Insulin secretion from pancreatic β cells is essential for glucose homeostasis. An insufficient response to the demand for insulin results in diabetes. We previously showed that β cell–specific deletion of Zfp148 (β-Zfp148KO) improves glucose tolerance and insulin secretion in mice. Here, we performed Ca2+ imaging of islets from β‑Zfp148KO and control mice fed both a chow and a Western-style diet. β-Zfp148KO islets demonstrated improved sensitivity and sustained Ca2+ oscillations in response to elevated glucose levels. β-Zfp148KO islets also exhibited elevated sensitivity to amino acid–induced Ca2+ influx under low glucose conditions, suggesting enhanced mitochondrial phosphoenolpyruvate-dependent (PEP-dependent), ATP-sensitive K+ channel closure, independent of glycolysis. RNA-Seq and proteomics of β-Zfp148KO islets revealed altered levels of enzymes involved in amino acid metabolism (specifically, SLC3A2, SLC7A8, GLS, GLS2, PSPH, PHGDH, and PSAT1) and intermediary metabolism (namely, GOT1 and PCK2), consistent with altered PEP cycling. In agreement with this, β-Zfp148KO islets displayed enhanced insulin secretion in response to l-glutamine and activation of glutamate dehydrogenase. Understanding pathways controlled by ZFP148 may provide promising strategies for improving β cell function that are robust to the metabolic challenge imposed by a Western diet.
Christopher H. Emfinger, Eleonora de Klerk, Kathryn L. Schueler, Mary E. Rabaglia, Donnie S. Stapleton, Shane P. Simonett, Kelly A. Mitok, Ziyue Wang, Xinyue Liu, Joao A. Paulo, Qinq Yu, Rebecca L. Cardone, Hannah R. Foster, Sophie L. Lewandowski, José C. Perales, Christina M. Kendziorski, Steven P. Gygi, Richard G. Kibbey, Mark P. Keller, Matthias Hebrok, Matthew J. Merrins, Alan D. Attie
Vertical sleeve gastrectomy (VSG) results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium, however the mechanism remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the nuclear bile acid receptor, farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express eGFP in ISC/progenitor cells and performed RNA-seq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by GLP-1) in mouse intestinal organoids following treatment with bile acids, an FXR agonist, and a FXR antagonist. RNA-seq of ISCs revealed that bile acids receptors are expressed in ISCs and that VSG explicitly alters expression of several genes that regulate EEC differentiation. Mouse intestinal organoids treated with bile acids and two different FXR agonists increased GLP-1-positive cell numbers, and administration of an FXR antagonist blocked these effects. Taken together, these data indicate that VSG drives ISC fate towards EEC differentiation through bile acid signaling.
Ki-Suk Kim, Bailey C.E. Peck, Yu-Han Hung, Kieran Koch-Laskowski, Landon Wood, Priya H. Dedhia, Jason R. Spence, Randy J. Seeley, Praveen Sethupathy, Darleen A. Sandoval
HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR–double KO (ALKO), and ALDH2 rs671–knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency–induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.
Luxiao Li, Shanshan Zhong, Rui Li, Ningning Liang, Lili Zhang, Shen Xia, Xiaodong Xu, Xin Chen, Shiting Chen, Yongzhen Tao, Huiyong Yin
Mothers that underwent bariatric surgery are at higher risk for delivering a small-for-gestational age (SGA) infant. This phenomenon is attributed to malabsorption and rapid weight loss following surgery. We compared pregnancy outcomes in lean mice that underwent sham surgery or sleeve gastrectomy (SG). SG led to a reduction in glucose levels and an increase in postprandial levels of glucagon-like peptide 1 (Glp1) without affecting mice weight during pregnancy. Pups of SG-operated mice (SG pups) were born SGA. The placenta and pancreas of the pups were not affected by SG, although a high-fat diet caused hepatic steatosis and glucose intolerance in male SG pups. Treatment with a Glp1 receptor antagonist during pregnancy normalized the birth weight of SG pups and diminished the adverse response to a high-fat diet without affecting glucose levels of pregnant mice. The antagonist did not affect the birth weight of pups of sham-operated mice. Our findings link elevated Glp1 signaling, rather than weight loss, to the increased prevalence of SGA births following bariatric surgery with metabolic consequences for the offspring. The long-term effects of bariatric surgery on the metabolic health of offspring of patients require further investigation.
Liron Hefetz, Rachel Ben-Haroush Schyr, Michael Bergel, Yhara Arad, Doron Kleiman, Hadar Israeli, Itia Samuel, Shira Azulai, Arnon Haran, Yovel Levy, Dana Sender, Amihai Rottenstreich, Danny Ben-Zvi
BACKGROUND. Although traditional lipid parameters and coronary imaging techniques are valuable for cardiovascular disease (CVD) risk prediction, better diagnostic tests are still needed. METHODS. In a prospective, observational study, 795 subjects had extensive cardiometabolic profiling, including emerging biomarkers, such as apolipoprotein E (ApoE)-containing HDL-cholesterol. Coronary artery calcium (CAC) score was assessed in the entire cohort, and quantitative coronary computed tomography angiographic (CCTA) characterization (Medis, Qangio) of total (TB), non-calcified (NCB) and fibrous plaque burden (FB) was performed in a sub-cohort (n=300) of patients stratified by concentration of ApoE-HDL-C. Total and HDL-containing apolipoprotein C-III (ApoC-III) were also measured. RESULTS. Most patients had a clinical diagnosis of coronary artery disease (CAD) (n=80.4% of 795), with mean age of 59 years, male (57%) and about half on statin treatment. The low ApoE-HDL-C group had more severe stenosis (11% vs. 2%, overall P<0.001), with higher CAC as compared to high ApoE-HDL-C. On quantitative CCTA, high ApoE-HDL-C group had lower NCB (β=-0.24, P=0.0001), which tended to be significant in fully adjusted model (β=-0.32, P=0.001) and altered by ApoC-III in HDL levels. Low ApoE-HDL-C was significantly associated with LDL particle number (β=0.31; P=0.0001). Finally, when stratified by FB, ApoC-III in HDL showed a more robust predictive value of CAD over ApoE-HDL-C (AUC: 0.705, P=0.0001) in a fully adjusted model. CONCLUSIONS. ApoE-containing HDL-C showed a significant association with early coronary plaque characteristics and is affected by the presence of ApoC-III, indicating that low ApoE-HDL-C and high ApoC-III may be important markers of CVD severity. CLINICAL TRIAL REGISTRATION. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01621594. FUNDING. This work was supported by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health Intramural Research Program. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Alexander V. Sorokin, Nidhi Patel, Khaled M. Abdelrahman, Clarence Ling, Mart Reimund, Giorgio Graziano, Maureen Sampson, Martin Playford, Amit K. Dey, Aarthi Reddy, Heather L. Teague, Michael Stagliano, Marcelo Amar, Marcus Y. Chen, Nehal Mehta, Alan T. Remaley
Post-exertional malaise (PEM) is a hallmark symptom of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). We monitored the evolution of 1,157 plasma metabolites in 60 ME/CFS cases (45 females, 15 males) and in 45 matched healthy control subjects (30 females, 15 males) before and after two maximal Cardiopulmonary Exercise Test (CPET) challenges separated by 24 hours, with the intent of provoking PEM in patients. Four timepoints allowed exploration of the metabolic response to maximal energy-producing capacity and the recovery pattern of ME/CFS cases compared to the healthy control group. Baseline comparison identified several significantly different metabolites, along with an enriched percentage of yet-to-be identified compounds. Additionally, temporal measures demonstrated an increased metabolic disparity between cohorts, including unknown metabolites. The effects of exertion in the ME/CFS cohort predominantly highlighted lipid- as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component to the homeostasis of many organs in the body, including the brain.
Arnaud Germain, Ludovic Giloteaux, Geoffrey E. Moore, Susan M. Levine, John K. Chia, Betsy A. Keller, Jared Stevens, Carl J. Franconi, Xiangling Mao, Dikoma C. Shungu, Andrew Grimson, Maureen R. Hanson
The lung airways are constantly exposed to inhaled toxic substances, resulting in cellular damage that is repaired by local expansion of resident bronchiolar epithelial club cells. Disturbed bronchiolar epithelial damage repair lays at the core of many prevalent lung diseases including chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis, and lung cancer. However, it is still not known how bronchiolar club cell energy-metabolism contributes to this process. Here we show that Adipose TriGlyceride Lipase (ATGL), the rate-limiting enzyme for intracellular lipolysis, is critical for normal club cell function in mice. Deletion of the gene encoding ATGL, Pnpla2 (Atgl), induced substantial triglyceride accumulation, decreased mitochondrial numbers and decreased mitochondrial respiration in club cells. This defect manifested as bronchiolar epithelial thickening and increased airway resistance under baseline conditions. After naphthalene induced epithelial denudation, a regenerative defect was apparent. Mechanistically, dysfunctional PPARα lipid-signaling underlies this phenotype because, (i) ATGL was needed for PPARα lipid-signalling in regenerating bronchioles, and (ii) administration of the specific PPARα agonist WY14643 restored normal bronchiolar club cell ultrastructure and regenerative potential. Our data emphasize the importance of the cellular energy-metabolism for lung epithelial regeneration and highlight the significance of ATGL mediated lipid catabolism for lung health.
Manu Manjunath Kanti, Isabelle Striessnig-Bina, Beatrix I. Wieser, Silvia Schauer, Gerd Leitinger, Thomas O. Eichmann, Martina Schweiger, Margit Winkler, Elke Winter, Andrea Lana, Iris Kufferath, Leigh M. Marsh, Grazyna Kwapiszewska, Rudolf Zechner, Gerald Hoefler, Paul W. Vesely
While critical for neurotransmitter synthesis, 14-3-3 proteins are often assumed to have redundant functions due to their ubiquitous expression, but despite this assumption, various 14-3-3 isoforms have been implicated in regulating metabolism. We previously reported contributions of 14-3-3ζ in β-cell function, but these studies were performed in tumor-derived MIN6 cells and systemic knockout mice. To further characterize the regulatory roles of 14-3-3ζ in β-cell function, we generated β-cell-specific 14-3-3ζ knockout mice. Although no effects on beta-cell mass were detected, potentiated glucose-stimulated insulin secretion (GSIS), mitochondrial function, and ATP synthesis were observed. 14-3-3ζ deletion also altered the β-cell transcriptome, as genes associated with mitochondrial respiration and oxidative phosphorylation were upregulated. Acute 14-3-3 protein inhibition in mouse and human islets recapitulated the enhancements in GSIS and mitochondrial function, suggesting that 14-3-3ζ is the critical isoform in β-cells. In dysfunctional db/db islets and human islets from type 2 diabetic donors, expression of Ywhaz/YWHAZ, the gene encoding 14-3-3ζ, was inversely associated with insulin secretion, and pan-14-3-3 protein inhibition led to enhanced GSIS and mitochondrial function. Taken together, this study demonstrates important regulatory functions of 14-3-3ζ in the regulation of β-cell function and provides a deeper understanding of how insulin secretion is controlled in β-cells.
Yves Mugabo, Cheng Zhao, Ju Jing Tan, Anindya Ghosh, Scott A. Campbell, Evgenia Fadzeyeva, Frédéric Paré, Siew Siew Pan, Maria Galipeau, Julia Ast, Johannes Broichhagen, David J. Hodson, Erin E. Mulvihill, Sophie Petropoulos, Gareth E. Lim
The intermittent fasting (IF) diet has profound benefits for diabetes prevention. However, the precise mechanisms underlying IF’s beneficial effects remain poorly defined. Here, we show that the expression levels of cyclooxygenase-2 (COX-2), an enzyme that produces prostaglandins, are suppressed in white adipose tissue (WAT) of obese humans. In addition, the expression of COX-2 in WAT is markedly upregulated by IF in obese mice. Adipocyte-specific depletion of COX-2 led to reduced fractions of CD4+Foxp3+ Tregs and a substantial decrease in the frequency of CD206+ macrophages, an increase in the abundance of γδT cells in WAT under normal chow diet conditions, and attenuation of IF-induced antiinflammatory and insulin-sensitizing effects, despite a similar antiobesity effect in obese mice. Mechanistically, adipocyte-derived prostaglandin E2 (PGE2) promoted Treg proliferation through the CaMKII pathway in vitro and rescued Treg populations in adipose tissue in COX-2–deficient mice. Ultimately, inactivation of Tregs by neutralizing anti-CD25 diminished IF-elicited antiinflammatory and insulin-sensitizing effects, and PGE2 restored the beneficial effects of IF in COX-2–KO mice. Collectively, our study reveals that adipocyte COX-2 is a key regulator of Treg proliferation and that adipocyte-derived PGE2 is essential for IF-elicited type 2 immune response and metabolic benefits.
Chunqing Wang, Xing Zhang, Liping Luo, Yan Luo, Xin Yang, Xiaofeng Ding, Lu Wang, Huyen Le, Lily Elizabeth R. Feldman, Xuebo Men, Cen Yan, Wendong Huang, Yingmei Feng, Feng Liu, Xuexian O. Yang, Meilian Liu
Monocytes play an important role in the regulation of alloimmune responses after heart transplantation (HTx). Recent studies have highlighted the importance of immunometabolism in the differentiation and function of myeloid cells. While the importance of glucose metabolism in monocyte differentiation and function has been reported, a role for fatty acid β-oxidation (FAO) has not been explored. Heterotopic HTx was performed using hearts from Balb/c donor mice implanted into C57Bl/6 recipient mice and treated with etomoxir (eto), an irreversible inhibitor of carnitine palmitoyltransferase 1 (Cpt1), a rate-limiting step of FAO, or vehicle control. FAO inhibition prolonged HTx survival, reduced early T cell infiltration/activation and reduced dendritic cell (DC) and macrophage infiltration to heart allografts of eto-treated recipients. ELISPOT demonstrated eto-treated HTx were less reactive to activated donor antigen presenting cells. FAO inhibition reduced monocyte-to-DC and monocyte-to-macrophage differentiation in vitro and in vivo. FAO inhibition did not alter the survival of heart allografts when transplanted into Ccr2-deficient recipients, suggesting the effects of FAO inhibition were dependent on monocyte mobilization. Finally, we confirmed the importance of FAO on monocyte differentiation in vivo using conditional deletion of Cpt1a. Our findings demonstrate that targeting FAO attenuates alloimmunity after HTx, in part through impairing monocyte differentiation.
Yuehui Zhu, Hao Dun, Li Ye, Yuriko Terada, Leah P. Shriver, Gary J. Patti, Daniel Kreisel, Andrew E. Gelman, Brian W. Wong
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