Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Zhang, Le; Ebenezer, Philip J.; Dasuri, Kalavathi; Fernandez-Kim, Sun Ok; Francis, Joseph; Mariappan, Nithya; Gao, Zhan‐Guo; Ye, Jianping; Bruce‐Keller, Annadora J.; Keller, Jeffrey N.

doi:10.1152/ajpendo.00059.2011

Cited by 62 publications

(48 citation statements)

References 76 publications

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“…It has been demonstrated that enlarged fat pads show a senescence phenotype because of increased oxidative stress. 2,3,29,32 Accordingly, in the AT of old mice, we found a senescenceassociated b-galactosidase (SA-b gal) activity, which was accompanied by higher levels of oxidized proteins in terms of carbonylation with respect to young mice (Supplementary Figure 1C). We also detected a high percentage of apoptotic cells in AT from old mice, as assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay (Figure 1b).…”

Section: Resultsmentioning

confidence: 81%

Proline oxidase–adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation

et al. 2013

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The nutrient-sensing lipolytic enzyme adipose triglyceride lipase (ATGL) has a key role in adipose tissue function, and alterations in its activity have been implicated in many age-related metabolic disorders. In adipose tissue reduced blood vessel density is related to hypoxia state, cell death and inflammation. Here we demonstrate that adipocytes of poorly vascularized enlarged visceral adipose tissue (i.e. adipose tissue of old mice) suffer from limited nutrient delivery. In particular, nutrient starvation elicits increased activity of mitochondrial proline oxidase/dehydrogenase (POX/PRODH) that is causal in triggering a ROS-dependent induction of ATGL. We demonstrate that ATGL promotes the expression of genes related to mitochondrial oxidative metabolism (peroxisome proliferator-activated receptor-a, peroxisome proliferator-activated receptor-c coactivator-1a), thus setting a metabolic switch towards fat utilization that supplies energy to starved adipocytes and prevents cell death, as well as adipose tissue inflammation. Taken together, these results identify ATGL as a stress resistance mediator in adipocytes, restraining visceral adipose tissue dysfunction typical of age-related metabolic disorders. A growing body of evidence emerges on the molecular mechanisms that determine how ageing impacts fat tissue function and how this, in turn, leads to age-related disorders.1,2 During ageing while the subcutaneous fat progressively decrease, visceral adipose tissue (AT) bed expands and resident adipocytes become relatively hypoxic because of the inability of the vasculature to keep pace with AT remodelling.2-9 Suppression of vascularization generally results in enhanced tissue metabolic perturbations such as apoptosis and inflammation, as a consequence of hypoxia and reduced nutrient delivery. 10-15Adipose triglyceride lipase (ATGL) is a nutrient-sensing lipolytic enzyme expressed in most tissues of the body with highest mRNA levels and enzyme activity found in white and brown AT. 16 The important role of ATGL in lipolysis became evident from observations in ATGL knockout (KO) mice, which accumulate triglycerides (TGs) in essentially all organs.16 ATGL selectively performs the rate-limiting initial step in TG hydrolysis releasing the first fatty acid (FA) from the glycerol backbone and produces diacylglycerol (DAG). DAG is promptly hydrolyzed by hormone-sensitive lipase (HSL) to generate monoacylglycerol and a second FA. Monoacylglycerol lipase (MGL) then hydrolyzes monoacylglycerol, thus producing glycerol and a third FA. The FAs generated by white AT can enter the circulation and be taken up by other tissue for b-oxidation and subsequent ATP generation. Alterations in ATGL activity have been found in many age-related metabolic disorders including insulin resistance states. 17,18 Recently, ATGL-mediated fat catabolism has been involved in the activation of peroxisome proliferator-activated receptor-a (PPARa)/peroxisome proliferator-activated receptor-g coactivator-1a (PGC-1a) network, sustaining a more efficient...

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Section: Resultsmentioning

confidence: 81%

Proline oxidase–adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation

et al. 2013

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“…RT-PCR experiments were performed as done previously by our laboratory [38]. Total RNA from 30 mg mouse striatum was isolated using RNeasy Mini Kit (Qiagen, Valencia, CA) following the manufacturer’s instructions with minor modifications.…”

Section: Methodsmentioning

confidence: 99%

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity–brain interactions in mice

Zhang

Dasuri

Fernandez-Kim

et al. 2013

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Cerebral amyloid angiopathy (CAA) occurs in nearly every individual with Alzheimer’s disease (AD) and Down’s syndrome, and is the second largest cause of intracerebral hemorrhage. Mouse models of CAA have demonstrated evidence for increased gliosis contributing to CAA pathology. Nearly two thirds of Americans are overweight or obese, with little known about the effects of obesity on the brain, although increasingly the vasculature appears to be a principle target of obesity effects on the brain. In the current study we describe for the first time whether diet induced obesity (DIO) modulates glial reactivity, amyloid levels, and inflammatory signaling in a mouse model of CAA. In these studies we determine that DIO does not significantly alter gross Aβ levels, astrocyte (GFAP) or microglial (IBA-1) gliosis in the CAA mice. However, within the hippocampal gyri a localized increase in reactive microglia were increased in the CA1 and stratum oriens relative to CAA mice on a control diet. DIO was observed to selectively increase IL-6 in CAA mice, with IL-1β and TNF-α not increased in CAA mice in response to DIO. Taken together, these data show that prolonged DIO does not significantly alter gross levels of Aβ or gliosis in CAA mice, but appears to elevate some localized microglial reactivity within the hippocampal gyri and selective markers of inflammatory signaling. These data are consistent with many of the studies in the existing literature using other models of Aβ pathology, which surprisingly show a mixed profile of DIO effects towards pathological processes in mouse models of neurodegenerative disease. The importance for considering the potential impact of ceiling effects in Aβ pathogenesis within the various mouse models, the lack of consistency for DIO based experimentation, and the current experimental limitations for DIO in mice to fully replicate metabolic dysfunction present in human obesity, are discussed.

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“…The release of these growth factors and activation of transcription factors further affects mesenchymal stem cell differentiation to adipocyte or osteoblast in fat distribution, increasing susceptibility to lipotoxicity in bone marrow [12,13]. Interestingly, studies from Keller JN et al found that oxidative stress accumulates in aged adipose tissue [14]. Oxidative stress is known to increase with aging and also alters the gene expression of important regulators of the cell cycle, such as p53, p16 and p19 and further affect the other molecular markers expression of aging (sirt1, c-fos and IGF-1).…”

Section: Introductionmentioning

confidence: 99%

Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma

et al. 2014

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Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Cited by 62 publications

References 76 publications

Proline oxidase–adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation

Proline oxidase–adipose triglyceride lipase pathway restrains adipose cell death and tissue inflammation

Prolonged diet induced obesity has minimal effects towards brain pathology in mouse model of cerebral amyloid angiopathy: Implications for studying obesity–brain interactions in mice

Delayed animal aging through the recovery of stem cell senescence by platelet rich plasma

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