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1.  Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins 
Cells have evolved a highly integrated network of mechanisms to coordinate cellular survival/death, proliferation, differentiation, and repair with metabolic states. It is, therefore, not surprising that proteins with canonical roles in cell death/survival also modulate nutrient and energy metabolism and vice versa. The finding that many BCL-2 (B cell lymphoma 2) proteins reside at mitochondria or can translocate to this organelle has long motivated investigation into their involvement in normal mitochondrial physiology and metabolism. These endeavors have led to the discovery of homeostatic roles for BCL-2 proteins beyond apoptosis. Here, we predominantly focus on recent findings that link select BCL-2 proteins to carbon substrate utilization at the level of mitochondrial fuel choice, electron transport, and metabolite import independent of their cell death regulatory function.
doi:10.1016/j.tem.2015.02.004
PMCID: PMC4380665  PMID: 25748272
BCL-2 proteins; mitochondria; OXPHOS; glucose; fatty acids; metabolism
2.  Emerging Roles of GPER in Diabetes and Atherosclerosis 
G protein-coupled estrogen receptor (GPER) is a 7-transmembrane receptor implicated in rapid estrogen signaling. Originally cloned from vascular endothelial cells, GPER plays a central role in the regulation of vascular tone and cell growth, as well as lipid and glucose homeostasis. This review highlights our knowledge of the physiological and pathophysiological functions of GPER in the pancreas, peripheral and immune tissues, and the arterial vasculature. Recent findings of its roles in obesity, diabetes, and atherosclerosis, including the GPER-dependent regulation of lipid metabolism and inflammation, are presented. The therapeutic potential of targeting GPER-dependent pathways in chronic diseases such as coronary artery disease and diabetes and in the context of menopause is also discussed.
doi:10.1016/j.tem.2015.02.003
PMCID: PMC4731095  PMID: 25767029
atherosclerosis; diabetes; estrogen receptor; rapid signaling; GPER
3.  Obesity Impairs the Action of the Neuroendocrine Ghrelin System 
Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight gain and glucose intolerance on a high calorie diet, there is little information about the metabolic actions of ghrelin in the obese state. In this review, we discuss the novel concept of obesity-induced central ghrelin resistance in neural circuits regulating behavior, and impaired ghrelin secretion from the stomach. Interestingly, weight loss restores ghrelin secretion and function, and we hypothesize that ghrelin resistance is a mechanism designed to protect a higher body weight set-point established during times of food availability, to maximize energy reserves during a time of food scarcity.
doi:10.1016/j.tem.2015.09.010
PMCID: PMC4814209  PMID: 26542050
4.  Functional Genomics of PCOS: From GWAS to Molecular Mechanisms 
Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. PCOS has a strong heritable component based on familial clustering and twin studies. Genome-wide association studies (GWAS) identified several PCOS candidate loci including, DENND1A, LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3. Here, we review the functional roles of strong PCOS candidate loci focusing on FSHR, LHCGR, INSR and DENND1A. We propose that these candidates comprise a hierarchical signaling network by which DENND1A, LHCGR, INSR, RAB5B, adapter proteins, and associated downstream signaling cascades converge to regulate theca cell androgen biosynthesis. Future elucidation of the functional gene networks predicted by the PCOS GWAS will result in new diagnostic and therapeutic approaches for women with PCOS.
doi:10.1016/j.tem.2014.12.004
PMCID: PMC4346470  PMID: 25600292
PCOS; hyperandrogenism; theca; genomics; GWAS; signaling
5.  Adipocytokines and Hepatic Fibrosis 
Obesity and metabolic syndrome pose significant risk for progression of many types of chronic illnesses, including liver disease. Hormones released from adipocytes, adipocytokines, associated with obesity and metabolic syndrome, have been shown to control hepatic inflammation and fibrosis. Hepatic fibrosis is the final common pathway that can result in cirrhosis, and can ultimately require liver transplantation. Initially, two key adipocytokines, leptin and adiponectin, appeared to control many fundamental aspects of the cell and molecular biology related to hepatic fibrosis and its resolution. Leptin appears to act as a profibrogenic molecule while adiponectin possesses strong-anti-fibrotic properties. In this review, we emphasize pertinent data associated with these, and recently discovered, adipocytokines that may drive or halt the fibrogenic response in the liver.
doi:10.1016/j.tem.2015.01.002
PMCID: PMC4718075  PMID: 25656826
Adiponectin; leptin; liver fibrosis; adipocytokines; hepatic stellate cells
6.  Iron homeostasis: a new job for macrophages in adipose tissue? 
Elevated serum ferritin and increased cellular iron concentrations are risk factors for diabetes; however, the etiology of this association is unclear. Metabolic tissues such as pancreas, liver, and adipose tissue (AT), as well as the immune cells resident in these tissues, may be involved. Recent studies demonstrate that the polarization status of macrophages has important relevance to their iron handling capabilities. Furthermore, a subset of macrophages in AT have elevated iron concentrations and a gene expression profile indicative of iron handling, a capacity diminished in obesity. Because iron overload in adipocytes increases systemic insulin resistance, iron handling by AT macrophages may have relevance not only to adipocyte iron stores but also to local and systemic insulin sensitivity.
doi:10.1016/j.tem.2014.12.005
PMCID: PMC4315734  PMID: 25600948
iron; adipose tissue; inflammation; macrophage
7.  Lymphocyte roles in metabolic dysfunction: of men and mice 
Type 2 diabetes (T2D) is a metabolic disease associated with obesity-related insulin resistance (IR) and chronic inflammation. Animal studies indicate IR can be caused and/or exacerbated by systemic/tissue-specific alterations in lymphocyte differentiation and function. Human studies also indicate obesity and/or inflammation promotes IR. Nevertheless, clinical trials with anti-inflammatory therapies have yielded modest impacts on established T2D. Unlike mouse models where obesity is predominantly associated with IR, 20–25% of obese people are metabolically healthy with high insulin sensitivity. The uncoupling of obesity from IR in humans but not in animal models advocates for a more comprehensive understanding of mediators/mechanisms in human obesity-promoted IR, and better integration of knowledge from human studies into animal experiments to efficiently pursue T2D prevention and treatment.
doi:10.1016/j.tem.2014.12.001
PMCID: PMC4315738  PMID: 25573740
insulin resistance; type 2 diabetes; obesity; lymphocyte subsets
8.  Power2: The power of yeast genetics applied to the powerhouse of the cell 
The budding yeast Saccharomyces cerevisiae has served as a remarkable model organism for numerous seminal discoveries in biology. This paradigm extends to the mitochondria, a central hub for cellular metabolism, where studies in yeast have helped reinvigorate the field and launch an exciting new era in mitochondrial biology. Here, we discuss few recent examples in which yeast research has laid a foundation for our understanding of evolutionarily conserved mitochondrial processes and functions; from the key factors and pathways involved in the assembly of the OXPHOS complexes, to metabolite transport, lipid metabolism, and interorganelle communication. We also highlight new areas of yeast mitochondrial biology that will likely aid in our understanding of mitochondrial etiology of disease in the years to come.
doi:10.1016/j.tem.2014.12.002
PMCID: PMC4315768  PMID: 25591985
Yeast; Mitochondria; oxidative phosphorylation; transporters; lipid metabolism; interorganelle communication
9.  When Less is More: Novel Mechanisms of Iron Conservation 
Disorders of iron homeostasis are very common, yet the molecular mechanisms of iron regulation remain understudied. Over 20 years have passed since the first characterization of iron regulatory proteins (IRP) as mediators of cellular iron deficiency response in mammals through iron acquisition. However, little is known about other mechanisms necessary for adaptation to low-iron states. In this review we present recent evidence that establishes existence of a new iron regulatory pathway aimed at iron conservation and optimization of iron use through suppression of non-essential iron-consuming processes. Moreover, we discuss the possible links between iron homeostasis and energy metabolism uncovered by studies of iron deficiency response.
doi:10.1016/j.tem.2013.07.003
PMCID: PMC4720524  PMID: 23948590
iron deficiency; metabolism; diabetes; tristetraprolin; Cth1/2
10.  Tissue-specific Actions of the Metabolic Hormones FGF15/19 and FGF21 
Fibroblast growth factors (FGFs) 15/19 and 21 belong to a subfamily of FGFs that function as hormones. Produced in response to specific nutritional cues, they act on overlapping sets of cell surface receptors composed of classic FGF receptors in complex with βKlotho, and regulate metabolism and related processes during periods of fluctuating energy availability. Pharmacologically, both FGF15/19 and FGF21 cause weight loss and improve both insulin sensitivity and lipid parameters, in rodent and primate models of metabolic disease. Recently, FGF21 was shown to have similar effects in obese patients with type 2 diabetes. Here, we discuss emerging concepts in FGF15/19 and FGF21 tissue specific actions and critically assess their putative role as candidate targets for treating metabolic disease.
doi:10.1016/j.tem.2014.10.002
PMCID: PMC4277911  PMID: 25476453
βKlotho; brown adipose tissue; hypothalamus; sympathetic nervous system; arginine vasopressin; corticotropin-releasing factor
11.  Metabolic Enzymes Enjoying New Partnerships as RNA-Binding Proteins 
In the past century, few areas of biology advanced as much as our understanding of the pathways of intermediary metabolism. Initially considered unimportant in terms of gene regulation, crucial cellular fate changes, cell differentiation, or malignant transformation are now known to involve ‘metabolic remodeling’ with profound changes in the expression of many metabolic enzyme genes. This review focuses on the recent identification of RNA-binding activity of numerous metabolic enzymes. We discuss possible roles of this unexpected second activity in feedback gene regulation (‘moonlighting’) and/or in the control of enzymatic function. We also consider how metabolism-driven post-translational modifications could regulate enzyme–RNA interactions. Thus, RNA emerges as a new partner of metabolic enzymes with far-reaching possible consequences to be unraveled in the future.
Trends
Genetic control of metabolism is currently best understood at the level of transcription and epigenetics. Only limited information is available on post-transcriptional regulation of metabolism.
While a few metabolic enzymes were previously known to moonlight as RNA-binding proteins in physiologically relevant contexts, recent discoveries highlight that several dozen of metabolic enzymes belonging to a wide spectrum of pathways exhibit RNA-binding activity in living mammalian cells.
Abundant RNA–enzyme interactions might suggest novel roles of RNA in affecting enzyme function, for instance, as competitive inhibitors or allosteric regulators. A function of RNA as assembly scaffold for enzyme complexes is also conceivable, with potentially wide-ranging implications for our understanding of how cells organize and control metabolic flux. Finally, enzymes can moonlight as regulators of (m)RNAs, as exemplified by aconitase/IRP1 and GAPDH.
doi:10.1016/j.tem.2015.09.012
PMCID: PMC4671484  PMID: 26520658
metabolic enzymes; metabolon; RNA; RNA-binding proteins; post-transcriptional regulation; post-translational modifications
12.  Cholesterol and Breast Cancer Pathophysiology 
Cholesterol is a risk factor for breast cancer although the mechanisms by which this occurs are not well understood. One hypothesis is that dyslipidemia results in increased cholesterol content in cell membranes thus impacting membrane fluidity and subsequent signaling. Additionally, studies demonstrate that the metabolite, 27-hydroxycholesterol (27HC), can function as an estrogen, increasing the proliferation of estrogen receptor positive breast cancer cells. This was unexpected as 27HC and other oxysterols activate the liver X receptors resulting in the reduction of intracellular cholesterol. Resolution of this paradox will require a dissection of the molecular mechanisms by which ER and LXR converge in breast cancer cells. Regardless, the observation that 27HC influences breast cancer provides rationale for strategies that target cholesterol metabolism.
doi:10.1016/j.tem.2014.10.001
PMCID: PMC4268141  PMID: 25458418
13.  Nuclear Receptor Rev-erbα: Up, Down, and All Around 
Rev-erbα is a nuclear receptor that links circadian rhythms to transcriptional control of metabolic pathways. Rev-erbα is a potent transcriptional repressor, and plays an important role in the core mammalian molecular clock while also serving as a critical regulator of clock output in metabolic tissues including liver and brown adipose tissue. Recent findings have shed new light on the role of Rev-erbα and its paralog Rev-erbβ in rhythm generation, as well as additional regulatory roles for Rev-erbα in other tissues that contribute to energy expenditure, inflammation, and behavior. This review highlights physiological functions of Rev-erbα and β in multiple tissues and discusses the therapeutic potential and challenges of targeting these pathways in human disease.
doi:10.1016/j.tem.2014.06.011
PMCID: PMC4252361  PMID: 25066191
Rev-erbα; Circadian Rhythm; Nuclear Receptor; Metabolism; Transcriptional Regulation
14.  Munc18c: A Controversial Regulator of Peripheral Insulin Action 
Insulin resistance, a hallmark of impaired glucose tolerance and type 2 diabetes (T2D), arises from dysfunction of insulin action and subsequent glucose uptake by peripheral tissues, predominantly skeletal muscle and fat. Exocytosis of glucose transporter (GLUT4)-containing vesicles facilitated by soluble NSF attachment receptor (SNARE) protein isoforms and Munc18c mediates this glucose uptake. Emerging evidences, including recent human clinical studies, point to pivotal roles for Munc18c in peripheral insulin action in adipose and skeletal muscle. Intriguing new advances are also initiating debates regarding the molecular mechanism(s) controlling Munc18c action. Thus, the objective of this review is to present a balanced perspective of new continuities and controversies surrounding the regulation and requirement for Munc18c in the regulation of peripheral insulin action.
doi:10.1016/j.tem.2014.06.010
PMCID: PMC4253632  PMID: 25028245
SNARE proteins; GLUT4 vesicle exocytosis; glucose uptake; skeletal muscle; adipose
15.  Protein and Amino Acid Restriction, Aging and Disease: from yeast to humans 
Many of the effects of dietary restriction (DR) on longevity and health span in model organisms have been linked to reduced protein and amino acid (AA) intake and the stimulation of specific nutrient signaling pathways. Studies in yeast have shown that addition of serine, threonine, and valine in media promotes cellular sensitization and aging by activating different but connected pathways. Protein or essential AA restriction extends both lifespan and healthspan in rodent models. In humans, protein restriction (PR) has been associated with reduced cancer, diabetes, and overall mortality. Thus, interventions aimed at lowering the intake of proteins or specific AAs can be beneficial and have the potential to be widely adopted and effective in optimizing healthspan.
doi:10.1016/j.tem.2014.07.002
PMCID: PMC4254277  PMID: 25153840
healthspan; longevity; CR; FMD; dietary-intervention
16.  Nutrient control of Drosophila longevity 
Dietary restriction (DR) extends lifespan of many animals including Drosophila melanogaster. Recent work with flies shows longevity is controlled by the ratio of consumed protein relative to carbohydrates. Since reduced insulin/IGF and TOR signaling increase Drosophila lifespan, these pathways are candidate mediators of DR. This idea, however, has ambiguous experimental support. The Nutritional Geometric Framework, which dissects the impact of nutrient protein relative to carbohydrates, may provide an approach to resolving the roles for these pathways in DR. Nutrient sensing of protein and carbohydrate may occur in the fat body through signals to hypothalamic-like neurons in the fly brain, and thus control secretion of insulin-like peptides that regulate longevity.
doi:10.1016/j.tem.2014.02.006
PMCID: PMC4177520  PMID: 24685228
dietary restriction; aging; geometric framework; lifespan extension; insulin/IGF signaling; TOR
17.  Insights into Obesity and Diabetes at the Intersection of Mouse and Human Genetics 
Many of our insights into obesity and diabetes come from studies in mice carrying natural or induced mutations. In parallel, genome-wide association studies in humans have identified numerous genes that are causally associated with obesity and diabetes, but discovering the underlying mechanisms required in-depth studies in mice. We discuss the advantages of studying natural variation in mice and summarize several examples where the combination of human and mouse genetics opened windows into fundamental physiological pathways. A noteworthy example is the melanocortin-4 receptor and its role in energy balance. The pathway was delineated by discovering the gene responsible for the Agouti mutation in mice. With more targeted phenotyping, we predict that additional pathways relevant to human pathophysiology will discovered.
doi:10.1016/j.tem.2014.06.006
PMCID: PMC4177963  PMID: 25034129
diabetes; obesity; mouse genetics; human genetics; complex traits; gene mapping; GWAS
18.  C. elegans Metabolic Gene Regulatory Networks Govern the Cellular Economy 
Diet greatly impacts metabolism in health and disease. In response to the presence or absence of specific nutrients, metabolic gene regulatory networks sense the metabolic state of the cell and regulate metabolic flux accordingly, for instance by the transcriptional control of metabolic enzymes. Here we discuss recent insights regarding metazoan metabolic regulatory networks using the nematode Caenorhabditis elegans as a model, including the modular organization of metabolic gene regulatory networks, the prominent impact of diet on the transcriptome and metabolome, specialized roles of nuclear hormone receptors in responding to dietary conditions, regulation of metabolic genes and metabolic regulators by microRNAs, and feedback between metabolic genes and their regulators.
doi:10.1016/j.tem.2014.03.004
PMCID: PMC4178166  PMID: 24731597
C. elegans; metabolic network; gene regulatory network; gene expression; nutrient response; life history traits; nuclear hormone receptors; transcription; bacteria
19.  The role of BMPs in endothelial cell function and dysfunction 
The bone morphogenetic protein (BMP) family of proteins has a multitude of roles throughout the body. In embryonic development, BMPs promote endothelial specification and subsequent venous differentiation. The BMP pathway also plays important roles in the adult vascular endothelium, promoting angiogenesis and mediating shear and oxidative stress. The canonical BMP pathway functions through the Smad transcription factors; however, other intracellular signaling cascades can be activated, and receptor complexes beyond the traditional type I and type II receptors add additional layers of regulation. Dysregulated BMP signaling has been linked to vascular diseases, including pulmonary hypertension and atherosclerosis. This review addresses recent advances in the roles of BMP signaling in the endothelium and how BMPs affect endothelial dysfunction and human disease.
doi:10.1016/j.tem.2014.05.003
PMCID: PMC4149816  PMID: 24908616
21.  Clock genes, intestinal transport and plasma lipid homeostasis 
Light and food are two major environmental factors that impact daily life. Light entrainment is centrally controlled by suprachiasmatic nuclei of the hypothalamus. Food entrainment might require cooperation between the intestine and dorsomedial hypothalamus. Clock genes that are essential for light entrainment also play a part in food entrainment. Understanding the role of clock genes in the entrainment of intestinal functions, as well as in gut–brain communication during food entrainment, will enhance our understanding of gastrointestinal and metabolic disorders. This review highlights recent studies examining light- and food-entrained regulation of plasma lipids and of various intestinal activities and offers insight into the role of the intestine in food entrainment.
doi:10.1016/j.tem.2009.01.001
PMCID: PMC4544755  PMID: 19349191
22.  Revealing transcription factors during human pancreatic β cell development 
Developing cell-based diabetes therapies requires examining transcriptional mechanisms underlying human β cell development. However, increased knowledge is hampered by low availability of fetal pancreatic tissue and gene targeting strategies. Rodent models have elucidated transcription factor roles during islet organogenesis and maturation, but differences between mouse and human islets have been identified. The past 5 years have seen strides toward generating human β cell lines, the examination of human transcription factor expression, and studies utilizing induced pluripotent stem cells (iPS cells) and human embryonic stem (hES) cells to generate β-like cells. Nevertheless, much remains to be resolved. We present current knowledge of developing human β cell transcription factor expression, as compared to rodents. We also discuss recent studies employing transcription factor or epigenetic modulation to generate β cells.
doi:10.1016/j.tem.2014.03.013
PMCID: PMC4167784  PMID: 24831984
diabetes mellitus; transcription factor; human; organogenesis; epigenetics
23.  Cellular Communication and Heterogeneity in Pancreatic Islet Insulin Secretion Dynamics 
Coordinated pulses of electrical activity and insulin secretion are a hallmark of the islet of Langerhans. These coordinated behaviors are lost when β-cells are dissociated, which also leads to increased insulin secretion at low glucose. Islets without gap junctions exhibit asynchronous electrical activity similar to dispersed cells, but their secretion at low glucose is still clamped off, putatively by a juxtacrine mechanism. Mice lacking β-cell gap junctions have near-normal average insulin levels, but are glucose intolerant due to reduced first-phase and pulsatile insulin secretion, illustrating the importance of temporal dynamics. We review the quantitative data on islet synchronization and the current mathematical models that have been developed to explain these behaviors and generate greater understanding of the underlying mechanisms.
doi:10.1016/j.tem.2014.02.005
PMCID: PMC4112137  PMID: 24679927
Islet of Langerhans; Microscopy; Fluorescence; Computer modeling; Calcium waves
24.  ZINC TRANSPORTER 8 (ZNT8) AND BETA CELL FUNCTION 
Human pancreatic β cells have exceptionally high zinc content. In β cells the highest zinc concentration is in insulin secretory granules, from which it is co-secreted with the hormone. Uptake of zinc into secretory granules is mainly mediated by zinc transporter 8 (ZnT8), the product of the SLC30A8 gene. The minor alleles of several single nucleotide polymorphisms (SNPs) in SLC30A8 are associated with decreased risk of type 2 diabetes (T2D), but the precise mechanisms underlying the protective effects remain uncertain. In this article we review current knowledge of the role of ZnT8 in maintaining zinc homeostasis in β cells, its role in glucose metabolism based on knockout mouse studies, and current theories regarding the link between ZnT8 function and T2D.
doi:10.1016/j.tem.2014.03.008
PMCID: PMC4112161  PMID: 24751356
Islet; SLC30A8; Slc30a8
25.  mTORC2 in the center of cancer metabolic reprogramming 
Metabolic reprogramming is a central hallmark of cancer, enabling tumor cells to obtain the macromolecular precursors and energy needed for rapid tumor growth. Understanding how oncogenes coordinate altered signaling with metabolic reprogramming and global transcription may yield new insights into tumor pathogenesis, and provide a new landscape of promising drug targets, while yielding important clues into mechanisms of resistance to the signal transduction inhibitors currently in use. Here we review the recently identified central regulatory role for mTORC2, a downstream effector of many cancer-causing mutations, in metabolic reprogramming and cancer drug resistance. We consider the impact of mTORC2-related metabolism on epigenetics and therapeutics, with a particular focus on the intractable malignant brain tumor, glioblastoma (GBM).
doi:10.1016/j.tem.2014.04.002
PMCID: PMC4077930  PMID: 24856037
mTORC2; c-Myc; metabolic reprogramming; epigenetics; drug resistance; glioblastoma

Results 1-25 (242)