👤 Laura E Downing

There is increasing interest in the importance of patterns of accumulation and overall daily time-use composition of physical activity (PA) and sedentary time (SED) for children's cardiometabolic health. This study examined cross-sectional associations between the time-use composition of PA and SED patterns with cardiometabolic risk factors in 4-year-olds. Data were drawn from the Barwon Infant Study 4-year review (n = 467). Accelerometer data were classified into short (≤ 1-minute) and long (> 1-min) SED, light-, moderate-, and vigorous-intensity PA (LPA, MPA, VPA) bouts. A waking time-use composition of eight distinct components (total volumes plus short and long bouts of SED, LPA MPA, VPA) was constructed using compositional data analysis. Linear mixed models examined associations between composition patterns and body mass index (BMI), percent body fat, triceps and subscapular skinfold thickness, blood pressure, heart rate, carotid-femoral pulse wave velocity, and aortic and carotid intima-media thickness. Adjusted models indicated a higher ratio of long versus short LPA bouts was associated with higher z-BMI (β = 1.69, SE = 0.83, p = 0.04), percent body fat (β = 10.72, SE = 3.71, p = 0.004), and z-triceps (β = 1.90, SE = 0.93, p = 0.04). A higher ratio of long versus short MPA bouts was associated with lower z-BMI (β = - 0.99, SE = 0.46, p = 0.03) and percent body fat (β = - 4.63, SE = 1.93, p = 0.02). A higher total volume of MPA versus VPA was associated with higher percent body fat (β = 4.07, SE = 1.63, p = 0.01) and z-triceps (β = 1.05, SE = 0.43, p = 0.01). Other outcomes showed no associations (p ≥   0.05). In preschoolers, accumulating LPA in shorter bursts, MPA in longer bursts, and maintaining a higher proportion of VPA may support healthier adiposity profiles. These findings underscore the importance of minimizing prolonged sedentary time and encouraging sustained, high-intensity PA from early childhood. Show less

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on agouti-related protein (AgRP) nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. However, MC3R knockout (KO) mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting, cold exposure, or ghrelin while exhibiting normal inhibition of AgRP neurons by sensory detection of food in the ad libitum-fed state. Using a conditional MC3R KO model, we show that the control of AgRP neuron activation by fasting and ghrelin requires the specific presence of MC3R within AgRP neurons. Thus, MC3R is a crucial player in the responsiveness of the AgRP soma to both hormonal and neuronal signals of energy need. Show less

The melanocortin-3 receptor (MC3R) is a negative regulator of the central melanocortin circuitry via presynaptic expression on AgRP nerve terminals, from where it regulates GABA release onto secondary MC4R-expressing neurons. Hence, animals lacking MC3R (MC3R KO) exhibit hypersensitivity to MC4R agonists. However, MC3R KO mice also exhibit defective behavioral and neuroendocrine responses to fasting. Here, we demonstrate that MC3R KO mice exhibit defective activation of AgRP neurons in response to fasting and cold exposure, while exhibiting normal inhibition of AgRP neurons by sensory detection of food. Further, using an AgRP-specific MC3R knockout model, we show that the control of AgRP neuron activation by MC3R is cell-autonomous. One mechanism underlying this involves the response to ghrelin, which is also blunted in mice with AgRP-specific deletion of the MC3R. Thus, MC3R is a crucial player in the control of energy homeostasis by the central melanocortin system, not only acting presynaptically on AgRP neurons, but via AgRP cell-autonomous regulation of fasting- and cold-induced neuronal activation as well. Show less

Histone deacetylases (HDACs) have emerged as epigenetic regulators of risk factors associated with the metabolic syndrome (MetS), and certain botanical extracts have proven to be potent HDAC inhibitors. Understanding the role of dietary procyanidins in HDAC inhibition is important in exploring the therapeutic potential of natural products. C57BL/6 mice were gavaged with vehicle (water) or grape seed procyanidin extract (GSPE, 250 mg/kg) and terminated 14 h later. Liver and serum were harvested to assess the effect of GSPE on HDAC activity, histone acetylation, Pparα activity and target-gene expression, and serum lipid levels. GSPE increased histone acetylation and decreased Class I HDAC activity in vivo, and dose-dependently inhibited recombinant HDAC2 and 3 activities in vitro. Accordingly, Pparα gene and phosphorylated protein expression were increased, as were target genes involved in fatty acid catabolism, suggesting increased Pparα activity. Serum fibroblast growth factor 21 (Fgf21) was elevated, and triglyceride levels were reduced by 28%. GSPE regulates HDAC and Pparα activities to modulate lipid catabolism and reduce serum triglycerides in vivo. Show less

Pediatric osteosarcoma is characterized by multiple somatic chromosomal lesions, including structural variations (SVs) and copy number alterations (CNAs). To define the landscape of somatic mutations in pediatric osteosarcoma, we performed whole-genome sequencing of DNA from 20 osteosarcoma tumor samples and matched normal tissue in a discovery cohort, as well as 14 samples in a validation cohort. Single-nucleotide variations (SNVs) exhibited a pattern of localized hypermutation called kataegis in 50% of the tumors. We identified p53 pathway lesions in all tumors in the discovery cohort, nine of which were translocations in the first intron of the TP53 gene. Beyond TP53, the RB1, ATRX, and DLG2 genes showed recurrent somatic alterations in 29%-53% of the tumors. These data highlight the power of whole-genome sequencing for identifying recurrent somatic alterations in cancer genomes that may be missed using other methods. Show less