CBMR International Postdoctoral Program
The CBMR International Postdoctoral Program supports competitive international recruitment of postdoctoral fellows to the Novo Nordisk Foundation Center of Basic Metabolic Research.
The postdoctoral research fellowships are aimed at early career researchers with a basic science background or clinicians who aspire to a career in academic medicine. We are particularly interested in candidates who are familiar with integrative research approaches within the broad area of basic metabolic research with an application towards human pathophysiology.
Each postdoctoral fellow will receive a competitive package including salary and running costs for three years, and be part of an international scientific collaboration at the Maersk Tower www.maersktower.ku.dk.
Postdoc Projects starting in 2020
Serotonin or 5-hydroxytryptamine (5-HT) is commonly known as an important neurotransmitter of the central nervous system (CNS). However, ~95% of 5-HT is produced in the gut by enterochromaffin cells, where it is responsible for several gastrointestinal functions, such as gut motility and transit time. The role of peripheral 5-HT in energy homeostasis is being uncovered lately – circulating 5-HT is elevated in high-fat fed animals and obese humans; gut-derived 5-HT promotes gluconeogenesis in hepatocytes; and 5-HT signaling in white adipocytes promotes lipolysis and insulin resistance. Even though gut-derived 5-HT cannot cross the blood-brain barrier, it can still signal the vagus nerve that serves as a major connection between the enteric and central nervous systems, thus affecting appetite and eating behavior via CNS. Thus, gut-derived 5-HT must be considered as an important regulator of obesity and metabolism.
Gut microbiota synthesize and secrete numerous metabolites that act as signaling molecules and therefore likely regulate 5-HT production in the gut. It is becoming clear now that there is bidirectional communication between host and gut microbiota mediated by 5-HT, making gut microbial regulation of 5-HT production a therapeutic target for metabolic disorders. We aim to identify gut bacteria that regulate 5-HT production in EC cells, thereby regulating host metabolism. This cross-disciplinary project brings together research in microbiome, cellular metabolism and metabolomics to answer a key question in regulation of 5-HT biosynthesis. We expect that this project will identify specific gut bacteria and their metabolites that regulate 5-HT biosynthesis as therapeutic targets for metabolic disorders.
Read more about the Arumugam Group here
The Barrès Group seeks a trained bioinformatician with experience in comparative genomics, to work as part of an international lab group with a focus on hypothesis-driven research. The overarching objective of the proposed project is to map, using a comparative biology approach of sperm epigenomes of animals distributed across various phyla, genes undergoing epigenetic variation under nutritional stress. We will determine if genes controlling brain development are uniquely susceptible to epigenetic variation in response to nutritional changes in humans. The ultimate objective of this research is to understand when and in what taxa epigenetic control of brain genes evolved and whether different mechanisms are present in different taxa.
This project represents a close collaboration with staff at the Single Cell Sequencing Platform at CBMR, as well as national and international collaborations with Dr. Mads Bertelsen at Copenhagen Zoo and Dr. Justine O’Brien at Taronga Zoo in Sydney. Through the extensive bioinformatic work required by this study, this research will further develop an ongoing collaboration with bioinformatics expert A/Prof Workman (Co-PI) from the Technical University of Denmark.
We are seeking a highly motivated and qualified fellow with a background in molecular and cellular biology to investigate the molecular mechanisms regulating the activity of thermogenic adipocytes. The project aims to mechanistically dissect the functions of a key DNA- and RNA-binding protein (DRBP) in promoting and maintaining the thermogenic capacity of adipocytes. In collaboration with groups at the CBMR and internationally, the postdoctoral fellow will use a multidisciplinary approach combining RNA/protein complex purification, OMICS technologies and a wide range of biological assays using gain- and loss-of function studies in mouse and human adipocytes to decipher the molecular mechanisms controlled by this DRBP to facilitate the metabolic functions of thermogenic adipocytes.
Read more about the Emanuelli Group here
Type 2 diabetes is determined by a complex interplay between environmental and genetic factors. Using a combination of in-house human genetic and transgenic animal studies, the potential role of the so-called ADAMTS-9 enzyme in glucose metabolism and insulin sensitivity has only recently been established by researchers at the CBMR (Graae et al., Diabetes 2019 68:502-514).
ADAMTS (short for ‘a disintegrin and metalloproteinase with thrombospondin motifs’) is a family of key enzymes mediating the ectodomain shedding of numerous cell surface molecules, thereby affecting many cellular processes of both physiological and pathological importance. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS-9 as a potential novel mode of treating insulin resistance.
The project is based on the following hypotheses: a) that ADAMTS-9 is druggable by small-molecules competing with endogenous substrate binding and b) that ADAMTS-9 inhibitors may provide a unique opportunity for beneficial effects on glucose metabolism and insulin sensitivity, comprising a potential novel applicable approach to insulin resistance and type 2 diabetes therapy complementing other therapeutic strategies. To probe these two hypotheses and to characterize the physiological role of ADMATS-9 in insulin resistance and type-2 diabetes in general, we have over the last years developed unique ADMATS-9 binders (inhibitors) which will be used to characterize in-vitro and ex-vivo assays of increasing complexity to describe the role of ADAMTS-9 and to investigate e.g. how ADAMTS-9 impairs insulin sensitivity, mitochondria function and glucose homeostasis in vitro, ex-vivo and in-vivo proof-of-concept studies.
Brown thermogenic adipocytes have unparalleled energy-expending capacities with therapeutic potential to treat metabolic disease. Adipose thermogenesis is activated by exposure to environmental cold, which stimulates thermogenic catabolism of lipids and carbohydrates. This physiological response improves metabolic homeostasis and is strongly controlled by G protein-coupled receptors (GPCRs). This includes the canonical thermogenic effectors, the b-adrenergic receptors (bARs), as well as the secretin, glucagon, gastric inhibitory polypeptide, and adenosine receptors. Yet despite the profound ability of adipose thermogenesis to improve energy homeostasis and counteract metabolic disease, the prevalence of classical brown adipocytes in humans remains highly debated. However, subcutaneous white adipocytes are ubiquitously present in man and can be rendered thermogenically viable. Similar to classic brown adipocytes, activated subcutaneous adipocytes can significantly improve metabolic health. Therefore, understanding what signaling pathways promote the thermogenic competence of this adipocyte subtype poses immense therapeutic potential. Moreover, our knowledge of this process in humans is virtually nonexistent.
To this end, in this CBMR international postdoctoral fellowship, we seek to investigate GPCR signaling in human adipose during thermogenic activation to improve our basic understanding of physiology and potentially uncover new therapeutic targets for obesity.
In this project, we aim to delineate the genetic components of human taste and food preference to find novel mechanisms regulating human food intake with impact on metabolic disease by leveraging novel scale-based questionnaire with existing large-scale biobank, phenotype and genetic data.
Typical food intake measures (e.g., frequency surveys, dietary records) are difficult to complete and memory issues, dietary restraints and under- or over reporting lead to inaccurate conclusions about diet-disease relationships. Here we will derive a simple questionnaire to obtain information on aspects of taste and food preference in humans in a large-scale setting. The project benefits from previously produced data from several cohorts representing approximately 100,000 individuals. Questionnaire data will be combined with existing genome-wide genotyping data. Given the nature of the cohorts, it will thereby be possible to estimate heritability of taste and food preference and in a large set of individuals, we will analyse genome-wide genetic variation in relation to inter-individual variation in taste and food preference.
The expected outcome of the research project is to define novel genes, proteins and potentially mechanisms involved in regulation of human taste and food preference thereby bringing knowledge with the potential for translation to clinical medicine by deriving novel drug targets for obesity and metabolic disease.
Childhood obesity is a major health challenge associated with several comorbidities (e.g. dyslipidemia, hypertension, insulin resistance, non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D)), which often tracks into adulthood, resulting in severe long-term consequences. Childhood obesity is a multifactorial disorder with a strong genetic component. Estimates of the heritability of BMI (the proportion of phenotypic variance of BMI, which is attributable to genetic factors) range between 47-90%. The precipitation of cardiometabolic comorbidities among obese children is likely due to the combined genetic effect of obesity and tissue and cell type specific other risk variants, i.e. risk variants for T2D or NAFLD. Recent studies suggest that polygenic risk scores (PRS) that integrate effects of a very large number of variants, including many that lack significant genomewide associations, can identify individuals with extreme levels of risk for disease, including obesity and T2D.
Our ambition is to define tissue and cell type specific PRS to identify the subset of obese children who are i) at highest risk of progression to type 2 diabetes and ii) at highest risk of developing NAFLD. Furthermore, we will examine whether these children respond satisfactorily to a structured lifestyle intervention. The project focus on translation of information from tissue specific single cell RNA profiling and single cell ATAC seq to generate cell type specific PRS. The generated PRS will be examined in more than 6,000 deep phenotyped and genotyped children followed at the Pediatric Department of Holbæk University Hospital.
Insulin resistance and increased risk of type 2 diabetes are closely linked to obesity, but there is wide individual variability in the metabolic tolerance for carrying excess body fat. Recent studies have shown that multiple genetic loci are associated with higher insulin resistance but, paradoxically, lower levels of gluteofemoral fat, which appears to play a key role in the development of insulin resistance. However, the current understanding of the biological mechanisms that mediate the genetic relationship between lower gluteofemoral fat and higher insulin resistance remains limited. In the present research project, we strive to understand these mechanisms by a combination of in silico computational approaches and experimental studies guided by the in silico analyses.
Your tasks will involve utilizing data from genome-wide association studies, large cohort studies, and other available data sources to examine the genetic relationship between gluteofemoral fat and insulin resistance. Your findings will also guide in vitro experimental studies that aim to identify gene enhancer regions mediating this relationship.
Type 2 diabetes (T2D) is a heritable multifactorial disease with incompletely understood etiologic biological pathways. Given the considerable heterogeneity in phenotypic characteristics and treatment responses of T2D patients, subgrouping of patients may yield more effective treatment procedures (Udler, PLOS Medicine 2018).
In the Pers lab we study cellular heterogeneity underlying human obesity and T2D. Our goal is to understand how the central nervous system regulates body weight and blood glucose levels. In this project we aim to combine large-scale human single-cell data – constructed from primarily peripheral tissue samples derived from longitudinally and deeply phenotyped individuals – with well-powered T2D genome-wide association data to (a) develop novel approaches to subtype T2D patients and to (b) leverage these approaches to identify T2D patient subgroups with distinct metabolic risk phenotypes and relevant treatment outcomes.
As the successful candidate you would have the opportunity to develop your own ideas and approaches. Being part of the Pers lab, you would work closely with the rest of the group (molecular biologists, neurobiologists and bioinformaticians) as well as dedicated specialists from the CBMR Single-Cell Omics Platform (molecular biologists, computer scientists and mathematicians) in a conducive and ambitious environment. You would be assisted by prof. Torben Hansen (CBMR) on clinical aspects of the project and by associate prof. Morten Mørup (Technical University of Denmark) on aspects related to machine learning and statistical procedures. For more information on the project please contact the principal investigator Tune H Pers (email@example.com).
Read more about the Pers Group here
Glycogen is a primary form of energy storage that is essential for physical activity and glucose homeostasis. Muscle glycogen phosphorylase (PYGM) is one of the key enzymes in glycogen metabolism, as it plays a critical role in glycogen breakdown during exercise and prolonged fasting. Genetic defects (loss of function) of the myophosphorylase gene (Pygm) cause a typical metabolic myopathy (McArdles’ disease) characterized by severe exercise intolerance, premature fatigue and muscle weakness during exercise, and in some cases myoglobinuria. PYGM is activated by the allosteric binding of 5’-adenosine monophosphate (AMP) or by phosphorylation of its Ser15 residue by phosphorylase kinase. Phosphorylation converts phosphorylase b form, which is inactive without AMP, to phosphorylase a form, which is active in the absence of AMP. Relative importance of these two molecular-switch mechanisms (allosteric vs. phosphorylation) under physiological setting in vivo is unknown.
The primary goal of the current project is to elucidate the physiological role that allosteric (AMP)- and phospho-dependent activation of PYGM plays in regulating glycogen metabolism in muscle at molecular and whole-body levels using an original approach, including a novel allosteric-deficient (AMP-insensitive PYGM) knockin mouse model. Similar approach we undertook (allosteric-deficient knockin models) led to identifications of key molecular mechanisms and physiological roles for insulin-mediated glycogen synthesis (Bouskila et al, Cell Metab, 2010) and glucose-lowering action of the most widely used diabetes drug metformin (Hunter et al, Nat Med, 2018).
The central nervous system plays a major role in regulating food intake based on feedback systems from peripheral organs, including adipose tissue. Brown adipose tissue (BAT) is a subtype of adipose tissue with specialized energetic properties. BAT produces heat in response to cold by switching from an idle state to a highly energy-consuming state. Our overarching hypothesis is that BAT secretes bioactive peptides, which communicate its metabolic status to the brain and thereby regulate appetite.
With the current project, we will screen for novel bioactive brown fat derived peptides or proteins with a potential neuroregulatory effect, which will be assessed experimentally at a later stage in the project. Your tasks would be to analyze large-scale transcriptomics studies of adrenergically activated brown fat cells, human plasma peptidomics with samples obtained before, during and after cooling and, finally, single nuclei transcriptomics data of human brown fat tissue obtained from obese and normal-weight subjects. You will work in close synergy with the biologists and technical staff in the group to generate datasets, interpret the data, and bring candidate so-called “batokines” further into functional studies of the effect on neuronal circuits. This project is a part of an overall strategy of exploring the role of brown fat in metabolic regulation in adult humans, with the goal of identifying novel drug targets against obesity and its associated diseases.
Adipose tissue plays an important role in mediating the health-promoting effects of exercise training. The beneficial effects of exercise are associated with adipose tissue browning and the modification of its lipid and secretory profile. However, in humans, the molecular mechanisms driving adipose tissue adaptation(s) to exercise, as well as the relevance of adipose tissue and adipose tissue-derived signals in the metabolic response to exercise, remain unclear.
Our overarching hypothesis for this postdoctoral project is that physical activity is beneficial for women with disturbed lipolysis, and that exercise-induced secreted proteins helps protecting against long-term body weight gain and cardiometabolic complications. Your task would be to apply mass-spectrometry-based proteomics to map a signature of adipose tissue secretome in a) untrained pre-menopausal women b) untrained and habitually exercising postmenopausal women, and c) response to an acute exercise bout in pre and postmenopausal women. Follow-up studies involve investigating the role of the shortlisted candidate secreted proteins in vitro and in vivo metabolism in human and murine cell systems and mouse models.