Glucocorticoid steroids such as prednisone are prescribed for chronic muscle conditions
such as Duchenne muscular dystrophy, where their use is associated with prolonged
ambulation. The positive effects of chronic steroid treatment in muscular dystrophy are
paradoxical because these steroids are also known to trigger muscle atrophy. Chronic
steroid use usually involves once-daily dosing, although weekly dosing in children has
been suggested for its reduced side effects on behavior. In this work, we tested steroid
dosing in mice and found that a single pulse of glucocorticoid steroids improved
sarcolemmal repair through increased expression of annexins A1 and A6, which mediate
myofiber repair. This increased expression was dependent on glucocorticoid response
elements upstream of annexins and was reinforced by the expression of forkhead box O1
(FOXO1). We compared weekly versus daily steroid treatment in mouse models of acute muscle
injury and in muscular dystrophy and determined that both regimens provided comparable
benefits in terms of annexin gene expression and muscle repair. However, daily dosing
activated atrophic pathways, including F-box protein 32 (
Mattia Quattrocelli, David Y. Barefield, James L. Warner, Andy H. Vo, Michele Hadhazy, Judy U. Earley, Alexis R. Demonbreun, Elizabeth M. McNally
Natalia Rakova, Kento Kitada, Kathrin Lerchl, Anke Dahlmann, Anna Birukov, Steffen Daub, Christoph Kopp, Tetyana Pedchenko, Yahua Zhang, Luis Beck, Bernd Johannes, Adriana Marton, Dominik N. Müller, Manfred Rauh, Friedrich C. Luft, Jens Titze
Natriuretic regulation of extracellular fluid volume homeostasis includes suppression of the renin-angiotensin-aldosterone system, pressure natriuresis, and reduced renal nerve activity, actions that concomitantly increase urinary Na+ excretion and lead to increased urine volume. The resulting natriuresis-driven diuretic water loss is assumed to control the extracellular volume. Here, we have demonstrated that urine concentration, and therefore regulation of water conservation, is an important control system for urine formation and extracellular volume homeostasis in mice and humans across various levels of salt intake. We observed that the renal concentration mechanism couples natriuresis with correspondent renal water reabsorption, limits natriuretic osmotic diuresis, and results in concurrent extracellular volume conservation and concentration of salt excreted into urine. This water-conserving mechanism of dietary salt excretion relies on urea transporter–driven urea recycling by the kidneys and on urea production by liver and skeletal muscle. The energy-intense nature of hepatic and extrahepatic urea osmolyte production for renal water conservation requires reprioritization of energy and substrate metabolism in liver and skeletal muscle, resulting in hepatic ketogenesis and glucocorticoid-driven muscle catabolism, which are prevented by increasing food intake. This natriuretic-ureotelic, water-conserving principle relies on metabolism-driven extracellular volume control and is regulated by concerted liver, muscle, and renal actions.
Kento Kitada, Steffen Daub, Yahua Zhang, Janet D. Klein, Daisuke Nakano, Tetyana Pedchenko, Louise Lantier, Lauren M. LaRocque, Adriana Marton, Patrick Neubert, Agnes Schröder, Natalia Rakova, Jonathan Jantsch, Anna E. Dikalova, Sergey I. Dikalov, David G. Harrison, Dominik N. Müller, Akira Nishiyama, Manfred Rauh, Raymond C. Harris, Friedrich C. Luft, David H. Wassermann, Jeff M. Sands, Jens Titze
Cancer cells preferentially utilize glucose and glutamine, which provide macromolecules and antioxidants that sustain rapid cell division. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of these nutrients. The folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Here, using hepatocellular carcinoma (HCC) as a cancer model, we have observed a reduction in growth rate upon withdrawal of folate. We found that an enzyme in the folate cycle, methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L), plays an essential role in support of cancer growth. We determined that MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. Our observations further suggest that MTHFD1L contributes to the production and accumulation of NADPH to levels that are sufficient to combat oxidative stress in cancer cells. The elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for HCC. Taken together, our study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting.
Derek Lee, Iris Ming-Jing Xu, David Kung-Chun Chiu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Lynna Lan Li, Cheuk-Ting Law, Felice Ho-Ching Tsang, Larry Lai Wei, Cerise Yuen-Ki Chan, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong
Many cancer-associated mutations that deregulate cellular metabolic responses to hypoxia also reprogram carbon metabolism to promote utilization of glutamine. In renal cell carcinoma (RCC), cells deficient in the von Hippel–Lindau (
Arimichi Okazaki, Paulo A. Gameiro, Danos Christodoulou, Laura Laviollette, Meike Schneider, Frances Chaves, Anat Stemmer-Rachamimov, Stephanie A. Yazinski, Richard Lee, Gregory Stephanopoulos, Lee Zou, Othon Iliopoulos
Obesity is characterized by aberrant fat accumulation. However, the intracellular signaling pathway that senses dietary fat and leads to fat storage remains elusive. Here, we have observed that the levels of histone deacetylase 6 (HDAC6) and the related family member HDAC10 are markedly reduced in adipose tissues of obese animals and humans. Mice with adipocyte-specific depletion of
Hui Qian, Yuanying Chen, Zongqian Nian, Lu Su, Haoyong Yu, Feng-Jung Chen, Xiuqin Zhang, Wenyi Xu, Linkang Zhou, Jiaming Liu, Jinhai Yu, Luxin Yu, Yan Gao, Hongchao Zhang, Haihong Zhang, Shimin Zhao, Li Yu, Rui-Ping Xiao, Yuqian Bao, Shaocong Hou, Pingping Li, Jiada Li, Haiteng Deng, Weiping Jia, Peng Li
SIRT2 is a cytoplasmic sirtuin that plays a role in various cellular processes, including tumorigenesis, metabolism, and inflammation. Since these processes require iron, we hypothesized that SIRT2 directly regulates cellular iron homeostasis. Here, we have demonstrated that SIRT2 depletion results in a decrease in cellular iron levels both in vitro and in vivo. Mechanistically, we determined that SIRT2 maintains cellular iron levels by binding to and deacetylating nuclear factor erythroid-derived 2–related factor 2 (NRF2) on lysines 506 and 508, leading to a reduction in total and nuclear NRF2 levels. The reduction in nuclear NRF2 leads to reduced ferroportin 1 (FPN1) expression, which in turn results in decreased cellular iron export. Finally, we observed that
Xiaoyan Yang, Seong-Hoon Park, Hsiang-Chun Chang, Jason S. Shapiro, Athanassios Vassilopoulos, Konrad T. Sawicki, Chunlei Chen, Meng Shang, Paul W. Burridge, Conrad L. Epting, Lisa D. Wilsbacher, Supak Jenkitkasemwong, Mitchell Knutson, David Gius, Hossein Ardehali
Leptin contributes to the control of resting metabolic rate (RMR) and blood pressure (BP) through its actions in the arcuate nucleus (ARC). The renin-angiotensin system (RAS) and angiotensin AT1 receptors within the brain are also involved in the control of RMR and BP, but whether this regulation overlaps with leptin’s actions is unclear. Here, we have demonstrated the selective requirement of the AT1A receptor in leptin-mediated control of RMR. We observed that AT1A receptors colocalized with leptin receptors (LEPRs) in the ARC. Cellular coexpression of AT1A and LEPR was almost exclusive to the ARC and occurred primarily within neurons expressing agouti-related peptide (AgRP). Mice lacking the AT1A receptor specifically in LEPR-expressing cells failed to show an increase in RMR in response to a high-fat diet and deoxycorticosterone acetate–salt (DOCA-salt) treatments, but BP control remained intact. Accordingly, loss of RMR control was recapitulated in mice lacking AT1A in AgRP-expressing cells. We conclude that angiotensin activates divergent mechanisms to control BP and RMR and that the brain RAS functions as a major integrator for RMR control through its actions at leptin-sensitive AgRP cells of the ARC.
Kristin E. Claflin, Jeremy A. Sandgren, Allyn M. Lambertz, Benjamin J. Weidemann, Nicole K. Littlejohn, Colin M.L. Burnett, Nicole A. Pearson, Donald A. Morgan, Katherine N. Gibson-Corley, Kamal Rahmouni, Justin L. Grobe
Obesity causes insulin resistance, and PPARγ ligands such as rosiglitazone are insulin sensitizing, yet the mechanisms remain unclear. In C57BL/6 (B6) mice, obesity induced by a high-fat diet (HFD) has major effects on visceral epididymal adipose tissue (eWAT). Here, we report that HFD-induced obesity in B6 mice also altered the activity of gene regulatory elements and genome-wide occupancy of PPARγ. Rosiglitazone treatment restored insulin sensitivity in obese B6 mice, yet, surprisingly, had little effect on gene expression in eWAT. However, in subcutaneous inguinal fat (iWAT), rosiglitazone markedly induced molecular signatures of brown fat, including the key thermogenic gene
Raymond E. Soccio, Zhenghui Li, Eric R. Chen, Yee Hoon Foong, Kiara K. Benson, Joanna R. Dispirito, Shannon E. Mullican, Matthew J. Emmett, Erika R. Briggs, Lindsey C. Peed, Richard K. Dzeng, Carlos J. Medina, Jennifer F. Jolivert, Megan Kissig, Satyajit R. Rajapurkar, Manashree Damle, Hee-Woong Lim, Kyoung-Jae Won, Patrick Seale, David J. Steger, Mitchell A. Lazar
Peptides derived from pre-proglucagon (GCG peptides) act in both the periphery and the CNS to change food intake, glucose homeostasis, and metabolic rate while playing a role in anxiety behaviors and physiological responses to stress. Although the actions of GCG peptides produced in the gut and pancreas are well described, the role of glutamatergic GGC peptide–secreting hindbrain neurons in regulating metabolic homeostasis has not been investigated. Here, we have shown that chemogenetic stimulation of GCG-producing neurons reduces metabolic rate and food intake in fed and fasted states and suppresses glucose production without an effect on glucose uptake. Stimulation of GCG neurons had no effect on corticosterone secretion, body weight, or conditioned taste aversion. In the diet-induced obese state, the effects of GCG neuronal stimulation on gluconeogenesis were lost, while the food intake–lowering effects remained, resulting in reductions in body weight and adiposity. Our work suggests that GCG peptide–expressing neurons can alter feeding, metabolic rate, and glucose production independent of their effects on hypothalamic pituitary-adrenal (HPA) axis activation, aversive conditioning, or insulin secretion. We conclude that GCG neurons likely stimulate separate populations of downstream cells to produce a change in food intake and glucose homeostasis and that these effects depend on the metabolic state of the animal.
Ronald P. Gaykema, Brandon A. Newmyer, Matteo Ottolini, Vidisha Raje, Daniel M. Warthen, Philip S. Lambeth, Maria Niccum, Ting Yao, Yiru Huang, Ira G. Schulman, Thurl E. Harris, Manoj K. Patel, Kevin W. Williams, Michael M. Scott