Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy

Lasheras, Jaime; Vila, María; Zamora, Mónica; Riu, Efrén; Pardo, Rosario; Poncelas, Marcos; Cases, Ildefonso; Ruiz‐Meana, Marisol; Hernández, Cristina; Feliu, Jaume Cruz i; Simó, Rafael; Garcı́a-Dorado, David; Villena, Josep A.

doi:10.1016/j.mce.2016.04.004

Cited by 12 publications

(17 citation statements)

References 45 publications

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“…PGC-1β, together with PGC-1α, was identified as a master regulator of fatty acid oxidation gene expression in stress induced cardiac hypertrophy and heart failure [44]. Although the effects of PGC-1β on metabolic relative cardiac dysfunction, especially DCM, are hardly known, the upregulation of PGC-1β in diabetic heart has been observed in several animal models [32, 45]. PGC-1β was further determined as the top hub gene together with PPARα by transcriptome bioinformatics analysis in DCM [45].…”

Section: Discussionmentioning

confidence: 99%

“…Although the effects of PGC-1β on metabolic relative cardiac dysfunction, especially DCM, are hardly known, the upregulation of PGC-1β in diabetic heart has been observed in several animal models [32, 45]. PGC-1β was further determined as the top hub gene together with PPARα by transcriptome bioinformatics analysis in DCM [45]. In addition, PGC-1α has been widely accepted as the key contributor to the metabolic disorder in DCM via coactivating PPAR [10, 46].…”

Section: Discussionmentioning

confidence: 99%

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MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα

Yin

Zhang

et al. 2019

Cardiovasc Diabetol

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Background Metabolic abnormalities have been implicated as a causal event in diabetic cardiomyopathy (DCM). However, the mechanisms underlying cardiac metabolic disorder in DCM were not fully understood. Results Db/db mice, palmitate treated H9c2 cells and primary neonatal rat cardiomyocytes were employed in the current study. Microarray data analysis revealed that PGC-1β may play an important role in DCM. Downregulation of PGC-1β relieved palmitate induced cardiac metabolism shift to fatty acids use and relevant lipotoxicity in vitro. Bioinformatics coupled with biochemical validation was used to confirm that PGC-1β was one of the direct targets of miR-30c. Remarkably, overexpression of miR-30c by rAAV system improved glucose utilization, reduced excessive reactive oxygen species production and myocardial lipid accumulation, and subsequently attenuated cardiomyocyte apoptosis and cardiac dysfunction in db/db mice. Similar effects were also observed in cultured cells. More importantly, miR-30c overexpression as well as PGC-1β knockdown reduced the transcriptional activity of PPARα, and the effects of miR-30c on PPARα was almost abated by PGC-1β knockdown. Conclusions Our data demonstrated a protective role of miR-30c in cardiac metabolism in diabetes via targeting PGC-1β, and suggested that modulation of PGC-1β by miR-30c may provide a therapeutic approach for DCM. Electronic supplementary material The online version of this article (10.1186/s12933-019-0811-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα

Yin

Zhang

et al. 2019

Cardiovasc Diabetol

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“…Interestingly, several members of the nuclear receptor superfamily have been reported to be involved in diabetic cardiomyopathy pathophysiology. The peroxisome proliferator‐activated receptors (PPARγ and PPARδ) and liver X receptors have been proposed as endogenous cardioprotective receptors against diabetic cardiomyopathy, while mineralocorticoid receptor and estrogen‐related receptor‐γ exacerbate diabetic injury. The present study added novel evidence that nuclear melatonin receptor RORα acts as an endogenous protective nuclear receptor against diabetic cardiomyopathy and shed light on the therapeutic potential of targeted melatonin‐RORα axis manipulation to delay diabetic cardiomyopathy development.…”

Section: Discussionmentioning

confidence: 99%

Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy

Zhao

Ding

et al. 2017

Journal of Pineal Research

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Diabetic cardiomyopathy is a major complication that significantly contributes to morbidity and mortality in diabetics with few therapies. Moreover, antidiabetic drugs reported inconsistent or even adverse cardiovascular effects, suggesting that it is important to exploit novel therapeutic targets against diabetic cardiomyopathy. Here, we observed that the nuclear melatonin receptor, the retinoic acid-related orphan receptor-α (RORα), was downregulated in diabetic hearts. By utilizing a mouse line with RORα disruption, we demonstrated that RORα deficiency led to significantly augmented diastolic dysfunction and cardiac remodeling induced by diabetes. Microscopic and molecular analyses further indicated that the detrimental effects of RORα deficiency were associated with aggravated myocardial apoptosis, autophagy dysfunction, and oxidative stress by disrupting antioxidant gene expression. By contrast, restoration of cardiac RORα levels in transgenic mice significantly improved cardiac functional and structural parameters at 8 weeks after diabetes induction. Consistent with genetic manipulation, pharmacological activation of RORα by melatonin and SR1078 (a synthetic agonist) showed beneficial effects against diabetic cardiomyopathy, while the RORα inhibitor SR3335 significantly exacerbated cardiac impairments in diabetic mice. Collectively, these findings suggest that cardiac-targeted manipulation of nuclear melatonin receptor RORα may hold promise for delaying diabetic cardiomyopathy development.

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“…Gene-expression profiling in WAT of AL and CR mice was performed as previously described (12). In brief, total RNA was isolated from inguinal WAT of C57BL6/J WT mice fed AL or subjected to CR (n = 5) with Trizol reagent, further purified using the RNeasy Mini kit (Qiagen, Germantown, MD, USA) and CR mice.…”

Section: Microarray Analysismentioning

confidence: 99%

Calorie restriction prevents diet‐induced insulin resistance independently of PGC‐1‐driven mitochondrial biogenesis in white adipose tissue

et al. 2018

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Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis by mechanisms that are not fully understood. Given the relevance of white adipose tissue (WAT) in glucose homeostasis, we aimed at identifying the main cellular processes regulated in WAT in response to CR in a pathologic context of obesity. For this, a gene‐expression profiling study was first conducted in mice fed ad libitum or subjected to 40% CR. We found that the gene network related to mitochondria was the most highly upregulated in WAT by CR. To study the role that increased mitochondrial biogenesis plays on glucose homeostasis following CR, we generated a mouse model devoid of the coactivators peroxisome proliferator‐activated receptor ³ coactivator 1 (PGC‐1)α and PGC‐1β specifically in adipocytes. Our results show that mice lacking PGC‐1s in adipocytes are unable to increase mitochondrial biogenesis in WAT upon CR. Despite a blunted induction of mitochondrial biogenesis in response to calorie deprivation, mice lacking adipose PGC‐1s still respond to CR by improving their glucose homeostasis. Our study demonstrates that PGC‐1 coactivators are major regulators of CR‐induced mitochondrial biogenesis in WAT and that increased mitochondrial biogenesis and oxidative function in adipose tissue are not required for the improvement of glucose homeostasis mediated by CR.—Pardo, R., Vila, M., Cervela, L., de Marco, M., Gama‐Pérez, P., González‐Franquesa, A., Statuto, L., Vilallonga, R., Simó, R., Garcia‐Roves, P. M., Villena, J. A. Calorie restriction prevents diet‐induced insulin resistance independently of PGC‐1‐driven mitochondrial biogenesis in white adipose tissue. FASEB J. 33, 2343–2358 (2019). http://www.fasebj.org

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Gene expression profiling in hearts of diabetic mice uncovers a potential role of estrogen-related receptor γ in diabetic cardiomyopathy

Cited by 12 publications

References 45 publications

MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα

MiR-30c/PGC-1β protects against diabetic cardiomyopathy via PPARα

Novel protective role of the circadian nuclear receptor retinoic acid‐related orphan receptor‐α in diabetic cardiomyopathy

Calorie restriction prevents diet‐induced insulin resistance independently of PGC‐1‐driven mitochondrial biogenesis in white adipose tissue

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