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Inhibition of Acetyl-CoA Carboxylase 1 (ACC1) and 2 (ACC2) Reduces Proliferation and De Novo Lipogenesis of EGFRvIII Human Glioblastoma Cells
Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis and de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis and oxidative metabolic pathways, we investigated whether use of a dual ACC inhibitor would provide a potential therapy against certain lipogenic cancers. The impact of dual ACC1/ACC2 inhibition was investigated using a dual ACC1/ACC2 inhibitor as well as dual siRNA knock down on the cellular viability and metabolism of two glioblastoma multiform cancer cell lines, U87 and a more aggressive form, U87 EGFRvIII. We first demonstrated that while ACCi inhibited DNL in both cell lines, ACCi preferentially blunted the U87 EGFRvIII cellular proliferation capacity. Metabolically, chronic treatment with ACCi significantly upregulated U87 EGFRvIII cellular respiration and extracellular acidification rate, a marker of glycolytic activity, but impaired mitochondrial health by reducing maximal respiration and decreasing mitochondrial ATP production efficiency. Moreover, ACCi treatment altered the cellular lipids content and increased apoptotic caspase activity in U87 EGFRvIII cells. Collectively these data indicate that ACC inhibition, by reducing DNL and increasing cellular metabolic rate, may have therapeutic utility for the suppression of lipogenic tumor growth and warrants further investigation.
Journal Article
The Adipocyte Acquires a Fibroblast-Like Transcriptional Signature in Response to a High Fat Diet
Visceral white adipose tissue (vWAT) expands and undergoes extensive remodeling during diet-induced obesity. Much is known about the contribution of various stromal vascular cells to the remodeling process, but less is known of the changes that occur within the adipocyte as it becomes progressively dysfunctional. Here, we performed a transcriptome analysis of isolated vWAT adipocytes to assess global pathway changes occurring in response to a chronic high fat diet (HFD). The data demonstrate that the adipocyte responds to the HFD by adopting a fibroblast-like phenotype, characterized by enhanced expression of ECM, focal adhesion and cytoskeletal genes and suppression of many adipocyte programs most notably those associated with mitochondria. This study reveals that during obesity the adipocyte progressively becomes metabolically dysfunctional due to its acquisition of fibrogenic functions. We propose that mechano-responsive transcription factors such as MRTFA and SRF contribute to both upregulation of morphological genes as well as suppression of mitochondrial programs.
Journal Article
The Design and Implementation of the 2016 National Survey of Children’s Health
Introduction Since 2001, the Health Resources and Services Administration’s Maternal and Child Health Bureau (HRSA MCHB) has funded and directed the National Survey of Children’s Health (NSCH) and the National Survey of Children with Special Health Care Needs (NS-CSHCN), unique sources of national and state-level data on child health and health care. Between 2012 and 2015, HRSA MCHB redesigned the surveys, combining content into a single survey, and shifting from a periodic interviewer-assisted telephone survey to an annual self-administered web/paper-based survey utilizing an address-based sampling frame. Methods The U.S. Census Bureau fielded the redesigned NSCH using a random sample of addresses drawn from the Census Master Address File, supplemented with a unique administrative flag to identify households most likely to include children. Data were collected June 2016–February 2017 using a multi-mode design, encouraging web-based responses while allowing for paper mail-in responses. A parent/caregiver knowledgeable about the child’s health completed an age-appropriate questionnaire. Experiments on incentives, branding, and contact strategies were conducted. Results Data were released in September 2017. The final sample size was 50,212 children; the overall weighted response rate was 40.7%. Comparison of 2016 estimates to those from previous survey iterations are not appropriate due to sampling and mode changes. Discussion The NSCH remains an invaluable data source for key measures of child health and attendant health care system, family, and community factors. The redesigned survey extended the utility of this resource while seeking a balance between previous strengths and innovations now possible.
Journal Article
Playing for keeps
\"A burnt-out soccer star tries to win back his family but gets distracted by his wandering eye in this romantic comedy starring Gerard Butler. His bank account drained and his libido fatigued, professional soccer player George (Butler) hangs up his cleats and heads back to Virginia. Determined to do right in the eyes of his ex-wife (Jessica Biel) and their lonely son (Noah Lomax), George takes a job coaching a local soccer team and begins working to form the young players into true athletes. But with every cougar in town eyeing him from the sidelines, George finds that staying focused on the job and keeping his prurient impulses in check are easier said than done\"--Allmovie.com, viewed September 6, 2018.
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Investigation of spillover effects of a sugar-sweetened beverage tax on beverage purchasing in a nearby, non-taxed area: A quasi-experimental, difference-in-differences analysis
Evidence suggests that sugar-sweetened beverage (SSB) taxes reduce SSB purchasing and improve health outcomes in the taxed area. The extent to which purchasing also changes in nearby communities due to tax signaling effects is unclear. The objective of this study was to assess whether the SSB tax in Seattle, Washington, USA, influenced SSB purchasing in nearby communities within the same media market. We used retail scanner data on weekly sales of 3,531 beverages from 127 retailers in King County excluding Seattle and its bordering area (KC), and 243 retailers in a matched comparison area outside the regional media market. Matching was done via Mahalanobis distance based on pre-tax, county-level demographic measures from the American Community Survey. We estimated linear difference-in-differences in mean volume sold of taxed and nontaxed beverages comparing two years before (2016−2017) and after tax implementation (2018−2019) adjusting for beverage-level fixed effects. We also estimated the difference-in-differences in Seattle versus a matched comparison to estimate the tax effect in Seattle as context for potential effects in KC. For taxed beverages, the mean difference-in-differences in volume sold in KC was 172 liters (95% CI: −1,396, 1,740; P = 0.83), reflecting a 1% change from pre-tax levels in KC for a given beverage. There was suggestive evidence of increased volume sold for taxed and nontaxed soda, and taxed multipack beverages in KC relative to the comparison area. In Seattle, the mean difference-in-differences in volume sold for taxed beverages was −3,628 liters (95% CI: −4,622, −2,634; P < 0.001), reflecting a 20% decline for a given beverage in association with the tax. We did not find evidence of spillover effects in the form of reduced volume sold of SSB in communities near but not bordering the tax in Seattle. Studies in other contexts are needed to investigate spillover on purchasing as well as possible explanations for observed increases in purchases of taxed and nontaxed soda.
Journal Article
Brown Fat Determination and Development from Muscle Precursor Cells by Novel Action of Bone Morphogenetic Protein 6
Brown adipose tissue (BAT) plays a pivotal role in promoting energy expenditure by the virtue of uncoupling protein-1 (UCP-1) that differentiates BAT from its energy storing white adipose tissue (WAT) counterpart. The clinical implication of \"classical\" BAT (originates from Myf5 positive myoblastic lineage) or the \"beige\" fat (originates through trans-differentiation of WAT) activation in improving metabolic parameters is now becoming apparent. However, the inducers and endogenous molecular determinants that govern the lineage commitment and differentiation of classical BAT remain obscure. We report here that in the absence of any forced gene expression, stimulation with bone morphogenetic protein 6 (BMP6) induces brown fat differentiation from skeletal muscle precursor cells of murine and human origins. Through a comprehensive transcriptional profiling approach, we have discovered that two days of BMP6 stimulation in C2C12 myoblast cells is sufficient to induce genes characteristic of brown preadipocytes. This developmental switch is modulated in part by newly identified regulators, Optineurin (Optn) and Cyclooxygenase-2 (Cox2). Furthermore, pathway analyses using the Causal Reasoning Engine (CRE) identified additional potential causal drivers of this BMP6 induced commitment switch. Subsequent analyses to decipher key pathway that facilitates terminal differentiation of these BMP6 primed cells identified a key role for Insulin Like Growth Factor-1 Receptor (IGF-1R). Collectively these data highlight a therapeutically innovative role for BMP6 by providing a means to enhance the amount of myogenic lineage derived brown fat.
Journal Article
Unveiling the wasp-waist structure of the Falkland shelf ecosystem: the role of Doryteuthis gahi as a keystone species and its trophic influences
The Falkland Shelf is a highly productive ecosystem in the Southwest Atlantic Ocean. It is characterized by upwelling oceanographic dynamics and displays a wasp-waist structure, with few intermediate trophic-level species and many top predators that migrate on the shelf for feeding. One of these resident intermediate trophic-level species, the Patagonian longfin-squid Doryteuthis gahi, is abundant and plays an important role in the ecosystem. We used two methods to estimate the trophic structure of the Falkland Shelf food web, focusing on the trophic niche of D. gahi and its impacts on other species and functional groups to highlight the importance of D. gahi in the ecosystem. First, stable isotope measurements served to calculate trophic levels based on an established nitrogen baseline. Second, an Ecopath model was built to corroborate trophic levels derived from stable isotopes and inform about trophic interactions of D. gahi with other functional groups. The results of both methods placed D. gahi in the centre of the ecosystem with a trophic level of ~ 3. The Ecopath model predicted high impacts and therefore a high keystoneness for both seasonal cohorts of D. gahi. Our results show that the Falkland Shelf is not only controlled by species feeding at the top and the bottom of the trophic chain. The importance of species feeding at the third trophic level (e.g. D. gahi and Patagonotothen ramsayi) and observed architecture of energy flows confirm the ecosystem's wasp-waist structure with middle-out control mechanisms at play.
Journal Article