Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response post-exercise. Specifically, plasma ghrelin levels nearly double in mice when they are submitted to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, GHSR (ghrelin receptor)-null mice exhibit decreased food intake following HIIE and a diminished running distance (time until exhaustion) during a longer, step-wise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory DREADD virus AAV2-hSyn-DIO-hM4(Gi)-mCherry to the MBH of Ghsr-IRES-Cre mice, which express Cre-recombinase directed by the Ghsr promoter. We found that chemogenetic inhibition of GHSR-expressing MBH neurons [upon delivery of clozapine-N-oxide (CNO)] 1) suppressed food intake following HIIE by 31.3%, 2) reduced maximum running distance by 20.7%-22.7% and raised blood glucose and blood lactate levels by 18.4%-51.5% and 24.6%-39.2%, respectively, during an exercise endurance protocol, 3) reduced food intake following ghrelin administration by 57.2%, but 4) did not affect glucose tolerance. Further, HIIE increased MBH Ghsr expression. These results indicate that activation of ghrelin-responsive MBH neurons is required for the normal feeding response to HIIE and the usual amount of running exhibited during an exercise endurance protocol.
Omprakash Singh, Sean B. Ogden, Salil Varshney, Kripa Shankar, Deepali Gupta, Subhojit Paul, Sherri Osborne-Lawrence, Corine P. Richard, Nathan P. Metzger, Connor Lawrence, Luis León-Mercado, Jeffrey M. Zigman
Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone specific deletion of Fgf23 on bone and mineral metabolism in the Dmp1 knockout (Dmp1KO) mouse model of ARHR.At 12 weeks, Dmp1KO mice showed increased serum FGF23 and PTH levels, hypophosphatemia, impaired growth, rickets and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels, but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impairs osteoprogenitors differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels. In conclusion, FGF23-induced hypophosphatemia is only partially responsible for the bone defects observed in Dmp1KO mice. Our data suggest that combined DMP1 repletion and FGF23 blockade could effectively correct ARHR-associated mineral and bone disorders.
Guillaume Courbon, Dominik Kentrup, Jane Joy Thomas, Xueyan Wang, Hao-Hsuan Tsai, Jadeah J. Spindler, John Von Drasek, Laura Mazudie Ndjonko, Marta Martinez-Calle, Sana Lynch, Lauriane Hivert, Xiaofang Wang, Wenhan Chang, Jian Q. Feng, Valentin David, Aline Martin
Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG–dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.
Sha-Sha Hu, Yue Han, Tian-Yuan Tan, Hui Chen, Jia-Wen Gao, Lan Wang, Min-Hui Yang, Li Zhao, Yi-Qing Wang, Yan-Qing Ding, Shuang Wang
Diabetes commonly affects cancer patients. We investigated the influence of diabetes on breast cancer biology using a three-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.
Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Z. Minas, Amy L. Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Amy L. Flis, Dean Mann, Olga Ioffe, Xin Wei Wang, Huaitian Liu, Christopher A. Loffredo, Anna Maria Napoles, Stefan Ambs
Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes’ autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.
Jian Lu, Xue Qi Li, Pei Pei Chen, Jia Xiu Zhang, Liang Liu, Gui Hua Wang, Xiao Qi Liu, Ting Ting Jiang, Meng Ying Wang, Wen Tao Liu, Xiong Zhong Ruan, Kun Ling Ma
Thyroid hormone (TH) levels are low during development, and the deiodinases control TH signaling through tissue-specific activation or inactivation of TH. Here we studied human iPSC-derived hepatic organoids and identified a robust induction in DIO2 expression (the deiodinase that activates T4 to T3) that occurs in hepatoblasts. The surge in D2-T3 per-sists until the hepatoblasts differentiate into hepatocytes- or cholangiocytes-like cells, nei-ther of which express DIO2. Preventing the induction of the D2-T3 signaling modified the expression of key transcription factors, decreased the number of hepatocyte-like cells by 60%, and increased the number of cholangiocyte-like cells by 55% without affecting the growth or the size of the mature liver organoid. Physiological levels of T3 could not ful-ly restore the transition from hepatoblasts to mature cells. This indicates that the timed surge in D2-T3 signaling critically determines the fate of developing human hepatoblasts and the transcriptome of the maturing hepatocytes, with physiological and clinical implica-tions for how the liver handles energy substrates.
Jorge Hidalgo-Álvarez, Federico Salas-Lucia, Diana Vera Cruz, Tatiana L. Fonseca, Antonio C. Bianco
In youth with obesity, the gut hormone potentiation of insulin secretion - the incretin effect - is blunted. We explored the longitudinal impact of the incretin effect during pubertal transition on beta cell function and insulin sensitivity. Youths with obesity and 2-h glucose≥120mg/dL underwent a 3-h OGTT and an isoglycemic intravenous glucose infusion to quantify the incretin effect. After 2 years, 30/39 participants had a repeated OGTT and were stratified into three tertiles according to the baseline incretin effect. Thirty participants completed the baseline and follow-up tests. The high-incretin effect group demonstrated a longitudinal increase in beta cell function (DIMM) (p=0.034), with greater insulin sensitivity at follow-up (p=0.034) and stable insulin secretion (φtotal) (p=0.077). A lower incretin effect at baseline was associated with a higher 1-h and 2-h glucose at follow-up (r = -0.558, p=0.001 and r = -0.533, p=0.004). The high-incretin effect group displayed a greater increase of GLP-17-36 than the moderate- and low-incretin group at baseline (p=0.008 and p=0.029), while such a difference did not persist after 2 years. Glucagon suppression was reduced at follow-up in those with low-baseline incretin respect to the high-incretin group (p=0.049).
Alfonso Galderisi, Domenico Tricò, Jessica O. Lat, Stephanie L. Samuels, Ram Weiss, Michelle Van Name, Bridget Pierpont, Nicola Santoro, Sonia Caprio
Aging and many illnesses and injuries impair skeletal muscle mass and function, but the molecular mechanisms are not well understood. To better understand the mechanisms, we generated and studied transgenic mice with skeletal muscle-specific expression of Growth Arrest and DNA Damage Inducible Alpha (GADD45A), a signaling protein whose expression in skeletal muscle rises during aging and a wide range of illnesses and injuries. We found that GADD45A induced several cellular changes that are characteristic of skeletal muscle atrophy, including a reduction in skeletal muscle mitochondria and oxidative capacity, selective atrophy of glycolytic muscle fibers, and paradoxical expression of oxidative myosin heavy chains despite mitochondrial loss. These cellular changes were at least partly mediated by MEKK4, a protein kinase that is directly activated by GADD45A. By inducing these changes, GADD45A decreased the mass of muscles that are enriched in glycolytic fibers, and it impaired strength, specific force, and endurance exercise capacity. Furthermore, as predicted by data from mouse models, we found that GADD45A expression in skeletal muscle was associated with muscle weakness in humans. Collectively, these findings identify GADD45A as a mediator of mitochondrial loss, atrophy, and weakness in mouse skeletal muscle and a potential target for muscle weakness in humans.
George R. Marcotte, Matthew J. Miller, Hawley E. Kunz, Zachary C. Ryan, Matthew D. Strub, Patrick M. Vanderboom, Carrie J. Heppelmann, Sarah Chau, Zachary D. Von Ruff, Sean P. Kilroe, Andrew T. McKeen, Jason M. Dierdorff, Jennifer I. Stern, Karl A. Nath, Chad E. Grueter, Vitor A. Lira, Andrew R. Judge, Blake B. Rasmussen, K. Sreekumaran Nair, Ian R. Lanza, Scott M. Ebert, Christopher M. Adams
Glycolysis is highly enhanced in Pancreatic ductal adenocarcinoma (PDAC) cells; thus, glucose restrictions are imposed on nontumor cells in the PDAC tumor microenvironment (TME). However, little is known about how such glucose competition alters metabolism and confers phenotypic changes in stromal cells in the TME. Here, we report that cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate from glycolysis-enhanced cancer cells as a fuel and exert immunosuppressive activity in the PDAC TME. The expression of lactate dehydrogenase A (LDHA), which regulates lactate production, was a poor prognostic factor for PDAC patients, and LDHA depletion suppressed tumor growth in a CAF-rich murine PDAC model. Coculture of CAFs with PDAC cells revealed that most of the glucose was taken up by the tumor cells and that CAFs consumed lactate via monocarboxylate transporter 1 to enhance proliferation through the TCA cycle. Moreover, lactate-stimulated CAFs upregulated IL6 expression and suppressed cytotoxic immune cell activity synergistically with lactate. Finally, the LDHA inhibitor FX11 reduced tumor growth and improved antitumor immunity in CAF-rich PDAC tumors. Our study provides new insights into crosstalk among tumor cells, CAFs, and immune cells mediated by lactate and offers therapeutic strategies for targeting LDHA enzymatic activity in PDAC cells.
Fumimasa Kitamura, Takashi Semba, Noriko Yasuda-Yoshihara, Kosuke Yamada, Akiho Nishimura, Juntaro Yamasaki, Osamu Nagano, Tadahito Yasuda, Atsuko Yonemura, Yilin Tong, Huaitao Wang, Takahiko Akiyama, Kazuki Matsumura, Norio Uemura, Rumi Itoyama, Luke Bu, Lingfeng Fu, Xichen Hu, Feng Wei, Kosuke Mima, Katsunori Imai, Hiromitsu Hayashi, Yo-ichi Yamashita, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto
Obesity promotes triple-negative breast cancer (TNBC), and effective interventions are urgently needed to break the obesity-TNBC link. Epidemiologic studies indicate that bariatric surgery reduces TNBC risk, while evidence is limited or conflicted for weight loss via low-fat diet (LFD) or calorie restriction (CR). Using a murine model of obesity-driven TNBC, we compared the antitumor effects of vertical sleeve gastrectomy (VSG) with LFD, chronic CR, and intermittent CR. Each intervention generated weight and fat loss and suppressed tumor growth relative to obese mice (greatest suppression with CR). VSG and CR regimens exerted both similar and unique effects, as assessed using multi-omic approaches, in reversing obesity-associated transcriptional, epigenetic, secretome, and microbiota changes and restoring antitumor immunity. Thus, in a murine model of TNBC, bariatric surgery and CR each reverse obesity-driven tumor growth via shared and distinct antitumor mechanisms, and CR is superior to VSG in reversing obesity’s procancer effects.
Kristina Camp, Michael F. Coleman, Tori McFarlane, Steven S. Doerstling, Subreen A. Khatib, Erika T. Rezeli, Alfor G. Lewis, Alexander J. Pfeil, Laura A. Smith, Laura W. Bowers, Farnaz Fouladi, Weida Gong, Elaine M. Glenny, Joel S. Parker, Ginger L. Milne, Ian M. Carroll, Anthony A. Fodor, Randy J. Seeley, Stephen D. Hursting
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