E2F1, a Novel Regulator of Metabolism.

In the past years, several lines of evidence have shown that cell cycle regulatory proteins also can modulate metabolic processes. The transcription factor E2F1 is a central player involved in cell cycle progression, DNA-damage response, and apoptosis. Its crucial role in the control of cell fate has been extensively studied and reviewed before; however, here, we focus on the participation of E2F1 in the regulation of metabolism. We summarize recent findings about the cell cycle-independent roles of E2F1 in various tissues that contribute to global metabolic homeostasis and highlight that E2F1 activity is increased during obesity. Finally, coming back to the pivotal role of E2F1 in cancer development, we discuss how E2F1 links cell cycle progression with different metabolic adaptations required for cell growth and survival

Cancer: Linking Powerhouses to Suicidal Bags.

Membrane-bound organelles are integrated into cellular networks and work together for a common goal: regulating cell metabolism, cell signaling pathways, cell fate, cellular maintenance, and pathogen defense. Many of these interactions are well established, but little is known about the interplay between mitochondria and lysosomes, and their deregulation in cancer. The present review focuses on the common signaling pathways of both organelles, as well as the processes in which they both physically interact, their changes under pathological conditions, and the impact on targeting those organelles for treating cancer

CDK4, a new metabolic sensor that antagonizes AMPK.

Cyclin-dependent kinase 4 (CDK4) is a positive regulator of cell cycle progression, however, there is growing evidence demonstrating that its function exceeds the control of cell division. Here we show that CDK4 is an important regulator of cellular substrate utilization through direct inhibition of the metabolic regulator AMPK (AMP-activated protein kinase)

Chromatin immunoprecipitation improvements for the processing of small frozen pieces of adipose tissue.

Chromatin immunoprecipitation (ChIP) has gained importance to identify links between the genome and the proteome. Adipose tissue has emerged as an active tissue, which secretes a wide range of molecules that have been related to metabolic and obesity-related disorders, such as diabetes, cardiovascular failure, metabolic syndrome, or cancer. In turn, epigenetics has raised the importance in discerning the possible relationship between metabolic disorders, lifestyle and environment. However, ChIP application in human adipose tissue is limited by several factors, such as sample size, frozen sample availability, high lipid content and cellular composition of the tissue. Here, we optimize the standard protocol of ChIP for small pieces of frozen human adipose tissue. In addition, we test ChIP for the histone mark H3K4m3, which is related to active promoters, and validate the performance of the ChIP by analyzing gene promoters for factors usually studied in adipose tissue using qPCR. Our improvements result in a higher performance in chromatin shearing and DNA recovery of adipocytes from the tissue, which may be useful for ChIP-qPCR or ChIP-seq analysis

Rb regulates fate choice and lineage commitment in vivo

February 1, 2011Mutation of the retinoblastoma gene (RB1) tumour suppressor occurs in one-third of all human tumours and is particularly associated with retinoblastoma and osteosarcoma[superscript 1]. Numerous functions have been ascribed to the product of the human RB1 gene, the retinoblastoma protein (pRb). The best known is pRb’s ability to promote cell-cycle exit through inhibition of the E2F transcription factors and the transcriptional repression of genes encoding cell-cycle regulators[superscript 1]. In addition, pRb has been shown in vitro to regulate several transcription factors that are master differentiation inducers[superscript 2]. Depending on the differentiation factor and cellular context, pRb can either suppress or promote their transcriptional activity. For example, pRb binds to Runx2 and potentiates its ability to promote osteogenic differentiation in vitro[superscript 3]. In contrast, pRb acts with E2F to suppress peroxisome proliferator-activated receptor γ subunit (PPAR-γ), the master activator of adipogenesis[superscript 4, 5]. Because osteoblasts and adipocytes can both arise from mesenchymal stem cells, these observations suggest that pRb might play a role in the choice between these two fates. However, so far, there is no evidence for this in vivo. Here we use mouse models to address this hypothesis in mesenchymal tissue development and tumorigenesis. Our data show that Rb status plays a key role in establishing fate choice between bone and brown adipose tissue in vivo.National Cancer Institute (U.S.) (Grant)National Institutes of Health (U.S.) (Grant

Sex-Biased Control of Inflammation and Metabolism by a Mitochondrial Nod-Like Receptor.

Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite, Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate in Nlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomics of female and male BMDMs revealed an altered steroid hormone signaling in Nlrx1-deficient cells, and a "masculinization" of Nlrx1-deficient female BMDMs. Thus, our findings suggest that NLRX1 prevents uncontrolled inflammation and metabolism in females and therefore may contribute to the sex differences observed in infectious and inflammatory diseases

KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response.

The endoplasmic reticulum (ER) unfolded protein response (UPR(er)) pathway plays an important role in helping pancreatic β cells to adapt their cellular responses to environmental cues and metabolic stress. Although altered UPR(er) gene expression appears in rodent and human type 2 diabetic (T2D) islets, the underlying molecular mechanisms remain unknown. We show here that germline and β cell-specific disruption of the lysine acetyltransferase 2B (Kat2b) gene in mice leads to impaired insulin secretion and glucose intolerance. Genome-wide analysis of Kat2b-regulated genes and functional assays reveal a critical role for Kat2b in maintaining UPR(er) gene expression and subsequent β cell function. Importantly, Kat2b expression is decreased in mouse and human diabetic β cells and correlates with UPR(er) gene expression in normal human islets. In conclusion, Kat2b is a crucial transcriptional regulator for adaptive β cell function during metabolic stress by controlling UPR(er) and represents a promising target for T2D prevention and treatment

Cdkn2a deficiency promotes adipose tissue browning.

Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis. We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients. We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression. Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders

The pathophysiological function of peroxisome proliferator-activated receptor-γ in lung-related diseases

Research into respiratory diseases has reached a critical stage and the introduction of novel therapies is essential in combating these debilitating conditions. With the discovery of the peroxisome proliferator-activated receptor and its involvement in inflammatory responses of cardiovascular disease and diabetes, attention has turned to lung diseases and whether knowledge of this receptor can be applied to therapy of the human airways. In this article, we explore the prospect of peroxisome proliferator-activated receptor-γ as a marker and treatment focal point of lung diseases such as asthma, chronic obstructive pulmonary disorder, lung cancer and cystic fibrosis. It is anticipated that peroxisome proliferator-activated receptor-γ ligands will provide not only useful mechanistic pathway information but also a possible new wave of therapies for sufferers of chronic respiratory diseases

Association of PPARγ2 polymorphisms with carcass and meat quality traits in a Pietrain x Jinhua F2 population

The PPARγ2 gene is a key regulator of both proliferation and preadipocyte differentiation in mammals. Herein its genotype and allele frequencies were analyzed using PCR-SSCP in eight pig breeds (N = 416). Two kinds of polymorphisms of the PPARγ2 gene were detected, including a previously reported shift SNP A177G (Met59Val) in exon 1 and a novel silent mutation G876A in exon 5. The results revealed that European pig breeds carry a higher allele A frequency at the A177G locus and a fixed GG genotype at the G876A locus. Allele A at the G876A locus was only found in Jinhua pigs. The association between haplotype (A177G/G876A) and carcass and meat quality traits was analyzed in a Pietrain x Jinhua F2 population (N = 248). The PPARγ2 gene was found to be significantly associated with backfat thickness at the shoulder (p < 0.05), 6–7th ribs (p < 0.01), last rib (p < 0.01), gluteus medius (p <0.05) and ham weight (p < 0.01). Significant effects of different haplotypes on ham weight and backfat thickness at the 6–7th ribs, last rib, and gluteus medius were also observed