Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

Jokinen, Riikka; Pirnes‐Karhu, Sini; Pietiläinen, Kirsi H.; Pirinen, Eija

doi:10.1016/j.redox.2017.02.011

Cited by 83 publications

(68 citation statements)

References 160 publications

(342 reference statements)

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“…Sirtuins are multifunctional enzymes that have multiple roles in adipocyte metabolism (10,36). In particular, the nuclear localized Sirt1 protein upregulates Ucp1 and browning of WAT through Pparg (28).…”

Section: Discussionmentioning

confidence: 99%

Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Botezelli

Overby

Lindo

et al. 2020

Preprint

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Hyperinsulinemia plays a causal role in adiposity tissue expansion. We have previously shown that mice with reduced insulin gene dosage have increased energy expenditure, but the tissue-specific molecular mechanisms involved in the effects of abrogated hyperinsulinemia have remained unclear. Herein we investigated the effects of genetically reducing insulin production on the abundance of oxidative mitochondrial complex proteins in liver, skeletal muscle, white adipose tissue and brown adipose tissue. To suppress insulin levels, we manipulated Ins1 gene dosage in mice lacking both Ins2 alleles to prevent compensation. Male Ins1+/+ or Ins1+/-littermates were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 4 weeks, starting at 8 weeks of age. As expected, HFD increased fasting hyperinsulinemia, and Ins1+/-mice had significantly lower circulating insulin compared with Ins1+/+ littermate controls. Fasting glucose and body weight were not significantly different between genotypes at any time over the 4 weeks of study. In liver and skeletal muscle, protein abundances reflecting complex I (Ndufb8), II (Sdhb), III (Uqcrc2), and V (Atp5a1) were not consistently different between groups. In mesenteric white adipose tissue, Ins1+/-mice had reduced abundance of Ndufb8 and Sdhb proteins. Ucp1 protein abundance was increased in the context of the HFD, and HFD alone had a dramatic inhibitory effect on Pparg protein levels. In inguinal white adipose tissue, Ins1+/-mice exhibited significant increases in all oxidative mitochondrial complexes measured, independent of diet. No changes in Ucp1 or Pparg protein, or Prdm16:Pparg association were found. While HFD increased the abundance of nuclear Sirt1, no effects on total Sirt3 protein levels were observed in this tissue. In brown adipose tissue, lowered insulin increased Sdhb protein levels that had been reduced by HFD. Ucp1 protein levels, Prdm16:Pparg association, and Sirt3 abundance were all increased in the absence of diet-induced hyperinsulinemia. Our data show that in young mice, reducing insulin upregulates oxidative proteins in inguinal fat without affecting Ucp1, while in mesenteric white fat and brown adipose tissue, reducing insulin upregulates Ucp1 in the context of HFD. Collectively, our results show that preventing hyperinsulinemia have depot-specific effects on adipose tissue metabolism and help explain the increased energy expenditure previously reported in Ins1+/-mice. Insulin is secreted from pancreatic β-cells in response to nutrient intake to regulate anabolism in multiple tissues. In addition to glucose homeostasis, insulin is a potent regulator of lipid homeostasis (42). Insulin signaling is required for glucose and lipid uptake into fat, as well as for the development and hypertrophy of adipocytes. Indeed, mice lacking insulin receptors in adipose tissue are protected against high fat diet and glucose intolerance (4, 34). Chronically elevated insulin levels are associated with obesity in human populations and preclinical models (2,3,7,27,31,39). Ph...

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Section: Discussionmentioning

confidence: 99%

Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Botezelli

Overby

Lindo

et al. 2020

Preprint

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show abstract

“…Then, the siRNA was transfected into cells via Lipofectamine 2000 transfection reagent according to the manufacturer's protocol [43]. After 48-96 hours, the cells were collected and the knockdown efficiency were determined via western blot analysis [44].…”

Section: The Small Rna Interference Assaymentioning

confidence: 99%

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Zhao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Mitochondrial homeostasis is implicated in the development and progression of endometriosis through poorly defined mechanisms. Mst1 is the major growth suppressor related to cancer migration, apoptosis and proliferation. However, whether Mst1 is involved in endometriosis apoptosis and migration via regulating the mitochondrial function remains to be elucidated. Methods: Expression of Mst1 in endometriosis was examined via western blots. Cellular apoptosis was detected via MTT and TUNEL assay. Gain of function assay about Mst1 was conducted via adenovirus over-expression. Mitochondrial functions were evaluated via mitochondrial membrane potential JC-1 staining, ROS flow cytometry analysis, mPTP opening assessment and immunofluorescence of HtrA2/Omi. The mitophagy activity were examined via western blots and immunofluorescence. Results: First, we found that Mst1 was significantly downregulated in the ectopic endometrium of endometriosis compared to the normal endometrium. However, the recovery of Mst1 function was closely associated with the inability of endometrial stromal cells (ESCs) to migrate and survive. A functional study indicated that regaining Mst1 enhanced Drp1 post-transcriptional phosphorylation at Ser616 and repressed Parkin transcription activity via p53, leading to mitochondrial fission activation and mitophagy inhibition. Excessive Drp1-related fission forced the mitochondria to liberate HtrA2/Omi into the cytoplasm. Moreover, Mst1-induced defective mitophagy evoked cellular

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“…To demonstrate whether the JNK pathway is necessary for hyperglycaemia-mediated mitochondrial fragmentation, loss-and gain-of-function assays for the JNK pathway were performed using a pathway blocker and agonist. SP600125 (SP), a JNK pathway blocker, was added to hyperglycaemia-treated cells [46], which was used as the negative control group. Meanwhile, Anisomycin (Ani), a JNK pathway agonist, was administered to MKP1-overexpressing cells, which was used as the positive control group [47].…”

Section: Mkp1 Controls Mitochondrial Fragmentation Via Inhibiting Thementioning

confidence: 99%

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

Zhang¹,

Feng²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Hyperglycaemia stress-induced renal injury is closely associated with mitochondrial dysfunction through poorly understood mechanisms. The aim of our study is to explore the upstream trigger and the downstream effector driving diabetic nephropathy via modulating mitochondrial homeostasis. Methods: A diabetic nephropathy model was generated in wild-type (WT) mice and MAP Kinase phosphatase 1 transgenic (MKP1-TG) mice using STZ injection. Cell experiments were conducted via high-glucose treatment in the human renal mesangial cell line (HRMC). MKP1 overexpression assay was carried out via adenovirus transfection. Renal function was evaluated via ELISA, western blotting, histopathological staining, and immunofluorescence. Mitochondrial function was determined via mitochondrial potential analysis, ROS detection, ATP measurement, mitochondrial permeability transition pore (mPTP) opening evaluation, and immunofluorescence for mitochondrial pro-apoptotic factors. Loss- and gain-of-function assays for mitochondrial fragmentation were performed using a pharmacological agonist and blocker. Western blotting and the pathway blocker were used to establish the signalling pathway in response to MKP1 overexpression in the presence of hyperglycaemia stress. Results: MKP1 was downregulated in the presence of chronic high-glucose stress in vivo and in vitro. However, MKP1 overexpression improved the metabolic parameters, enhanced glucose control, sustained renal function, attenuated kidney oxidative stress, inhibited the renal inflammation response, alleviated HRMC apoptosis, and repressed tubulointerstitial fibrosis. Molecular investigation found that MKP1 overexpression enhanced the resistance of HRMC to the hyperglycaemic injury by abolishing mitochondrial fragmentation. Hyperglycaemia-triggered mitochondrial fragmentation promoted mitochondrial dysfunction, as evidenced by decreased mitochondrial potential, elevated mitochondrial ROS production, increased pro-apoptotic factor leakage, augmented mPTP opening and activated caspase-9 apoptotic pathway. Interestingly, MKP1 overexpression strongly abrogated mitochondrial fragmentation and sustained mitochondrial homeostasis via inhibiting the JNK-CaMKII-Fis1 pathway. After re-activation of the JNK-CaMKII-Fis1 pathway, the beneficial effects of MKP1 overexpression on mitochondrial protection disappeared. Conclusion: Taken together, our data identified the protective role played by MKP1 in regulating diabetic renal injury via repressing mitochondrial fragmentation and inactivating the JNK-CaMKII-Fis1 pathway, which may pave the road to new therapeutic modalities for the treatment of diabetic nephropathy.

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Adipose tissue NAD+-homeostasis, sirtuins and poly(ADP-ribose) polymerases -important players in mitochondrial metabolism and metabolic health

Cited by 83 publications

References 160 publications

Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Adipose depot-specific upregulation of Ucp1 or mitochondrial oxidative complex proteins are early consequences of genetic insulin reduction in mice

Effect of Mst1 on Endometriosis Apoptosis and Migration: Role of Drp1-Related Mitochondrial Fission and Parkin-Required Mitophagy

Hyperglycaemia Stress-Induced Renal Injury is Caused by Extensive Mitochondrial Fragmentation, Attenuated MKP1 Signalling, and Activated JNK-CaMKII-Fis1 Biological Axis

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