Our Favorite Papers of 2017
Every year we like to come up with some of the papers we really enjoyed reading this year during our journal club. Previous years are:
Here are some of our favorites from this year:
Maida A, Chan JSK, Sjøberg KA, Zota A, Schmoll D, Kiens B, Herzig S & Rose AJ (2017). Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution. Mol Metab 6, 873–881. doi:10.1016/j.molmet.2017.06.009.
Lim J, Li L, Shirihai OS, Trudeau KM, Puertollano R & Raben N (2017).Modulation of mTOR signaling as a strategy for the treatment of Pompe disease. EMBO Mol Med 9, 353–370. doi:10.1016/j.molmet.2017.02.006.
Olsen JM, Csikasz RI, Dehvari N, Lu L, Sandström A, Öberg AI, Nedergaard J, Stone-Elander S & Bengtsson T (2017). β 3 -Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway. Mol Metab 6, 611–619. doi:10.1016/j.molmet.2017.02.006.
Rosario FJ, Powell TL & Jansson T (2016). Activation of placental insulin and mTOR signaling in a mouse model of maternal obesity associated with fetal overgrowth. Am J Physiol Regul integr Comp Physiol 310: R87-R93. doi:10.1152/ajpregu.00356.2015.
This study by Rosario and colleagues aimed to understand the effect of maternal obesity on the fetal outcomes. They hypothesized that maternal obesity activates placental insulin/IGF-I/mTOR and leptin signaling pathways. 12-week-old mice were assigned either to a control group receiving a control diet or an experimental group with induced obesity receiving a high-fat and high-sugar diet. Placental tissues were obtained at embryonic day 18.5. Interestingly, mice who were on a high-fat high-sugar diet had increased placental phosphorylation of 4E-BP1 and S6, IRS-1 and Akt, and STAT3. They further tested whether placentas of obese mice had increased inflammation, but there were no significant differences in inflammatory markers between lean and obese mothers. The authors concluded that a maternal high-fat high-sugar diet activates placental mTORC1, insulin/IGF-I, and STAT3 signaling. The upregulated pathways may influence an increased macronutrient flux from the mother to the fetus through the placenta, which may explain why obese mothers may give birth to macrosomic infants who are at a higher risk of developing metabolic syndrome later in life. I found this study very interesting, as the placenta is still an understudied organ, and the mechanisms that underlie the effects of maternal obesity on the fetus remain unclear. Fully understanding the altered placental pathways in maternal obesity can pave the way to future discoveries in the field that may help prevent or attenuate the undesired fetal outcomes of maternal obesity - Noura.
Vockley CM, D’Ippolito AM, McDowell IC, Majoros WH, Safi A, Song L, Crawford GE & Reddy TE (2016). Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome. Cell 166, 1269–1281.e19. doi:10.1016/j.cell.2016.07.049.
Kang S-H, Lee H-A, Kim M, Lee E, Sohn UD & Kim I (2017). Forkhead box O3 plays a role in skeletal muscle atrophy through expression of E3 ubiquitin ligases MuRF-1 and atrogin-1 in Cushing’s syndrome. Am J Physiol Metab 312, E495–E507. doi:10.1152/ajpendo.00389.2016.
Kang and colleagues sought to investigate how the glucocorticoid receptor (GR) regulates genes involved in muscle wasting under conditions of elevated glucocorticoids. They treated rats and L6 cells with either dexamethasone or ACTH to determine how GR signaling leads to FOXO3a, known to induce muscle atrophy, induction and subsequent expression of MuRF-1 and Atrogin-1. ACTH-treated rats had significant hindlimb muscle atrophy and increased FoxO3a, Atrogin-1 and MuRF-1 expression and dexamethasone treatment led to upregulation of FoxO3a, Atrogin-1 and MuRF-1 transcripts in L6 cells. Additionally they showed that dexamethasone caused decreased phosphorylation of FoxO3a leading to increased nuclear translocation, which was reversed with RU486 (GR antagonist). Lastly, they were able to find the GRE sites on FoxO3a where GR binds to activate transcription and the FBE binding sites on MuRF-1 and Atrogin-1 following dexamethasone treatment in L6 cells; siRNA of FoxO3a reduced dexamethasone-induced MuRF-1 and Atrogin-1 expression. I found this paper interesting and well done. Though glucocorticoids have long been known to cause muscle loss, there has not been much study into how this happens. I feel this is an important topic given the amount of people with chronically elevated glucocorticoids and the importance of muscle mass on overall health and wellness. I appreciate how thorough the authors were with their experiments in the investigation of this topic - Innocence.
Wang, X. J., Xiao, J. J., Liu, L., Jiao, H. C. & Lin, H. (2017) Excessive glucocorticoid-induced muscle MuRF1 overexpression is independent of Akt/FoXO1 pathway. Biosci. Rep. 37, BSR20171056. doi:10.1042/BSR20171056.
This article focused on the role of Atrogin-1 and MuRF1 in protein catabolism during high levels of glucocorticoid treatment. By stimulating MuRF1 protein proteolysis was found to overall increase however the same results were not seen with atrogin-1. All proteolysis was based upon the ubiquitin proteasome pathway. The authors observed the stimulation of MuRF and the involvement of mTOR and FOXO1 signaling pathways and concluded that MuRF1 activation is independent of Akt/FOXO1 pathway. All tests were performed in cultured C2C12 cells and the various treatments were given after 12 hour incubation. The article was ended with a possible pathway model of protein degradation independent of FOXO and a desire to apply this research towards muscle atrophy prevention. I enjoyed this article because of the clearly defined hypothesis and choice of model. I appreciated the 5 trials performed to encompass a variety of points along the pathways of glucocorticoids from GR inhibitors to mTOR. However I believe more explicit work could be performed to analyze the FOXO pathway as well as addressing Foxo1 vs Foxo3a. This paper has helped me to set up a DEX time course for my own C2C12 cells - Laura.
Molecular Adaptations to Ketogenic Diets
Douris, N. et al. Beta-adrenergic Receptors are Critical for Weight Loss but not for other Metabolic Adaptations to the Consumption of a Ketogenic Diet in Male Mice. Mol. Metab. 1–9 (2017). doi:10.1016/j.molmet.2017.05.017.
This paper from Eleftheria Maratos-Flier's group at Beth Israel and Harvard Medical School looked at the role of beta-adrenergic receptors in adaptations to ketogenic diets. Consistent with their previous work, they show that switching from normal chow to ketogenic diets are accompanied by an increase in basal metabolic rate. This effect is lost in the betaless mice, lacking the three beta-adrenergic receptors. They focus on brown fat as a tissue that may be causing this, and show a ketogenic-diet induced stabilization of UCP1 protein (but not RNA) as a potential mechanism - Dave.
Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, Perez G, Gutierrez-Casado E, Koike S, Knotts TA, Imai DM, Griffey SM, Kim K, Hagopian K, Haj FG, Baar K, Cortopassi GA, Ramsey JJ & Lopez-Dominguez JA (2017). A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 26, 539–546.e5. doi: 10.1016/j.cmet.2017.08.005.
Svensson K, Albert V, Cardel B, Salatino S & Handschin C (2016). Skeletal muscle PGC-1a modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J 30, 1976–1986.
Pomar CA, van Nes R, Sánchez J, Picó C, Keijer J, Palou A. Maternal consumption of a cafeteria diet during lactation in rats leads the offspring to a thin-outside-fat-inside phenotype. Int J Obes. 2017;41:1279. doi: 10.1038/ijo.2017.42.
Pomar and colleagues sought to identify the changes to offspring body weight and composition after maternal exposure to the western diet in rats, here modeled by the cafeteria diet. After 3 weeks of either ad libitum control or cafeteria diet to dams during lactation, milk composition was analyzed for macronutrient content and all offspring were weaned onto chow diet. Offspring were monitored for body composition, and metabolic health until they were sacrificed at 6 months of age. Dams who ate a cafeteria diet produced milk with lower protein content and greater triglyceride content compared to control dams. The provision of milk to the offspring produced differing phenotypes in the two sets of offspring. It was found that those offspring whose mothers had been exposed to cafeteria diet during lactation had lower body weights, driven by lower lean mass and greater fat mass compared to offspring of controls. Progeny of cafeteria diet dams also experienced hyperleptinemia, hypertriglyceridemia, and impaired glucose tolerance. This project was unique because it focused on one extremely narrow critical period of development, lactation; instead of the effects of both gestation and lactation. This group also modeled the typical human western diet particularly well, as cafeteria diet captures the variability of intake of the hyper-palatable and nutrient-poor choices available in an obesogenic food system better than high fat diet. The findings demonstrate that offspring may develop the thin-outside, fat-inside phenotype. This possibility is important to remember when examining the effects of diet during development, as the majority of diet-induced dysmetabolism is expected to occur in those who are obese. It demonstrates that body size does not always directly correlate to health status, as it fails to describe adiposity and lean mass, and includes no measure of metabolic health - Molly.
Fernandez-Twinn DS, Gascoin G, Musial B, Carr S, Duque-Guimaraes D, Blackmore HL, Alfaradhi MZ, Loche E, Sferruzzi-Perri AN, Fowden AL & Ozanne SE (2017). Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity. Sci Rep March 12;7:44650. doi:10.1038/srep44650.
Considering the increased prevalence of obesity amongst women of reproductive age, this study aimed to identify potential interventions that can reduce the effect of maternal obesity on the offspring outcome. Fernandez-Twinn and colleagues used a mouse model to replicate the effects of maternal obesity on the offspring. Mice were assigned to a control group receiving standard chow or experimental group on a high-energy palatable obesogenic diet supplemented with sweetened condensed milk. The exercise group on the obesogenic diet had scheduled physical activity on a treadmill 20 minutes daily a week prior to mating and for 17 days during gestation and allowed to rest during the two-day weekend. To control for environmental factors, non-exercise group had a static treadmill that they could not exercise on. Dams on obesogenic diet who exercised had reduced maternal glucose and insulin levels, similar to controls, compared to obese non-exercising dams. The exercise regimen decreased placental fat accretion and HIF1A expression, and exercise restored offspring insulin sensitivity at 8 weeks of age. Hence, moderate exercise had a positive impact on maternal, placental and offspring outcomes. Admitting that changing eating behavior is a challenge, finding novel ways to improve pregnancy outcomes without “dieting” per se is crucial. Hence, knowing that offspring of obese mothers who moderately exercise during gestation might have a lower risk of developing insulin resistance and disease is very promising - Noura.
Søberg S, Sandholt CH, Jespersen NZ, Toft U, Madsen AL, von Holstein-Rathlou S, Grevengoed TJ, Christensen KB, Bredie WLP, Potthoff MJ, Solomon TPJ, Scheele C, Linneberg A, Jørgensen T, Pedersen O, Hansen T, Gillum MP & Grarup N (2017). FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans. Cell Metab 25, 1045–1053.e6. doi:10.1016/j.cmet.2017.04.009.
Wanders D, Forney LA, Stone KP, Burk DH, Pierse A & Gettys TW (2017). FGF21 Mediates the Thermogenic and Insulin-Sensitizing Effects of Dietary Methionine Restriction but Not Its Effects on Hepatic Lipid Metabolism. Diabetes 66, 858–867. doi:10.2337/db16-1212.
Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X, Lu W, Esparza LA, Reya T, Le Zhan, Yanxiang Guo J, White E & Rabinowitz JD (2017). Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118. doi:10.1038/nature24057.
In this study from Joshua Rabinowitz’s lab, metabolic flux of lactate was determined in using stable isotope tracers. The focus here was on lactate, generated by anaerobic glycolysis. This is then the substrate for the Cori cycle, which was thought to primarily recycle lactate from muscle back into glucose via hepatic gluconeogenesis. Several really surprising results came out of this study. First of all, the turnover of lactate was extremely rapid, more than twice as fast as the turnover of glucose. Following where this lactate was going, Hui et al., showed that in all tissues tested (except brain), the majority of TCA cycle intermediates were derived from lactate (and do a lesser extent glutamine), not glucose. This means that glucose is negligible for anaplerosis in most tissues. This has several interesting repercussions, one of which is that glycolytic cells (such as fast twitch type II muscle fibers and glia) might support metabolism in nearby oxidative cells (type I muscle fibers, and neurons for example) by shuttling lactate to their TCA cycle - Dave.
Schweiger M, Romauch M, Schreiber R, Grabner GF, Hütter S, Kotzbeck P, Benedikt P, Eichmann TO, Yamada S, Knittelfelder O, Diwoky C, Doler C, Mayer N, Cecco W De, Breinbauer R, Zimmermann R & Zechner R (2017). Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice. Nat Commun; doi:10.1038/ncomms14859.
Galsgaard, K. D. et al. Disruption of glucagon receptor signaling causes hyperaminoacidemia exposing a possible liver - alpha-cell axis. Am. J. Physiol. - Endocrinol. Metab. ajpendo.00198.2017 (2017). doi:10.1152/ajpendo.00198.2017.