Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

Gupta, Dhananjay; Leahy, Averi A.; Monga, Navjot; Peshavaria, Mina; Jetton, Thomas L.; Leahy, Jack L.

doi:10.1074/jbc.m113.486852

Cited by 27 publications

(14 citation statements)

References 59 publications

(91 reference statements)

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“…Rosen et al showed that loss of PPARγ in pancreatic β-cells was associated with a hyperplastic response, but no metabolic abnormalities [38]. More recently, a FoxO1/PPARγ mediated network was proposed as a core element for β-cell compensation and failure in response to metabolic stress [39]. Overall our study shows that lack of PPARγ does not lead to defects in pancreatic beta cell function.…”

Section: Discussionsupporting

confidence: 61%

Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility

et al. 2019

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Background: The peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent transcription factor involved in many aspects of metabolism, immune response and development. Numerous studies relying on tissue-specific invalidation of the Pparg gene have shown distinct facets of its activity, whereas the effects of its systemic inactivation remain unexplored due to embryonic lethality. By maintaining PPARγ expression in the placenta, we recently generated a mouse model carrying Pparg full body deletion (Pparg Δ/Δ), which in contrast to a previously published model is totally deprived of any form of adipose tissue. Herein, we propose an indepth study of the metabolic alterations observed in this new model. Methods: Young adult mice, both males and females analyzed separately, were first phenotyped for their gross anatomical alterations. Systemic metabolic parameters were analyzed in the blood, in static and in dynamic conditions. A full exploration of energy metabolism was performed in calorimetric cages as well as in metabolic cages. Our study was completed by expression analyses of a set of specific genes. Main findings: Pparg Δ/Δ mice show a striking complete absence of any form of adipose tissue, which triggers a complex metabolic phenotype including increased lean mass with organomegaly, hypermetabolism, urinary energy loss, hyperphagia, and increased amino acid metabolism. Pparg Δ/Δ mice develop severe type 2 diabetes, characterized by hyperglycemia, hyperinsulinemia, polyuria and polydispsia. They show a remarkable metabolic inflexibility, as indicated by the inability to shift substrate oxidation between glucose and lipids, in both ad libitum fed state and fed/ fasted/refed transitions. Moreover, upon fasting Pparg Δ/Δ mice enter a severe hypometabolic state. Conclusions: Our data comprehensively describe the impact of lipoatrophy on metabolic homeostasis. As such, the presented data on Pparg Δ/Δ mice gives new clues on what and how to explore severe lipodystrophy and its subsequent metabolic complications in human.

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Section: Discussionsupporting

confidence: 61%

Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility

et al. 2019

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“…Moreover, KLF1 was strongly upregulated in IBxDU pigs (25.61), which suggest an important role of this TRF. Other important TRFs identified in the performed analysis were FOS and FOXO1 , involved in muscle differentiation and metabolism [63], but also in the regulation of adipogenic genes (as PPARG ) expression and IMF accumulation [54, 62]. These TRFs were also previously identified in BF muscle of newborn piglets [30].…”

Section: Discussionmentioning

confidence: 85%

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Ayuso

Fernández²,

Núñez³

et al. 2016

PLoS ONE

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Iberian pig production includes purebred (IB) and Duroc-crossbred (IBxDU) pigs, which show important differences in growth, fattening and tissue composition. This experiment was conducted to investigate the effects of genetic type and muscle (Longissimus dorsi (LD) vs Biceps femoris (BF)) on gene expression and transcriptional regulation at two developmental stages. Nine IB and 10 IBxDU piglets were slaughtered at birth, and seven IB and 10 IBxDU at four months of age (growing period). Carcass traits and LD intramuscular fat (IMF) content were measured. Muscle transcriptome was analyzed on LD samples with RNA-Seq technology. Carcasses were smaller in IB than in IBxDU neonates (p < 0.001), while growing IB pigs showed greater IMF content (p < 0.05). Gene expression was affected (p < 0.01 and Fold change > 1.5) by the developmental stage (5,812 genes), muscle type (135 genes), and genetic type (261 genes at birth and 113 at growth). Newborns transcriptome reflected a highly proliferative developmental stage, while older pigs showed upregulation of catabolic and muscle functioning processes. Regarding the genetic type effect, IBxDU newborns showed enrichment of gene pathways involved in muscle growth, in agreement with the higher prenatal growth observed in these pigs. However, IB growing pigs showed enrichment of pathways involved in protein deposition and cellular growth, supporting the compensatory gain experienced by IB pigs during this period. Moreover, newborn and growing IB pigs showed more active glucose and lipid metabolism than IBxDU pigs. Moreover, LD muscle seems to have more active muscular and cell growth, while BF points towards lipid metabolism and fat deposition. Several regulators controlling transcriptome changes in both genotypes were identified across muscles and ages (SIM1, PVALB, MEFs, TCF7L2 or FOXO1), being strong candidate genes to drive expression and thus, phenotypic differences between IB and IBxDU pigs. Many of the identified regulators were known to be involved in muscle and adipose tissues development, but others not previously associated with pig muscle growth were also identified, as PVALB, KLF1 or IRF2. The present study discloses potential molecular mechanisms underlying phenotypic differences observed between IB and IBxDU pigs and highlights candidate genes implicated in these molecular mechanisms.

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“…FOXO1 is a member of the forkhead family of TRF, which exerts important regulatory functions in developmental processes including muscle development [ 103 , 104 ]. FOXO1 regulates expression of several adipogenic genes, including PPARG [ 105 ] and muscle cells differentiation in association with SMAD [ 106 ], although inconsistent information exits regarding its specific role [ 106 , 107 ]. Moreover, several TRF with known functions on adipogenesis and lipid metabolism were identified in the present regulators analysis ( CEBPA , CEBPG , ZFP423 , EGR1 , ATF2 , ATF4 and PPARGC1B) .…”

Section: Resultsmentioning

confidence: 99%

Comparative Analysis of Muscle Transcriptome between Pig Genotypes Identifies Genes and Regulatory Mechanisms Associated to Growth, Fatness and Metabolism

Ayuso

Fernández²,

Núñez³

et al. 2015

PLoS ONE

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Iberian ham production includes both purebred (IB) and Duroc-crossbred (IBxDU) Iberian pigs, which show important differences in meat quality and production traits, such as muscle growth and fatness. This experiment was conducted to investigate gene expression differences, transcriptional regulation and genetic polymorphisms that could be associated with the observed phenotypic differences between IB and IBxDU pigs. Nine IB and 10 IBxDU pigs were slaughtered at birth. Morphometric measures and blood samples were obtained and samples from Biceps femoris muscle were employed for compositional and transcriptome analysis by RNA-Seq technology. Phenotypic differences were evident at this early age, including greater body size and weight in IBxDU and greater Biceps femoris intramuscular fat and plasma cholesterol content in IB newborns. We detected 149 differentially expressed genes between IB and IBxDU neonates (p < 0.01 and Fold-Change > 1. 5). Several were related to adipose and muscle tissues development (DLK1, FGF21 or UBC). The functional interpretation of the transcriptomic differences revealed enrichment of functions and pathways related to lipid metabolism in IB and to cellular and muscle growth in IBxDU pigs. Protein catabolism, cholesterol biosynthesis and immune system were functions enriched in both genotypes. We identified transcription factors potentially affecting the observed gene expression differences. Some of them have known functions on adipogenesis (CEBPA, EGRs), lipid metabolism (PPARGC1B) and myogenesis (FOXOs, MEF2D, MYOD1), which suggest a key role in the meat quality differences existing between IB and IBxDU hams. We also identified several polymorphisms showing differential segregation between IB and IBxDU pigs. Among them, non-synonymous variants were detected in several transcription factors as PPARGC1B and TRIM63 genes, which could be associated to altered gene function. Taken together, these results provide information about candidate genes, metabolic pathways and genetic polymorphisms potentially involved in phenotypic differences between IB and IBxDU pigs associated to meat quality and production traits.

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Peroxisome Proliferator-activated Receptor γ (PPARγ) and Its Target Genes Are Downstream Effectors of FoxO1 Protein in Islet β-Cells

Cited by 27 publications

References 59 publications

Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility

Systemic PPARγ deletion in mice provokes lipoatrophy, organomegaly, severe type 2 diabetes and metabolic inflexibility

Developmental Stage, Muscle and Genetic Type Modify Muscle Transcriptome in Pigs: Effects on Gene Expression and Regulatory Factors Involved in Growth and Metabolism

Comparative Analysis of Muscle Transcriptome between Pig Genotypes Identifies Genes and Regulatory Mechanisms Associated to Growth, Fatness and Metabolism

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