Failure

by Tsunehisa Yamamoto and Motoaki Sano

Int. J. Mol. Sci. 2022, 23(2), 996; https://doi.org/10.3390/ijms23020996 - 17 Jan 2022

Cited by 46 | Viewed by 8357

Abstract

The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps [...] Read more.

The heart requires fatty acids to maintain its activity. Various mechanisms regulate myocardial fatty acid metabolism, such as energy production using fatty acids as fuel, for which it is known that coordinated control of fatty acid uptake, β-oxidation, and mitochondrial oxidative phosphorylation steps are important for efficient adenosine triphosphate (ATP) production without unwanted side effects. The fatty acids taken up by cardiomyocytes are not only used as substrates for energy production but also for the synthesis of triglycerides and the replacement reaction of fatty acid chains in cell membrane phospholipids. Alterations in fatty acid metabolism affect the structure and function of the heart. Recently, breakthrough studies have focused on the key transcription factors that regulate fatty acid metabolism in cardiomyocytes and the signaling systems that modify their functions. In this article, we reviewed the latest research on the role of fatty acid metabolism in the pathogenesis of heart failure and provide an outlook on future challenges. Full article

(This article belongs to the Special Issue Nutrients (Amino Acid, Glucose and Lipid)-Mediated Signaling)

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