Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

Soccio, Raymond E.; Li, Zhenghui; Chen, Eric R.; Foong, Yee Hoon; Benson, Kiara K.; DiSpirito, Joanna R.; Mullican, Shannon E.; Emmett, Matthew J.; Briggs, Erika R.; Peed, Lindsey C.; Dzeng, Richard K.; Medina, Carlos J.; Jolivert, Jennifer F.; Kissig, Megan; Rajapurkar, Satyajit; Damle, Manashree; Lim, Hee‐Woong; Won, Kyoung Jae; Seale, Patrick; Steger, David J.; Lazar, Mitchell A.

doi:10.1172/jci91211

Cited by 48 publications

(57 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, adipocytes become less capable during onset of obesity in their crucial functions such as lipid storage that indirectly maintain normal hepatocyte and skeletal muscle glucose handling. Recent results exploring effects of HFD in mice on the global DNA site binding and transcriptional activity of PPARγ also show how environmental cues can modulate the epigenome and alter adipocyte function 150 .…”

Section: Cellular and Molecular Causes Of Impaired Insulin Responsivementioning

confidence: 99%

Insulin action and resistance in obesity and type 2 diabetes

Czech

2017

Nat Med

945

692

View full text Add to dashboard Cite

Nutritional excess is a major forerunner of type 2 diabetes and enhances the secretion of insulin but attenuates its metabolic actions in the liver, skeletal muscle and adipose tissue. However, conflicting evidence indicates a lack of knowledge of the timing of these events during the development of obesity and diabetes and is a key gap in our understanding of metabolic disease. This Perspective reviews alternate viewpoints and recent results on the temporal and mechanistic connections between hyperinsulinemia, obesity and insulin resistance. Although much attention has addressed early steps in the insulin signaling cascade, insulin resistance in obesity appears to be largely elicited downstream of these steps. New findings also connect insulin resistance to extensive metabolic crosstalk between liver, adipose, pancreas and skeletal muscle. These and other advances over the last 5 years offer both exciting opportunities and daunting challenges in developing new therapeutic strategies for the treatment of type 2 diabetes.

show abstract

Section: Cellular and Molecular Causes Of Impaired Insulin Responsivementioning

confidence: 99%

Insulin action and resistance in obesity and type 2 diabetes

Czech

2017

Nat Med

945

692

View full text Add to dashboard Cite

show abstract

“…It may, in turn, durably change the expression of PPARγ target genes. Consistent with this hypothesis, findings have shown that PPARγ down‐regulation in obese mice is associated with a decrease in genome‐wide association occupancy of PPARγ (30).…”

Section: Discussionmentioning

confidence: 67%

“…However, others have also shown that obesity is associated with a decline in the PPARγ2 activity and expression (29–33). These modifications seem to be strongly associated with the pathogenesis of the metabolic syndrome (30–33). The decrease in PPARγ2 gene expression might be seen as an adaptive mechanism to prevent further fat accumulation in WAT (33).…”

Section: Discussionmentioning

confidence: 99%

Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications

et al. 2018

View full text Add to dashboard Cite

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.

show abstract

“…The associations of impaired scWAT function with effects on energy balance and insulin sensitivity in Rosi-treated Cited4knockout mice are consistent with previous reports demonstrating the key role of subcutaneous fat for the therapeutic action of TZDs. This was evident in humans and rodents both at the level of gene expression and browning and at the level of tissue metabolism (Boden et al, 2005;Bogacka et al, 2005;Festuccia et al, 2009;Soccio et al, 2017). Obesity is associated with reduced capacity or compromised mitochondrial oxidation in adipose tissue and the ability of TZDs to restore these defects is likely to be important for insulin sensitization, possibly through the improvement of systemic lipid metabolism (Wilson-Fritch et al, 2004;Rong et al, 2007;Soccio et al, 2017).…”

Section: Oxygen Consumptionmentioning

confidence: 99%

“…Beyond their ability to enhance adipocyte formation and turnover, TZDs promote mitochondrial biogenesis and fatty acid oxidation in human and rodent white adipose tissue and increase its thermogenic potential ("browning";Okuno et al, 1998;Fukui et al, 2000;Yamauchi et al, 2001;Wilson-Fritch et al, 2004;Boden et al, 2005;Bogacka et al, 2005;Tang et al, 2011). Interestingly, the enrichment of pathways of mitochondrial oxidation and lipid metabolism in subcutaneous fat was recently shown to be the most prominent effect of the TZD rosiglitazone on the transcriptome across adipose tissues (Soccio et al, 2017). Increased capacity for adipose tissue thermogenesis is generally accepted to be protective against insulin resistance and dyslipidemia but to which extent the regulation of browning by TZDs mediates insulin sensitization remains unclear (Sidossis & Kajimura, 2015).…”

Section: Introductionmentioning

confidence: 99%

Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors

et al. 2018

View full text Add to dashboard Cite

Most antidiabetic drugs treat disease symptoms rather than adipose tissue dysfunction as a key pathogenic cause in the metabolic syndrome and type 2 diabetes. Pharmacological targeting of adipose tissue through the nuclear receptor PPARg, as exemplified by glitazone treatments, mediates efficacious insulin sensitization. However, a better understanding of the context‐specific PPARg responses is required for the development of novel approaches with reduced side effects. Here, we identified the transcriptional cofactor Cited4 as a target and mediator of rosiglitazone in human and murine adipocyte progenitor cells, where it promoted specific sets of the rosiglitazone‐dependent transcriptional program. In mice, Cited4 was required for the proper induction of thermogenic expression by Rosi specifically in subcutaneous fat. This phenotype had high penetrance in females only and was not evident in beta‐adrenergically stimulated browning. Intriguingly, this specific defect was associated with reduced capacity for systemic thermogenesis and compromised insulin sensitization upon therapeutic rosiglitazone treatment in female but not male mice. Our findings on Cited4 function reveal novel unexpected aspects of the pharmacological targeting of PPARg.

show abstract

Targeting PPARγ in the epigenome rescues genetic metabolic defects in mice

Cited by 48 publications

References 86 publications

Insulin action and resistance in obesity and type 2 diabetes

Insulin action and resistance in obesity and type 2 diabetes

Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications

Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors

Contact Info

Product

Resources

About