PPAR action in insulin resistance unraveled by metabolomics: potential clinical implications

Metabolomic analysis will provide the next large set of clues to further our understanding of human health and disease. A recent study has elucidated the significant differences in the metabolomes of adipocytes, serum and an adipocyte cell line after activation of two nuclear receptors, peroxisome proliferator activated receptor β/δ (PPARβ/δ) and PPARγ. These findings hold great promise for explaining fundamental differences in the mechanisms of PPAR agonists and for identifying targets for the treatment of diabetes

Investigating the Relationship between Instructors’ Use of Active Learning Strategies and Students’ Conceptual Understanding and Affective Changes in Introductory Biology: A Comparison of Two Active-Learning Environments

In response to calls for reform in undergraduate biology education, we conducted research examining how varying active-learning strategies impacted students’ conceptual understanding, attitudes, and motivation in two sections of a large-lecture introductory cell and molecular biology course. Using a quasi-experimental design, we collected quantitative data to compare participants’ conceptual understanding, attitudes, and motivation in the biological sciences across two contexts that employed different active-learning strategies and that were facilitated by unique instructors. Students participated in either graphic organizer/worksheet activities or clicker-based case studies. After controlling for demographic and presemester affective differences, we found that students in both active-learning environments displayed similar and significant learning gains. In terms of attitudinal and motivational data, significant differences were observed for two attitudinal measures. Specifically, those students who had participated in graphic organizer/worksheet activities demonstrated more expert-like attitudes related to their enjoyment of biology and ability to make real-world connections. However, all motivational and most attitudinal data were not significantly different between the students in the two learning environments. These data reinforce the notion that active learning is associated with conceptual change and suggests that more research is needed to examine the differential effects of varying active- learning strategies on students’ attitudes and motivation in the domain

A Role for PPARβ/δ in Tumor Stroma and Tumorigenesis

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a transcription factor that is activated by endogenous fatty acid ligands and by synthetic agonists. Its role in the regulation of skeletal muscle fatty acid catabolism, glucose homeostasis, and cellular differentiation has been established in multiple studies. On the contrary, a role for PPARβ/δ in tumorigenesis is less clear because there are contradictory reports in the literature. However, the majority of these studies have not examined the role of PPARβ/δ in the tumor stroma. Recent evidence suggests that stromal PPARβ/δ regulates tumor endothelial cell proliferation and promotes differentiation leading to the properly orchestrated events required for tumor blood vessel formation. This review briefly summarizes the significance of these studies that may provide clues to help explain the reported discrepancies in the literature regarding the role of PPARβ/δ in tumorigenesis

Partnering for Quail in South Carolina: A Cooperative Approach Making a Difference

The National Bobwhite Conservation Initiative (NBCI) identified 15 national quail focal areas throughout the distribution of the northern bobwhite (Colinus virginianus) in June 2016. The first NBCI Focal Area on U.S. Forest Service System land emerged from the existing 16,200-hectare Indian Creek Woodland and Savanna Restoration Initiative (ICWSRI). The ICWSRI is an ongoing collaborative project involving partners from 10 agencies and organizations in the Piedmont of South Carolina. Cooperation among federal and state agencies, non-governmental organizations (NGO), and private landowners, combined with assistance programs such as the Environmental Quality Incentives Program (EQIP) have currently resulted in 2,547 hectares (1,600 hectares on private land and 947 hectares on public land) of improved habitat for wildlife species associated with pine woodlands and savannas. Data obtained through the Breeding Bird Survey, spring whistle counts, and fall covey counts suggest a correlation between woodland and savanna restoration and avian response across the ICWSRI area. Fall covey count minimum population estimates (birds/ha) ranged from 1/38 in 2008 to 1/7 in 2016. Spring whistle count population density estimates (birds/ha) ranged from 1/37 in 2009 to 1/6 in 2012. Although monitoring suggests an initial increase in bobwhite densities across the project area, it is imperative to continue involving existing and additional partners to increase habitat availability, connectivity, and quality for bobwhite and associated species. Collaborative efforts and partnerships across ownership boundaries are necessary to increase bobwhite populations on a landscape scale. The Indian Creek project has effectively involved efforts from federal, state, NGO, and private partners to restore and improve bobwhite habitat and may serve as an example for other areas where incorporating a cooperative approach could positively influence bobwhite populations

Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPARα and PPARβ, with marginal effects on PPARγ, and decreased basal mRNA levels of PPARα target genes. Inhibition of PPARα activity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPARα interacted with E6-AP, and in mice treated with PPARα agonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPARα null mice, indicating a PPARα-dependent regulation. These studies suggest coordinate regulation of E6-AP and PPARα, and contribute to our understanding of the role of PPARs in cellular metabolism

Modes of Action and Species-Specific Effects of Di-(2-ethylhexyl)Phthalate in the Liver

The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. The biological action of DEHP is very similar to chemicals that are collectively known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds characterized as nongenotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called ‘peroxisome proliferation’ that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)α, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARα and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARα in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolism-related genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid, but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained hepatomegaly; (vii) chronic low-level oxidative stress and accumulation of DNA damage; (viii) selective clonal expansion of the initiated cells; (ix) appearance of the pre-neoplastic nodules; (x) development of adenomas and carcinomas

Regulatory mechanisms mediated by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer

Considerable progress has been made during the past twenty years towards elucidating the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in skin cancer. In 1999, the original notion that PPARβ/δ was involved with epithelial cell function was postulated based on a correlation between PPARβ/δ expression and the induction of mRNAs encoding proteins that mediate terminal differentiation in keratinocytes. Subsequent studies definitively revealed that PPARβ/δ could induce terminal differentiation and inhibit proliferation of keratinocytes. Molecular mechanisms have since been discovered to explain how this nuclear receptor can be targeted for preventing and treating skin cancer. This includes the regulation of terminal differentiation, mitotic signaling, endoplasmic reticulum stress, and cellular senescence. Interestingly, the effects of activating PPARβ/δ can preferentially target keratinocytes with genetic mutations associated with skin cancer. This review provides the history and current understanding of how PPARβ/δ can be targeted for both non-melanoma skin cancer and melanoma, and postulates how future approaches that modulate PPARβ/δ signaling may be developed for the prevention and treatment of these diseases

PPARβ/δ selectively regulates phenotypic features of age-related macular degeneration.

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a nuclear receptor that regulates differentiation, inflammation, lipid metabolism, extracellular matrix remodeling, and angiogenesis in multiple tissues. These pathways are also central to the pathogenesis of age-related macular degeneration (AMD), the leading cause of vision loss globally. With the goal of identifying signaling pathways that may be important in the development of AMD, we investigated the impact of PPARβ/δ activation on ocular tissues affected in the disease. PPARβ/δ is expressed and can be activated in AMD vulnerable cells, including retinal pigment epithelial (RPE) and choroidal endothelial cells. Further, PPARβ/δ knockdown modulates AMD-related pathways selectively. Specifically, genetic ablation of Pparβ/δ in aged mice resulted in exacerbation of several phenotypic features of early dry AMD, but attenuation of experimentally induced choroidal neovascular (CNV) lesions. Antagonizing PPARβ/δ in both in vitro angiogenesis assays and in the in vivo experimentally induced CNV model, inhibited angiogenesis and angiogenic pathways, while ligand activation of PPARβ/δ, in vitro, decreased RPE lipid accumulation, characteristic of dry AMD. This study demonstrates for the first time, selective regulation of a nuclear receptor in the eye and establishes that selective targeting of PPARβ/δ may be a suitable strategy for treatment of different clinical sub-types of AMD

PPARδ status and mismatch repair mediated neoplasia in the mouse intestine

BACKGROUND: Therapeutic regulation of PPARδ activity using selective agonists has been proposed for various disorders. However, the consequences of altered peroxisome proliferator-activated receptor delta (PPARδ) activity in the context of intestinal tumourigenesis remain somewhat unclear. Contradictory evidence suggesting PPARδ either attenuates or potentiates intestinal neoplasia. To further investigate the PPARδ dependency of intestinal tumourigenesis, we have analysed the consequences of PPARδ deficiency upon intestinal neoplasia occurring in mice with impaired mismatch DNA repair. METHODS: Mice deficient for both PPARδ and the mismatch repair gene Mlh1 were produced and the incidence and severity of intestinal neoplasia recorded. RESULTS: No significant differences between the control genotypes and the double mutant genotypes were recorded indicating that deficiency of PPARδ does not modify impaired mismatch repair induced neoplasia. CONCLUSION: In contrast with the previously observed acceleration of intestinal neoplasia in the context of the Apc(Min/+ )mouse, PPARδ deficiency does not alter the phenotype of mismatch repair deficiency. This data supports the notion that PPARδ is not required for adenoma formation and indicate that any pro-tumourigenic effect of PPARδ inactivation may be highly context dependent