scholarly journals SREBP-1c-Dependent Metabolic Remodeling of White Adipose Tissue by Caloric Restriction

2018 ◽  
Vol 19 (11) ◽  
pp. 3335 ◽  
Author(s):  
Masaki Kobayashi ◽  
Namiki Fujii ◽  
Takumi Narita ◽  
Yoshikazu Higami
Keyword(s):  
Adipose Tissue ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Regulatory Element ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Master Regulator ◽  
Beneficial Effects ◽  
Age Related ◽  
Metabolic Remodeling

Caloric restriction (CR) delays the onset of many age-related pathophysiological changes and extends lifespan. White adipose tissue (WAT) is not only a major tissue for energy storage, but also an endocrine tissue that secretes various adipokines. Recent reports have demonstrated that alterations in the characteristics of WAT can impact whole-body metabolism and lifespan. Hence, we hypothesized that functional alterations in WAT may play important roles in the beneficial effects of CR. Previously, using microarray analysis of WAT from CR rats, we found that CR enhances fatty acid (FA) biosynthesis, and identified sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA synthesis, as a mediator of CR. These findings were validated by showing that CR failed to upregulate factors involved in FA biosynthesis and to extend longevity in SREBP-1c knockout mice. Furthermore, we revealed that SREBP-1c is implicated in CR-associated mitochondrial activation through the upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Notably, these CR-associated phenotypes were observed only in WAT. We conclude that CR induces SREBP-1c-dependent metabolic remodeling, including the enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α in WAT, resulting in beneficial effects.

scholarly journals Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2054
Author(s):  
Masaki Kobayashi ◽  
Seira Uta ◽  
Minami Otsubo ◽  
Yusuke Deguchi ◽  
Ryoma Tagawa ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Mitochondrial Biogenesis ◽  
Molecular Mechanisms ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Leptin Signaling ◽  
Age Related ◽  
Metabolic Remodeling

Caloric restriction (CR) improves whole body metabolism, suppresses age-related pathophysiology, and extends lifespan in rodents. Metabolic remodeling, including fatty acid (FA) biosynthesis and mitochondrial biogenesis, in white adipose tissue (WAT) plays an important role in the beneficial effects of CR. We have proposed that CR-induced mitochondrial biogenesis in WAT is mediated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is transcriptionally regulated by sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA biosynthesis. We have also proposed that the CR-associated upregulation of SREBP-1 and PGC-1α might result from the attenuation of leptin signaling and the upregulation of fibroblast growth factor 21 (FGF21) in WAT. However, the detailed molecular mechanisms remain unclear. Here, we interrogate the regulatory mechanisms involving leptin signaling, SREBP-1c, FGF21, and PGC-1α using Srebp-1c knockout (KO) mice, mouse embryonic fibroblasts, and 3T3-L1 adipocytes, by altering the expression of SREBP-1c or FGF21. We show that a reduction in leptin signaling induces the expression of proteins involved in FA biosynthesis and mitochondrial biogenesis via SREBP-1c in adipocytes. The upregulation of SREBP-1c activates PGC-1α transcription via FGF21, but it is unlikely that the FGF21-associated upregulation of PGC-1α expression is a predominant contributor to mitochondrial biogenesis in adipocytes.

scholarly journals Sterol regulatory element-binding protein-1c orchestrates metabolic remodeling of white adipose tissue by caloric restriction

Aging Cell ◽  
2017 ◽  
Vol 16 (3) ◽  
pp. 508-517 ◽  
Author(s):  
Namiki Fujii ◽  
Takumi Narita ◽  
Naoyuki Okita ◽  
Masaki Kobayashi ◽  
Yurika Furuta ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Binding Protein ◽  
Regulatory Element ◽  
Metabolic Remodeling ◽  
Element Binding Protein ◽  
Sterol Regulatory Element

scholarly journals Contribution of PGC-1α to Obesity- and Caloric Restriction-Related Physiological Changes in White Adipose Tissue

2021 ◽  
Vol 22 (11) ◽  
pp. 6025
Author(s):  
Masaki Kobayashi ◽  
Yusuke Deguchi ◽  
Yuka Nozaki ◽  
Yoshikazu Higami
Keyword(s):  
Adipose Tissue ◽  
Caloric Restriction ◽  
White Adipose Tissue ◽  
Mitochondrial Gene ◽  
Energy Resource ◽  
Peroxisome Proliferator ◽  
Physiological Changes ◽  
Mitochondrial Gene Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
White Adipocytes

Peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α) regulates mitochondrial DNA replication and mitochondrial gene expression by interacting with several transcription factors. White adipose tissue (WAT) mainly comprises adipocytes that store triglycerides as an energy resource and secrete adipokines. The characteristics of WAT vary in response to systemic and chronic metabolic alterations, including obesity or caloric restriction. Despite a small amount of mitochondria in white adipocytes, accumulated evidence suggests that mitochondria are strongly related to adipocyte-specific functions, such as adipogenesis and lipogenesis, as well as oxidative metabolism for energy supply. Therefore, PGC-1α is expected to play an important role in WAT. In this review, we provide an overview of the involvement of mitochondria and PGC-1α with obesity- and caloric restriction-related physiological changes in adipocytes and WAT.

scholarly journals Metabolic remodeling of white adipose tissue in obesity

2014 ◽  
Vol 307 (3) ◽  
pp. E262-E277 ◽  
Author(s):  
Timothy D. Cummins ◽  
Candice R. Holden ◽  
Brian E. Sansbury ◽  
Andrew A. Gibb ◽  
Jasmit Shah ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Citrate Synthase ◽  
Krebs Cycle ◽  
Mitochondrial Respiratory Chain ◽  
Whole Body ◽  
Ultrastructural Changes ◽  
High Fat ◽  
Metabolic Remodeling

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity.

scholarly journals Caloric restriction mitigates age-associated hippocampal differential CG and non-CG methylation

2017 ◽  
Author(s):  
Niran Hadad ◽  
Archana Unnikrishnan ◽  
Jordan A. Jackson ◽  
Dustin R. Masser ◽  
Laura Otalora ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Caloric Restriction ◽  
Brain Aging ◽  
Regulatory Element ◽  
Memory Function ◽  
Promoter Hypermethylation ◽  
Epigenetic Mechanism ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Age Related

AbstractBrain aging is marked by cognitive decline and susceptibility to neurodegeneration. Caloric-restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal CNS cellular and memory functions, and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life-long CR prevents age-related DNA methylation changes in the brain. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24 month old mice fed a 40% calorierestricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base-specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ~40,000 differentially methylated CGs (dmCGs) and ~80,000 CHs (dmCHs) with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR-specific DNMT1 and TET3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the pro-longevity effects of CR working through an epigenetic mechanism.

scholarly journals Interactive effects of aging and aerobic capacity on energy metabolism–related metabolites of serum, skeletal muscle, and white adipose tissue

GeroScience ◽  
2021 ◽  
Author(s):  
Haihui Zhuang ◽  
Sira Karvinen ◽  
Timo Törmäkangas ◽  
Xiaobo Zhang ◽  
Xiaowei Ojanen ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Amino Acid ◽  
White Adipose Tissue ◽  
Aerobic Capacity ◽  
Amino Acid Metabolism ◽  
Acid Metabolism ◽  
Disease Risk ◽  
Whole Body ◽  
Whole Body Metabolism

AbstractAerobic capacity is a strong predictor of longevity. With aging, aerobic capacity decreases concomitantly with changes in whole body metabolism leading to increased disease risk. To address the role of aerobic capacity, aging, and their interaction on metabolism, we utilized rat models selectively bred for low and high intrinsic aerobic capacity (LCRs/HCRs) and compared the metabolomics of serum, muscle, and white adipose tissue (WAT) at two time points: Young rats were sacrificed at 9 months of age, and old rats were sacrificed at 21 months of age. Targeted and semi-quantitative metabolomics analysis was performed on the ultra-pressure liquid chromatography tandem mass spectrometry (UPLC-MS) platform. The effects of aerobic capacity, aging, and their interaction were studied via regression analysis. Our results showed that high aerobic capacity is associated with an accumulation of isovalerylcarnitine in muscle and serum at rest, which is likely due to more efficient leucine catabolism in muscle. With aging, several amino acids were downregulated in muscle, indicating more efficient amino acid metabolism, whereas in WAT less efficient amino acid metabolism and decreased mitochondrial β-oxidation were observed. Our results further revealed that high aerobic capacity and aging interactively affect lipid metabolism in muscle and WAT, possibly combating unfavorable aging-related changes in whole body metabolism. Our results highlight the significant role of WAT metabolism for healthy aging.

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