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Pancreatic alpha cells retain considerable plasticity and can – under the right circumstances – transdifferentiate into functionally mature beta cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used antimalarial drug artemether suppresses the alpha cell transcription factor Arx to promote transdifferentiation into beta cells. However, key initial experiments in this paper were carried out in islet cell lines and most subsequent validation experiments implied transdifferentiation without direct demonstration of alpha to beta cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary alpha cells into beta cells. Moreover, artemether reduces Ins2 expression in primary beta cells >100-fold, suppresses glucose uptake, and abrogates beta cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote alpha to beta cell transdifferentiation in treating diabetes.

“How do you deal with data manipulation and retractions?” Indicative of the nebulous nature of the issue, this is a question often posed to us in hushed tones, late at night at meetings or toward the end of a phone call. Though certainly not our favorite topic, due to the procedural complexities and inherent sadness involved, we would like to take a moment to shed some light on this type of retraction at Cell Metabolism.In simplified terms, retractions occur because the conclusions based on data presented in the paper cannot be relied upon anymore. Though still rare, the overall number of retractions has gone up in past years, contributing to the reproducibility concerns plaguing the biomedical community. However, it should be emphasized that not all retractions are due to data manipulation. At Cell Metabolism, papers are retracted if (1) there is proven scientific misconduct affecting the data presented, (2) the scope of corrections that would be needed is extensive, or (3) the changes needed would affect the conclusions of the paper. For the latter two retraction reasons, the mistakes might not be a consequence of fraud, falsification, or violation of ethical and publishing practices, but they are serious enough to shake the foundational conclusions.A common perception is that journals are reluctant to take action on reported concerns of data manipulation because months and sometimes years go by before anything happens. However, rather than being indicative of tergiversation on our part, the silence is due to the lengthy and confidential nature of the behind-the-scenes workings until the time we issue a retraction, if one is necessary. In order to start an investigation, we ask to be formally notified of concerns, usually in the form of an email, clearly detailing the issues at hand. Our current policy at Cell Metabolism is that the editors do not follow blog discussions on data manipulation because we cannot consistently and comprehensively monitor the ongoing discourse; also, our experience has been that it is difficult to ascertain the validity of many of the allegations—at face value, PowerPoint presentations showing blown-up images “with circles and arrows,” quoting Arlo Guthrie’s “Alice’s Restaurant,” invariably appear incriminating. In our opinion, to conclusively determine if there is an issue or not, one needs to see the raw data. Another point of contention that we wrestle with is that the majority of the notification emails are from anonymous “concerned readers.” We certainly understand the worry about backlash for a whistleblower, especially for a junior researcher, and have always respected the person’s wishes. However, there is a fine line between genuine reports and timewasters. Over the years, we have received our fair share of both serious and frivolous emails. Examples of the latter type include “Dr. X does not buffer their PBS appropriately; you can’t trust their data; you have to retract all their papers,” and “I saw Dr. Y present the data 4 years ago and they were different; clearly the authors are lying.” Our thought is that it is best to provide the journal with sufficient confidential information about the issue and context, and for the concerned reader to be available for follow-up questions from the editors.Fraudulent data fabrication and falsification can occur at various stages of the work—during data generation, analysis, and processing or during figure preparation. On the journal end, figures are usually the first problematic aspect that is detected. Is the western blot band A from Figure 1 the same as band B from Figure 6? Many bands look similar, but are they identical? We recently had a case at Cell Metabolism where the western blot bands in different experiments for different figures looked identical to all of us, including the authors, but after extensive analysis by a team of experts, the blots proved to be different. When a seemingly valid concern is raised, our first port of call is to ask the authors for the raw data, which raises another issue: how long can we reasonably expect authors to have access to the original data? Different institutions and funding bodies across the world have different statutes of limitations for data retention. Our current operating guideline at the journal is that, in most cases, 5–7 years is a reasonable time frame to expect authors to still have the data at hand. Based on the scope of the issues raised, we may also ask the authors to contact their institution’s office of research integrity, if they have not already done so, to review the concerns. Having the involvement of another reviewing body can add additional layers of complexity and delays, for example due to the type of confidentiality agreements that the institution may have. At the journal, we may wait to receive the official report of the investigation to alert the readers, although, depending on the circumstances, we may also proceed independently.In our experience, once it is determined that there are valid concerns surrounding a paper, most authors are willing to take the responsible course of action. Retractions are extremely distressing for all parties concerned—the authors, especially the ones who were not aware of the problem, the journal, and the community at large. They make us all pause and reflect. As scientists, we evaluate data with a skeptical eye, though our default is to trust that each other’s data have been generated in good faith. The underlying reasons for scientific misconduct are complex, and we all unwittingly play our part in the larger problem. At the journal, we are at the end of a chain of events, but we recognize that we can no longer just rely on the self-correcting nature of science and that effective collaboration with the community, funding bodies, and our publishing colleagues is needed to curb the real incidents of scientific misconduct.Our collective goal is to be more vigilant from submission to publication. At Cell Press, we screen the figures on accepted papers, although we fully appreciate that the lion’s share of scrutinizing the data falls on our reviewers, as experts in the field with first-hand knowledge of the type of data presented, to flag issues during peer review. We also often consult with statistical experts, especially for the Clinical and Translational Reports at Cell Metabolism. Reviewing is increasingly more challenging as science becomes more interdisciplinary and new technologies allow one to ask questions that we could not previously have tackled. As we approach “Reviewer Week,” we wanted to take this opportunity to recognize and thank our unsung heroes at Cell Metabolism, as well as at other journals, for the tremendous work they put in every day to ensure the rigor of published papers and maintain the credibility of the metabolism field. Every year we see thousands of papers, and we can honestly say that peer review works and that collaboration among authors, reviewers, and editors almost invariably results in stronger papers. Thank you, Reviewers, for the important work that you do.We hope that this Editorial has helped clarify what our current practices are regarding retractions at Cell Metabolism. As usual, please let us know if you have questions, feedback, or ideas for improving the journal and helping us better serve the community. We love hearing from you! Please continue to make the most of our monthly editorial office hours, email us, or catch us in person at meetings and lab visits.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This paper is being retracted because of concerns with Figures 2B and S3. In Figure S3, the SDS-PAGE gel image had molecular weight markers added from another autoradiograph and additional nonspecific bands obscured or removed. In the top panel of Figure 2, an actin Western blot was used instead of a GCK Western blot. This matter was investigated by the Medical Research Council (UK) under their Scientific Misconduct Policy and Procedures, and scientific misconduct pertaining to the issues described here against the first author Helen Freeman was found. Repetition of these experiments by other group members gave identical results to those shown in the paper. Nevertheless, although we feel that the scientific conclusions of the paper (that loss of NNT impairs insulin secretion and impairs glucose tolerance in C57BL/6J mice) still stand, given the conclusion of scientific misconduct against the first author, the authors think the most responsible course is to retract the paper. The authors sincerely apologize for the inconvenience caused by this retraction.

On April 25th, I received an email from Tae Jin Yun informing me that her PI, Cheolho Cheong, had passed away. This was not the first time that I had received such sad news, but this one felt very raw and painful. I did not know Cheolho personally but had been working closely with him for the previous few months on his Cell Metabolism paper (Yun et al., 2016, Cell Metabolism 23, 852–866). Despite the fact that I correspond with dozens of scientists every day, Cheolho stood out by his passion and enthusiasm for science. We talked extensively about his paper and his revision plans, experiments he was planning for the dendritic cell project, even those beyond the paper, and how he saw the field of atherosclerosis. He took the comments of the editors and reviewers to heart and worked hard at improving his paper. I was impressed by his reliability and his strong work ethics—he did not shy away from the hard path; in his own words, he liked “clear-cut evidences.” If he told me that he would get back to me about a specific piece of data within an hour, he actually would! In a world of chronic lateness, I appreciated that he was a man of his word. We also discussed science more broadly and his other projects, which intersected at least three different fields. It was obvious that he had a deep commitment to carrying on Ralph Steinman’s legacy and had an infectious passion for dendritic cells. I did not realize that anyone could love an immune cell type so much! Corresponding with Cheolho was inspiring, thought-provoking, and fun. When Tae Jin’s email came, I felt a tremendous sense of loss, and still do. I feel I was in the middle of several conversations with Cheolho that I will never finish. After his passing, I found out more about him from his colleagues and came to realize just how exceptional he was and what a tremendous loss this is for his friends, family, colleagues, and science.Among the many conversations my team and I had with Cheolho were his plans for a cover design. The authors of every accepted paper scheduled for an issue are invited to submit a cover design related to their paper. Cheolho was thinking of a play on the name of the enzyme he was investigating, Indoleamine 2,3-dioxygenase, IDO, and wanted to convey the synergy between plasmacytoid DCs (pDCs) and regulatory T cells (Tregs) to prevent atherosclerosis. He suggested a wedding ceremony between pDC and Treg as bride and groom exchanging their vows, standing on a heart-shaped floor to symbolize atherosclerosis and cardiovascular disease (Figure 1Figure 1).Figure 1Cheolho’s Initial Cover DraftView Large Image | View Hi-Res Image | Download PowerPoint SlideCheolho’s paper was scheduled to be published in the May issue, which had a gender focus. With his usual energy, he “proposed” two variations on the wedding theme. In the first one, Treg became a muscular super-heroine, akin to “Wonder Woman or She-Ra,” marrying an “ordinary man” (pDC) while “bad lipids run away” in fear (Figure 2Figure 2).Figure 2Cheolho’s Cover Image, Proposal OneArtwork by Yves Dumont.View Large Image | View Hi-Res Image | Download PowerPoint SlideFor the second cover proposal, he envisioned pDC still as an “ordinary man” in a tuxedo, saying “yes, IDO” while Treg, a “muscular firefighter woman,” extinguishes a fire, representing the lipid plaque (Figure 3Figure 3).Figure 3Cheolho’s Cover Image, Proposal TwoArtwork by Yves Dumont.View Large Image | View Hi-Res Image | Download PowerPoint SlideDespite a relatively short notice, he sent the final cover images to the journal office to be considered by the deadline. Again, with his distinctive attention to detail, he highlighted specific components of the images, such as which finger the wedding ring of Treg was placed on. Working with Cheolho on this cover image highlighted a different side of him to us—his sense of humor and his love for superheroes, to which his colleagues refer in the accompanying Obituary in this issue of Cell Metabolism. While writing this memoriam, I asked Gwen Randolph why Cheolho cast the pDC, his hero, as “an ordinary man,” and we shared some interesting speculations. “The funny thing,” she said, “is that his definition of an ordinary man is probably a superhero to us.” I thought it was a poignant metaphor for how Cheolho came across.Cell Metabolism would like to pay tribute to Cheolho’s dedication, passion, and enthusiasm; it was a privilege to work with him, and we feel his loss deeply. Our thoughts are with his family and friends.

In a recent paper in EMBO Molecular Medicine, Weis et al. reveal that cardiac endothelial cells can oxidize ketone bodies, which enhances cell proliferation, migration, and vessel sprouting. Furthermore, increasing ketone body levels with a ketogenic diet can increase endothelial cell proliferation and prevent blood vessel rarefication in hypertrophied mouse hearts. This suggests that increasing endothelial cell ketone oxidation has potential in treating heart failure.

Lactate released from skeletal muscle during high-intensity exercise gives rise to a surge in circulating lactate-derived pseudo-dipeptide metabolites including N-lactoyl-phenylalanine (Lac-Phe). In a recent Nature paper, Li et al. use genetic and pharmacological evidence to now propose Lac-Phe to be an "exercise hormone" that suppresses appetite and obesity.

Extracellular vesicles (EVs) and their cargo act as signaling moieties by transferring their cargo to recipient cells, thereby mediating intercellular communication in complex tissue environments such as the tumor microenvironment. In the accompanying paper, Kudo et al. describe the interaction between tumor EVs and soluble phospholipase released by macrophages, leading to the remodeling of EV membranes and the release of lipid mediators that facilitate tumor growth by inducing an immune-tolerant phenotype.

Animal models are invaluable resources for biomedical research, including research on the effects of diet on metabolism and disease. Usually, great care is taken to ensure comparable genetic backgrounds and environmental conditions when performing studies using animal models, since this minimizes introduction of variability that can confound detection of treatment-related phenotypic differences. However, many papers using animal models draw conclusions about dietary effects from comparisons of natural-ingredient chow with defined diets, despite marked differences in micro- and macronutrient content. When comparing the effects of a chow diet with a defined high-fat diet, the effects of the dietary fat will be confounded with the effects of other components in the diets. This issue is highlighted by a limited literature survey that was conducted to identify common problems in the use and reporting of rodent diets.All original research papers identified by the keywords “mouse high fat” published in 2007 in five high-impact journals were included in this evaluation. Of the 35 papers examined, only 14% (5 papers) compared diets using identical nutrients differing only in relative amounts of fat and carbohydrate (Figure 1Figure 1). Specific details regarding the dietary comparisons made were often lacking, and frequently conclusions were drawn from comparisons of defined high-fat diets to chow.Figure 1Diet Comparisons in Recent Research PapersPie chart showing the percentage of 35 original research papers evaluated that used appropriate diet comparisons (14%), that compared chow and defined high-fat diets (43%), and that presented insufficient information to evaluate diet comparisons (34%). In the “chow and defined” category (9%), both diet types were used but no direct comparison was made between them. The journals examined were Cell Metabolism (7 papers), Diabetes (the first 11 of 36 papers), The Journal of Clinical Investigation (12 papers), Nature (2 papers), and Nature Medicine (3 papers).View Large Image | View Hi-Res Image | Download PowerPoint SlideRegular chow is composed of agricultural byproducts such as ground wheat, corn, or oats, alfalfa and soybean meal, a protein source such as fish, and vegetable oil and is supplemented with minerals and vitamins. Thus, chow is a high-fiber diet containing complex carbohydrates, with fats from a variety of vegetable sources. Chow is inexpensive to manufacture and is palatable to rodents. In contrast, defined high-fat diets consist of amino acid-supplemented casein, corn starch, maltodextrose or sucrose, and soybean oil or lard, also supplemented with minerals and vitamins. Fiber is often provided by cellulose. Chow and defined diets may exert significant separate and independent unintended effects on the measured phenotypes in any research protocol.Two important differences between chow and defined diets are the phytoestrogen content from soy, which is high but variable in chow diets but absent from defined diets (reviewed in Thigpen et al., 2004xThigpen, J.E., Setchell, K.D., Saunders, H.E., Haseman, J.K., Grant, M.G., and Forsythe, D.B. ILAR J. 2004; 45: 401–416Crossref | PubMedSee all ReferencesThigpen et al., 2004), and from sucrose, which is used as a carbohydrate source in defined diets but is absent from chow. Dietary phytoestrogens influence food and water intake, anxiety-related behaviors, locomotor activity, learning and memory, fat deposition, blood insulin, leptin and thyroid levels, and lipogenesis and lipolysis in isolated rat adipocytes (Torre-Villalvazo et al., 2008xTorre-Villalvazo, I., Tovar, A.R., Ramos-Barragan, V.E., Cerbon-Cervantes, M.A., and Torres, N. J. Nutr. 2008; 138: 462–468PubMedSee all References, Lephart et al., 2004axLephart, E.D., Porter, J.P., Lund, T.D., Bu, L., Setchell, K.D., Ramoz, G., and Crowley, W.R. Nutr. Metab. (Lond). 2004; 1: 16Crossref | PubMed | Scopus (34)See all References; reviewed in Lephart et al., 2004bxLephart, E.D., Setchell, K.D., Handa, R.J., and Lund, T.D. ILAR J. 2004; 45: 443–454Crossref | PubMedSee all ReferencesLephart et al., 2004b). Sucrose is 50% fructose, and there is abundant evidence that fructose can exacerbate weight gain and contribute to insulin resistance and dyslipidemia (reviewed in Stanhope and Havel, 2008xStanhope, K.L. and Havel, P.J. Curr. Opin. Lipidol. 2008; 19: 16–24Crossref | PubMed | Scopus (121)See all ReferencesStanhope and Havel, 2008). Other effects that differ between chow and defined diets and may be related to either phytoestrogen or fructose content include bone-related changes, plasma estradiol, urinary calcium and corticosterone (Tou et al., 2005xTou, J.C., Arnaud, S.B., Grindeland, R., and Wade, C. Exp. Biol. Med. (Maywood). 2005; 230: 31–39PubMedSee all ReferencesTou et al., 2005), and solution taste preferences (Tordoff et al., 2002xTordoff, M.G., Pilchak, D.M., Williams, J.A., McDaniel, A.H., and Bachmanov, A.A. J. Nutr. 2002; 132: 2288–2297PubMedSee all ReferencesTordoff et al., 2002).When comparing the effects of chow with a defined high-fat diet, the effects of the dietary fat will be confounded with the effects of other components that differ between the diets. Just as it is essential that mouse strains be specified, constituents of experimental diets must be specified (Thigpen et al., 2004xThigpen, J.E., Setchell, K.D., Saunders, H.E., Haseman, J.K., Grant, M.G., and Forsythe, D.B. ILAR J. 2004; 45: 401–416Crossref | PubMedSee all References, Tordoff et al., 1999xTordoff, M.G., Bachmanov, A.A., Friedman, M.I., and Beauchamp, G.K. Science. 1999; 285: 2069PubMedSee all References, Everitt and Foster, 2004xEveritt, J.I. and Foster, P.M. ILAR J. 2004; 45: 417–424Crossref | PubMedSee all References). Specifics to be considered are the objectives of the study and whether the endpoints are affected by several diet components, the maintenance diet, or the palatability of the diet (Thigpen et al., 2004xThigpen, J.E., Setchell, K.D., Saunders, H.E., Haseman, J.K., Grant, M.G., and Forsythe, D.B. ILAR J. 2004; 45: 401–416Crossref | PubMedSee all ReferencesThigpen et al., 2004). Although this correspondence focuses on high-fat diet comparisons, these issues are applicable to any specific nutrient comparisons.

An integrated immunometabolic response during negative energy balance is required for host survival. Three new papers by Jordan et al. (2019), Nagai et al. (2019), and Collins et al. (2019) report that monocytes, naive B cells, and memory CD8 T cells use bone marrow as a haven to tide off periods of metabolic adversity to maintain immune-responsiveness.

In a new paper, Wade et al. (2021) analyzed the frequency of MC4R loss-of-function (LoF) mutations in a population-based Avon Longitudinal Study of Parents and Children. The frequency was 1 in 337 and the authors showed that MC4R LoF variants significantly correlated with increased body weight and fat mass in children and adults (cumulating in additional 17.76 kg weight in adulthood). Hence, the authors provide evidence that MC4R LoF variants are more common than previously expected.

Glycolysis supports effector T cell function but is detrimental to the immunosuppressive activity of regulatory T cells. In a recent issue of Nature, two papers address a role for glucose and lactate availability within the tumor microenvironment for the balance of pro- and anti-tumoral effects of T cells and the efficacy of neoadjuvant cancer immunotherapy.

Compelling evidence indicates that tumors may evade immunosurveillance by subverting the metabolism of immune cells. In a recent paper in Nature, Song et al. (2018) demonstrate that ovarian cancers activate IRE1α-XBP1 signaling within CD4+ T lymphocytes, thereby disrupting their bioenergetic function and contribution to anticancer immune responses.

Cancer cells frequently hijack normal metabolic pathways to promote their growth and metastasis. Two recent papers by Knott et al. (2018) and Pavlova et al. (2018) demonstrate that asparagine and glutamine work in concert to drive tumor growth and metastasis through modulation of cell survival, growth, and EMT regulatory pathways.

It has been more than a dozen years since FGF21 burst on the metabolism field in a paper showing that its pharmacologic administration caused weight loss and improved insulin sensitivity and lipoprotein profiles in obese rodents. Since then, FGF21 analogs have advanced all the way to clinical trials, and much progress has been made in understanding FGF21's pharmacology and physiology. In this Perspective, we highlight some of the interesting themes that have emerged from this first dozen years of FGF21 research, including its roles in autocrine/paracrine and endocrine responses to metabolic stress.

High abundance of brown adipose tissue (BAT) is linked to lower glycaemia in humans, leading to the belief that BAT may protect against diabetes. The relationship between BAT glucose utilization and systemic glucose homeostasis has not been defined. In this paper we have characterized glycaemic excursions and BAT thermogenic responses in human brown adipocytes, BAT explants, and healthy adults through supraclavicular temperature profiling, revealing their circadian coupling in vivo and in vitro, orchestrated by UCP1, GLUT4, and Rev-erbα biorhythms. Extent of glycated haemoglobin also correlated positively with environmental temperature among community-dwelling patients. These data uncover potential crosstalk between BAT and glucose regulatory pathways, evident on cellular, tissue, individual, and population levels, and provide impetus to search for BAT harnessing strategies for therapeutic purposes.

SummaryExercise provides many health benefits, including improved metabolism, cardiovascular health, and cognition. We have shown previously that FNDC5, a type I transmembrane protein, and its circulating form, irisin, convey some of these benefits in mice. However, recent reports questioned the existence of circulating human irisin both because human FNDC5 has a non-canonical ATA translation start and because of claims that many human irisin antibodies used in commercial ELISA kits lack required specificity. In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. This precise state-of-the-art method shows that human irisin is mainly translated from its non-canonical start codon and circulates at ∼3.6 ng/ml in sedentary individuals; this level is increased to ∼4.3 ng/ml in individuals undergoing aerobic interval training. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise.

Summary Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo., Graphical Abstract, Highlights • Mice with controlled Opa1 overexpression are viable and grow normally • Opa1 protects from muscular atrophy, heart and brain ischemia, and liver apoptosis • Opa1 reduces ROS production and cytochrome c release • Opa1-controlled cristae remodeling is a targetable component of tissue damage, Varanita et al. show that a mouse model of controlled overexpression of the master mitochondrial cristae biogenetic factor Opa1 resists skeletal muscle atrophy, heart and brain ischemic damage, and massive liver apoptosis by blunting mitochondrial dysfunction and cytochrome c release. Together with the accompanying paper by Civiletto et al., the authors offer a proof of principle of the potential for therapies targeting cristae remodeling in sporadic and genetic diseases.

Glycolysis is prudently regulated and coupled to cell growth. Phosphofructokinase 2 controls glycolytic flux by generating fructose 2,6-bisphosphate, an allosteric activator of phosphofructokinase 1. In a recent paper in Nature, Dasgupta et al. address the novel role of PFKFB4, an isoform of phosphofructokinase 2, in regulating gene expression to promote tumor growth.

The pancreatic islet β cell senses circulating levels of calorigenic nutrients to secrete insulin according to the needs of the organism. Altered insulin secretion is linked to various disorders such as diabetes, hypoglycemic states, and cardiometabolic diseases. Fuel stimuli, including glucose, free fatty acids, and amino acids, promote insulin granule exocytosis primarily via their metabolism in β cells and the production of key signaling metabolites. This paper reviews our current knowledge of the pathways involved in both positive and negative metabolic signaling for insulin secretion and assesses the role of established and candidate metabolic coupling factors, keeping recent developments in focus.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.We, the authors, wish to retract “Decoupling Ferritin Synthesis from Free Cytosolic Iron Results in Ferritin Secretion” by De Domenico et al. (Cell Metab., 13 (2011) 57–67, http://dx.doi.org/10.1016/j.cmet.2010.12.003 and “The Role of Ubiquitination in Hepcidin-Independent and Hepcidin-Dependent Degradation of Ferroportin” by De Domenico et al. (Cell Metab., 14 (2011) 635–646, http://dx.doi.org/10.1016/j.cmet.2011.09.008) because a number of errors have been detected in the assembly of the figures, and some of the original data were inappropriately removed from the laboratory. We stand by the validity of our studies; the data are reproducible, and the conclusions were not affected by the errors. However, we believe that the most responsible course of action is to retract the paper. We are preparing a new expanded version of this study for future submission. We deeply apologize to the community for the inconvenience.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Authors.We, the authors, wish to retract “Decoupling Ferritin Synthesis from Free Cytosolic Iron Results in Ferritin Secretion” by De Domenico et al. (Cell Metab., 13 (2011) 57–67, http://dx.doi.org/10.1016/j.cmet.2010.12.003 and “The Role of Ubiquitination in Hepcidin-Independent and Hepcidin-Dependent Degradation of Ferroportin” by De Domenico et al. (Cell Metab., 14 (2011) 635–646, http://dx.doi.org/10.1016/j.cmet.2011.09.008) because a number of errors have been detected in the assembly of the figures, and some of the original data were inappropriately removed from the laboratory. We stand by the validity of our studies; the data are reproducible, and the conclusions were not affected by the errors. However, we believe that the most responsible course of action is to retract the paper. We are preparing a new expanded version of this study for future submission. We deeply apologize to the community for the inconvenience.

The adult skeleton is constantly renewed through bone remodeling. Four recent papers (Baldock et al., 2007; Lee et al., 2007; Lundberg et al., 2007; Sato et al., 2007) provide new insights into central and peripheral control of this remodeling sequence. Two of the studies add to our knowledge of the complex hypothalamic modulation of bone turnover mediated by NMU and NPY via the sympathetic nervous system, while the other two focus on the peripheral neural target, the osteoblast, and its regulation by neuropeptides and osteocalcin. These findings support a new paradigm concerning the regulation of bone remodeling and provide a foundation for novel approaches to preventing osteoporosis.

Bone loss after menopause or gonadectomy has been attributed to the drop in estrogen levels. A recent paper (Sun et al., 2006) challenges this view by showing that the pituitary hormone FSH, previously thought to target only the gonads, also acts on osteoclasts to activate bone resorption. In conjunction with genetic studies, these data raise the possibility that FSH, independent of estrogen, causes hypogonadal bone loss.

SummaryThis paper describes a convergent mechanism for the feedback control of cholesterol synthesis and uptake mediated by SREBPs, membrane bound transcription factors. Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. In sterol-overloaded cells, Scap/SREBP binds to Insig-1, which retains the complex in the ER. Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes. Scap/SREBP moves to the Golgi, where SREBP is processed to liberate a nuclear fragment that activates genes for cholesterol synthesis and uptake and the gene for Insig-1. Ubiquitination is not necessary for release of Scap/SREBP from Insig-1, but it establishes a requirement for synthesis of new Insig-1 for feedback inhibition. When the new Insig-1 and cholesterol converge on Scap, Scap/SREBP binds to Insig-1, preventing ubiquitination. The Insig-1/Scap/SREBP complex accumulates in the ER, ready for liberation when the cell is again sterol deprived.

GDF11 was reported to decline with age and to have muscle and heart rejuvenating effects. These reports were disputed. A Cell Metabolism paper now shows that in human beings, GDF11 does not decline with age and is actually a risk factor for frailty and other morbidities (Schafer et al., 2016).

There is great interest in discovering targets for in vitro manipulation of autologous T cells that enhance their cytotoxicity against tumor targets as a potent cancer immunotherapy. In a recent Nature paper, Xu and colleagues reveal new insights into the link between cellular cholesterol metabolism and CD8 T cell functions.

An understanding of the full powers of brown adipose tissue (BAT) is only successively being accumulated. In a paper in Nature Medicine, Bartelt et al. (2011) add further impressive aspects to the potential powers of BAT in the combat against the metabolic syndrome by demonstrating its vast capacity for triglyceride clearance and glucose disposal.

Both intrauterine and postnatal environments contribute to diabetes risk. A recent paper highlights epigenetic mechanisms underlying beta cell dysfunction associated with intrauterine growth retardation, including repressive histone modification and DNA methylation during postnatal life. Thus, intrauterine stress can initiate a disturbing epigenetic cascade of progressive transcriptional repression linked to beta cell failure.

The neuropeptide AgRP promotes food intake and weight gain by antagonizing signaling at melanocortin 3 and 4 receptors in the brain, but the limited phenotype of mice lacking AgRP raised questions about its importance. Four recent studies addressed this by creating mice in which AgRP neurons, which also express NPY and GABA, are ablated postnatally, and although details vary, they suggest that AgRP neurons are more essential to feeding and weight gain than is AgRP itself. A recent paper in Cell Metabolism (Wortley et al., 2005) indicates that AgRP itself is important for feeding and weight gain, but only as mice age, and the mechanism may involve dysfunction of the thyroid axis.

Human genetics is revealing ever more variants that influence propensity to common diseases, but progress in translating these discoveries into the biological mechanisms responsible for predisposition continues to lag behind. A recent paper in Cell (Boj et al., 2012) using rodent models to examine how diabetes-associated variants near TCF7L2 perturb metabolic regulation provides surprising results.

Gerlic et al. contacted us a few months ago regarding the concerns expressed in the accompanying letter. We have communicated with them about their observations relative to conclusions from our original paper (Im et al., 2011) and for the field moving forward. Based on their data, we performed a separate DNA sequence analysis of the Nlrp1a locus in our SREBP-1a-deficient (SREBP-1aDF) mice and confirmed that it is derived from the 129 strain. However, the issues raised by this observation are almost certainly more complicated than the tight linkage between the Srebf1 and Nlrp1a loci and the extent of backcrossing.

We are pleased to present in this issue of Cell Metabolism a review series on brown adipocytes. Until recently, brown adipose tissue (BAT) was principally studied by a handful of investigators focused on rodents and newborn mammals, and, at times, their work was deemed more an exercise in scientific curiosity than an issue relevant to human health. In April of last year, this perception changed with the appearance of three papers in the New England Journal of Medicine that concretized the notion that a number of radiologists had previously suspected: Adults have brown adipocytes, and this population expands in response to cold. Brown adipocytes are involved in thermogenesis, a process of regulated energy dissipation, which, through mitochondrial uncoupling (chiefly involving Ucp1), keeps the animal warm. The demonstration that BAT is a physiologically relevant tissue in humans brings new interest in its role in metabolism and opens up for debate the possibility of harnessing its properties to combat obesity.So what are brown adipocytes, what do we already know about them, what key issues remain to be addressed, and what are the challenges to exploiting BAT therapeutically? In this special Brown Adipocyte Focus, we offer five Minireviews to get the ball rolling on these discussions. Sven Enerback reviews the recent evidence for BAT in humans and discusses how the application of new technologies will enable further noninvasive investigation of human BAT. Saverio Cinti and Andrea Frontini next address the plasticity of adipocytes and discuss white-to-brown and brown-to-white adipocyte transdifferentiation within the adipose tissue depot, and the concomitant tissue reorganization to accommodate the new cells. Whether the “browning” of white adipocytes within the adipose tissue depot is a result of dedifferentiation or selection of stem cells or committed precursors will be a fascinating area for further investigation. Bruce Spiegelman and colleagues pick up the discussion reviewing the key transcriptional regulators of brown fat development and outline exciting new data showing that brown adipocytes are developmentally closer to muscle tissue than white adipocytes. Leslie Kozak brings up whether we can realistically expect brown adipocytes to burn off excess dietary calories in order to maintain body weight under normal conditions. Jan Nedergaard and Barbara Cannon complete this series by underscoring the importance of physiological UCP1 activation to render brown adipocytes functional and advance a number of provocative hypotheses concerning the decrease of BAT with age and ways BAT could be involved in maintaining euglycemia.Each of these Minireviews brings a unique perspective on BAT, and we sincerely hope that you will enjoy reading them, as you continue thinking about this intriguing cell type. No doubt the coming years will bring forth a wealth of information about the roles of BAT in physiology and metabolic disease; we look forward to these developments.

Proopiomelanocortin (Pomc) neurons play a central role in energy homeostasis. Despite the complexity of Pomc posttranslational processing, regulation of Pomc gene expression often takes center stage. Complementary papers that zero in on distinct carboxypeptidases (Plum et al., 2009; Wallingford et al., 2009) now refocus the spotlight on regulated peptide cleavage.

Dear Editor,We would like to address the comments by Zammit and Arduini about their alternative perspective on our recently published paper in Cell Metabolism (Lopez et al., 2008xLopez, M., Lage, R., Saha, A.K., Perez-Tilve, D., Vazquez, M.J., Varela, L., Sangiao-Alvarellos, S., Tovar, S., Raghay, K., Rodriguez-Cuenca, S. et al. Cell Metab. 2008; 7: 389–399Abstract | Full Text | Full Text PDF | PubMed | Scopus (252)See all ReferencesLopez et al., 2008). We consider their suggestion about FAS downregulation an interesting and attractive hypothesis, but we are not that sure it could be directly implied from our results. If this was indeed the case, then it would be expected recovery of [malonyl-CoA] to normal values independently of the fasting time. Our data do not support this, since hypothalamic [malonyl-CoA] is not totally recovered in 48 hr refed rats previously fasted by 48 hr, despite the fact that fasting-induced hyperphagia is restored to normal feeding (Lopez et al., 2006xLopez, M., Lelliott, C.J., Tovar, S., Kimber, W., Gallego, R., Virtue, S., Blount, M., Vazquez, M.J., Finer, N., Powles, T. et al. Diabetes. 2006; 55: 1327–1336Crossref | PubMed | Scopus (110)See all ReferencesLopez et al., 2006). In our opinion it is more likely that the downregulation of FAS expression observed during fasting or ghrelin treatment acts as an adaptive mechanism that prevents excessive reduction of [malonyl-CoA] secondary to fasting-induced inactivation of ACC by AMPK. Supporting this concept are our data showing that the reduction in FAS levels is not further decreased by prolonged fasting over a period of 48 hr (Lopez et al., 2006xLopez, M., Lelliott, C.J., Tovar, S., Kimber, W., Gallego, R., Virtue, S., Blount, M., Vazquez, M.J., Finer, N., Powles, T. et al. Diabetes. 2006; 55: 1327–1336Crossref | PubMed | Scopus (110)See all ReferencesLopez et al., 2006). This suggests a tightly controlled low FAS threshold in hypothalamic neurons. Since malonyl-CoA plays a critical regulatory role in this system by acting both as a substrate for fatty acid biosynthesis and an inhibitor of CPT1 (Obici et al., 2003xObici, S., Feng, Z., Arduini, A., Conti, R., and Rossetti, L. Nat. Med. 2003; 9: 756–761Crossref | PubMed | Scopus (338)See all References, Wolfgang et al., 2006xWolfgang, M.J., Kurama, T., Dai, Y., Suwa, A., Asaumi, M., Matsumoto, S., Cha, S.H., Shimokawa, T., and Lane, M.D. Proc. Natl. Acad. Sci. USA. 2006; 103: 7282–7287Crossref | PubMed | Scopus (127)See all References, Lopez et al., 2008xLopez, M., Lage, R., Saha, A.K., Perez-Tilve, D., Vazquez, M.J., Varela, L., Sangiao-Alvarellos, S., Tovar, S., Raghay, K., Rodriguez-Cuenca, S. et al. Cell Metab. 2008; 7: 389–399Abstract | Full Text | Full Text PDF | PubMed | Scopus (252)See all References), we hypothesized that extremely low levels of [malonyl-CoA] may compromise neuronal viability, by preventing lipid biosynthesis and by allowing potentially harmful neuronal fatty acid oxidation during fasting, a situation of low energy surplus.With respect to the CPT1 effects on feeding, we showed that ghrelin increases hypothalamic CPT1 activity. To determine whether the effect of ghrelin on food intake involved the activation of CPT1, we investigated the effect on ghrelin's orexigenic action of etomoxir (10 μg), an inhibitor of CPT1. Using this selected dose, we were able to show that while etomoxir rapidly inhibited hypothalamic CPT1 activity, short-term feeding (2, 4, and 6 hr) was not affected; etomoxir exerted its anorectic effect 12 hr after administration (unpublished data). It is likely that by using a higher dose of etomoxir, we would have observed a faster anorectic action; however, the rationale of using the dose selected was to show that opposite effects of this drug and ghrelin occurred through the same downstream pathway.We assayed [malonyl-CoA] and CPT1 activity from whole hypothalamic samples and using similar dilutions; thus, an infinitesimal dilution of [malonyl-CoA] was unlikely. Supporting these data, we have recently obtained new results showing that under other experimental settings, our assays show a perfect [malonyl-CoA]:CPT1 activity correlation (unpublished data). We agree that our method is not specific for CPT1c. However, our interest in CPT1c stemmed from the recent evidence demonstrating that CPT1cKO mice have decreased feeding and body weight (Wolfgang et al., 2006xWolfgang, M.J., Kurama, T., Dai, Y., Suwa, A., Asaumi, M., Matsumoto, S., Cha, S.H., Shimokawa, T., and Lane, M.D. Proc. Natl. Acad. Sci. USA. 2006; 103: 7282–7287Crossref | PubMed | Scopus (127)See all ReferencesWolfgang et al., 2006). We also have data showing that CPT1a or CPT1b expression does not change after ghrelin treatment at any time evaluated (unpublished data). Specific activity assays for each CPT1 isoform, ideally associated to laser-capture microdissection of hypothalamic nuclei, will be required to better characterize the hypothalamic malonyl-CoA-CPT1 axis.

Exercise leads to changes in muscle phenotype with important implications for exercise performance and health. A recent paper in Cell by Narkar et al. (2008) shows that many of the adaptations in muscle phenotype elicited by exercise can be mimicked by genetic manipulation and drug treatment in mice.

Animal studies have revealed brain regions that control homeostatic feeding, but the rampant overeating contributing to the obesity epidemic suggests the participation of "nonhomeostatic" control centers. Recent papers by Batterham et al. (2007) and Farooqi et al. (2007) link peptide YY 3–36 and leptin to the activation of nonhomeostatic brain regions.

Scientific reproducibility in biological sciences has recently moved front and center, and at its heart lies experimental replication. The mounting number of sensational reports of irreproducibility and the dramatic estimates of ensuing economic burden that have been making headlines are an embarrassment to us all, even if the reports likely represent a small subset of papers. Ensuring reproducibility is the responsibility of all stakeholders, and steps are already being taken at several levels, starting in the lab, with carefully validated reagents, experimental conditions, and protocols, all the way to post-publication vetting to ensure that the data we produce and publish are sound.

The CNS melanocortin pathway plays an important role in the control of body weight. Two papers in this issue of Cell Metabolism, Lee et al., 2006 and Biebermann et al., 2006, suggest that beta MSH--a product of POMC processing--plays an unanticipated role in this pathway in humans.

The secondary complications of diabetes are the major factors limiting quality of life and longevity in diabetic patients. Among these complications, cardiovascular disease is the major cause of morbidity and mortality. Based on a recent paper by Vikramadithyan et al. (2005), this preview addresses the role of aldose reductase as a contributor to the pathogenesis of diabetic macrovascular disease.

SummaryThe endogenous lipid signaling agent oleoylethanolamide (OEA) has recently been described as a peripherally acting agent that reduces food intake and body weight gain in rat feeding models. This paper presents evidence that OEA is an endogenous ligand of the orphan receptor GPR119, a G protein-coupled receptor (GPCR) expressed predominantly in the human and rodent pancreas and gastrointestinal tract and also in rodent brain, suggesting that the reported effects of OEA on food intake may be mediated, at least in part, via the GPR119 receptor. Furthermore, we have used the recombinant receptor to discover novel selective small-molecule GPR119 agonists, typified by PSN632408, which suppress food intake in rats and reduce body weight gain and white adipose tissue deposition upon subchronic oral administration to high-fat-fed rats. GPR119 therefore represents a novel and attractive potential target for the therapy of obesity and related metabolic disorders.

The search for eternal youth is as old as mankind. In a recent Nature paper, Boon et al find that miR34 and its mRNA target PNUTS mediate DNA damage repair and provoke cardiac senescence. Interrupting the miR-34a/PNUTS pathway promises to favorably modify age- and stress-induced cardiac degeneration[AG1] (Boon et al., 2013). “Middle age ends and senescence begins, the day your descendants outnumber your friends.” Ogden Nash. “It’s not the years, Honey, it’s the mileage.” Indiana Jones from Raiders of the Lost Ark.

Metformin, developed from an ancient herbal remedy, remains the front-line drug for treatment of type 2 diabetes. Several targets to account for its therapeutic effects have been proposed, but a recent paper suggests a novel mechanism in which it antagonizes the cyclic AMP-dependent effects of glucagon on hepatic glucose production.

Elevated levels of circulating lipids are the major cause of cardiovascular disease, but beneficial outcomes might be realized by targeting lipid carriers. Two papers in this issue of Cell Metabolism (So et al., 2012; Wang et al., 2012) demonstrate how modulation of one arm of the unfolded protein response can decrease plasma levels of VLDL particles and their associated lipids.

Exercise exerts beneficial effects on systemic metabolism. A recent Nature paper (Boström et al., 2012) identifies irisin as an exercise-induced hormone secreted by skeletal muscle in mice and humans. Irisin promotes brown adipocyte recruitment in white fat and improves systemic metabolism by increasing energy expenditure.

The unfolded protein response (UPR) coordinates translational and transcriptional changes triggered by unfolded proteins within the endoplasmic reticulum. Two recent papers (Oliveira et al., 2009; Vecchi et al., 2009) show that the UPR modulates transcription of the hormone hepcidin, which controls plasma iron levels and perhaps innate immunity.

AMP-activated protein kinase (AMPK) has attracted much attention for its key role in energy homeostasis. Three new papers providing structural information on mammalian and yeast AMPK homologs give insights into the binding of the regulatory nucleotides AMP and ATP and how mutations are associated with cardiac glycogen storage disorders.

Essential nutrients enter the body through a variety of specific transporter molecules expressed in the intestinal epithelium. A recent paper by Qiu et al. (2006) elegantly demonstrates that one of these transporters, previously thought to carry heme, is in fact an important folate transporter.

Adiponectin, an adipocyte secretory hormone, has been causally linked to insulin resistance in the metabolic syndrome and diabetes. A recent paper (Mao et al., 2006) shows that the APPL1 adaptor protein binds to the intracellular domain of adiponectin receptors and mediates some of adiponectin's actions, identifying a novel mechanism linking adiponectin to insulin sensitization.

The role of reactive oxygen species (ROS) in the cellular response to cellular oxygen sensing has been controversial. Three papers in this issue of Cell Metabolism (Brunelle et al., 2005; Guzy et al., 2005; Mansfield et al., 2005) used genetic tools to establish that ROS produced by mitochondria are required for the normal induction of HIF (hypoxia-inducible factor), which is a master regulator of oxygen-sensitive gene expression, by low oxygen.

Stress-activated kinases control metabolism by antagonizing the early steps of insulin signal transduction. Two papers now demonstrate that Jnk, the prototypical stress-activated kinase, controls life span in Drosophila and C. elegans by promoting phosphorylation of the forkhead protein FoxO (Oh et al., 2005; Wang et al., 2005). The findings provide yet another mechanism by which metabolic and stress responses are integrated via phosphorylation of FoxO proteins.