Hagberg Lab

Karolinska Institutet, Stockholm

THE HAGBERG LAB INTEGRATES VASCULAR BIOLOGY WITH NUTRIENT BIOCHEMISTRY TO STUDY WHY WHITE ADIPOSE TISSUE DYSFUNCTION DEVELOPS DURING OBESITY AND HOW IT LEADS TO DISEASE, WITH THE AIM OF IDENTIFYING NEW CLINICAL TREATMENT OPTIONS TO PREVENT OR REVERSE THE EMERGENCE OF OBESITY-ASSOCIATED DISEASES. OUR RESEARCH IS FOCUSED ON HUMAN ADIPOCYTES THAT WE STUDY USING IN VITRO CULTURE MODELS IN COMBINATION WITH IN VIVO RESEARCH TO MECHANISTICALLY TEST OUR FINDINGS. WE ARE A YOUNG, DYNAMIC RESEARCH GROUP LOCATED AT ONE OF THE BRAND-NEW RESEARCH BUILDINGS AT KAROLINSKA INSTITUTET IN STOCKHOLM, SWEDEN, WITHIN A STIMULATING SCIENTIFIC ENVIRONMENT WITH NUMEROUS POSSIBILITIES FOR INTERESTING COLLABORATIONS, CLINICAL INTERACTIONS AND TOP NOTCH SCIENCE LECTURES.

Ongoing research

– What is the contribution of adipose tissue dysfunction to the development of systemic dyslipidaemia and cardiovascular disease? Can we influence circulating cholesterol levels by ameliorating adipose tissue health?

Using current cellular and molecular techniques we investigate how our fat cells (adipocytes) contribute to the circulating cholesterol pool, and how lipoprotein-bound cholesterol is taken up and handled by human adipocytes. Our aim is to understand the contribution of the fat tissue to emerging dyslipidaemia and vascular lesions both in humans and atherogenic mice, to better understand the interplay between obesity, increased adipose tissue and the associated increased risk for cardiovascular disease. Ultimately, we want to use our insights from adipose tissue biology to identify novel biomarkers for subjects at heightened cardiovascular risk and characterize new therapeutic targets within the adipose tissue that can be used to lower the risk for disease events.

Primary isolated mature human adipocytes stained with green LCA-lectin to visualize the cell membrane and blue Hoechst to visualized the nuclei, imaged using confcal microscopy.

– Can we develop improved in vitro models for the study of human adipocytes that better mimic the specialized features of this unique cell type?

By combining our insights from adipose tissue biology with recent developments in spheroids culturing our lab has developed a novel adipocyte spheroid model that allows differentiation of human adipocyte progenitors (pre-adipocytes) into mature adipocytes with a largely unilocular cell morphology and larger lipid droplets than any currently available method. The spheroid model is easy to set up and handle and ideally suited for testing lipid dynamics, metabolite fluxes and the influence of drugs on human adipocytes (unpublished data, Hagberg lab).

Adipocyte spheroids. In contrast to human pre-adipocytes differentiated using standard culturing techniques (left), culturing pre-adipocytes as floating cell aggregates or so-called spheroids leads to improved in vivo-like cell morphology and significantly larger lipid droplet sizes (middle image with zoomed image to the right).

– What are the vascular pathways governing nutrient uptake from the circulation to the adipocytes?

Timely uptake of nutrients that are meant for storage instead of oxidation is of outmost importance for whole body metabolic balance, but the pathways working within the adipose tissue vascular endothelium to govern nutrient uptake are still poorly understood, as is the balance between enough uptake of lipids to the adipose tissue to protect peripheral organs, and too much uptake, leading to obesity. We aim to decipher the molecular pathways in primary human endothelial cells that govern the uptake of fatty acids, cholesterol and other nutrients to the adipose tissue, and use a combination of in vitro and in vivo models to test their functional relevance for both adipose tissue function and whole-body metabolism in health and obesity.

Human subcutaneous adipose tissue piece stained for lipid content (Bodipy, green), nuclei (Hoechst, blue) and vessels (UEA1 lectin, red) and imaged using confocal microscopy.

Hagberg Lab

About the lab

The Hagberg lab is currently in its third year after joining the Cardiovascular Medicine division at the Department of Medicine Solna at Karolinska Institutet in August 2019. We are also a part of the Centre for Molecular Medicine (CMM) and affiliated to the Strategic Research Programme in Diabetes (SRP Diabetes). Together we have created an inspiring and creative scientific environment characterised by discussion, hard work, collaboration and positivity. I have a long-standing interest in mentorship and believe it is one of the fundamentals of being a group leader. I believe that sharing methodology and knowledge through collaboration can produce science that is beneficiary for all, and only by supporting each other can we bring forward the best science. It is also important that all victories, large and small, should be celebrated and that hard work and perseverance recognized. If you want to know more about me please reach out to me or see my university page at www.ki.se, including a short CV.

Current lab members (from left): Fabiana Baganha, postdoc; Ruby Schipper, PhD student; Carolina Hagberg, PI; Anneli Olsson, lab manager; Max Larsson, MD student; Alana Vanity, MSc student and Alice Maestri, co-supervised visiting PhD student.

Join us!

My lab offers great science, dedicated mentoring and an inspirational scientific environment! If you have a scholarship or a chance to apply for one please get in touch directly, otherwise check out the funded opportunities below:

Current Openings

Postdoc. We are always looking for enthusiastic and creative researchers with a PhD and a strong research background in experimental cellular/molecular research. Please reach out to enquire about current projects and opportunities to apply for individual postdoc fellowships.

For further information please send your CV together with reference information to Carolina.hagberg@ki.se.

Location

The Hagberg lab is a part of the Cardiovascular Medicine division, a well-established larger network of researchers in metabolism, atherosclerosis and cardiovascular inflammation, located on the 8^th floor of the brand new BioClinicum Research building at the Karolinska Institutet campus in Solna, Stockholm, Sweden (see map below). The building boasts with newly built labs, open desk and social areas and a stunning view over the university campus. The research division offers an interactive scientific environment focused on both preclinical and clinical cardio-metabolic research with numerous opportunities for collaborative projects and interesting lectures, as well as access to both in-house, Biomedicum and CMM core facilities and seminars.

Photography Ulf Sirborn.

The Karolinska Institutet university campus (www.ki.se) is situated just outside Stockholm, with good public transport connection to the city centre and close proximity to the buzzling neighbourhood of Rörstrandsgatan and the beautiful Hagaparken. Karolinska Institutet is an entirely medical university, with around 4,700 employees and 2,000 graduate students and its research divided into 22 Departments focusing on all aspects of pre-clinical and clinical medical investigation. This medical focus attracts some of the best researchers to come and lecture at the campus. In addition, the Nobel Assembly at Karolinska Institutet annually selects the Nobel Prize laureates in Physiology and Medicine, and one can attend the prize lectures each year.

Publications

22 published papers, H-factor 14, Sum of impact factors 411, Total no. citations 1704 (WoS)

2019-

Börgeson E, Boucher J, Hagberg CE. Of mice and men: Pinpointing species differences in adipose tissue biology.

Frontiers in Cell and Developmental Biology 10:1003118 (2022).

Baganha F, Schipper R, and Hagberg CE. Towards better models for studying human adipocytes in vitro.

Adipocyte, 11(1):413-419 (2022).

Soták M, Rajan MR, Clark M, Harms M, Rani A, Kraft JD, Tandio D, Shen T, Borkowski K, Fiehn O, Newman JW, Quiding-Järbrink M, Biörserud C, Apelgren P, Staalesen T, Hagberg CE, Boucher J, Wallenius V, Lange S, Börgeson E. Lipoxins reduce obesity-induced adipose tissue inflammation in 3D-cultured human adipocytes and explant cultures.

iScience, 25(7):104602 (2022).

Soták M, Rajan MR, Clark M, Biörserud C, Wallenius V, Hagberg CE, Börgeson E. Healthy subcutaneous and omental adipose tissue is associated with high expression of extracellular matrix components.

Int. Journal of Molecular Sciences, 23(1):520 (2022).

Ioannidou A, Fisher RM, Hagberg CE. The multifaceted roles of the adipose tissue vasculature.

Obesity Reviews, 23(4):e13403 (2022)

Ioannidou A*, Altar S*, Schipper R, Baganha F, Åhlander M, Hornell A, Fisher R, Hagberg CE. Hypertrophied human adipocyte spheroids as in vitro model of weight gain and adipose tissue dysfunction. *shared first authors

Journal of Physiology, 600(4):869-883 (2022).

Li Q*, Hagberg CE*, Silva Cascales H, Lang S, Hyvönen MT, Salehzadeh F, Chen P, Alexandersson I, Terezaki E, Harms MJ, Kutschke M, Arifen N, Krämer N, Aouadi M, Boucher J, Thorell A, Spalding KL. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. *shared first authors

Nature Medicine, 27(11):1941-1953(2021).

Harms MJ, Li Q, Lee S, Zhang C, Kull B, Hallen S, Thorell A, Alexandersson I, Hagberg CE, Peng XR, Mardinoglu A, Kirsty Spalding KL, Boucher J. Mature human adipocytes cultured under permeable membranes maintain identity, function, and can transdifferentiate into brown-like adipocytes.

Cell Reports, 27(1):213-225. 2019

2014-2018

Hagberg CE. Understanding obesity one adipocyte at a time. Science Trends 2018. Link

Hagberg CE#, Li Q, Kutschke M, Bhowmick D, Kiss E, Shabalina IG, Harms MJ, Shilkova O, Kozina V, Nedergaard J, Boucher J, Thorell A, Spalding KL. Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity.

Cell Reports. 24(10):2746-2756, 2018 #Corresponding author Link

Mehlem A, Palombo I, Wang X, Hagberg CE, Eriksson U, Falkevall A. PGC-1α coordinates mitochondrial respiratory capacity and muscular fatty acid uptake via regulation of VEGF-B.

Diabetes, 65(4):861-73, 2016 Link

Muhl L, Moessinger C, Adzemovic MZ, De Zwart-Dijkstra M, Nilsson I, Zeitelhofer M, Hagberg CE, Huusko J, Falkevall A, Ylä-Herttuala S, Eriksson U. The expres-sion of Vascular Endothelial Growth Factor (VEGF)-B and its receptor (VEGFR1) in the murine heart, lung and kidney.

Cell Tissue Res., 365(1):51-63, 2016 Link

Abreu-Vieira G, Hagberg CE, Spalding KL, Cannon B, Nedergaard J. Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis.

Am J Physiol Endocrinol Metab. 308: E822–E829, 2015 Link

Pirinen E, Canto C, Jo YS, Morato L, Zhang H, Menzies KJ, Williams EG, Mouchiroud L, Moullan N, Hagberg C, Li W, Timmers S, Imhof R, Verbeek J, Pujol A, Van Loon B, Viscomi C, Zeviani M, Schrauwen P, Sauve Aa, Schoonjans K, Auwerx J. Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.

Cell Metabolism 19;6 1034-41, 2014 Link

2009-2013

Hagberg C*, Mehlem A*, Falkevall A, Muhl L, Eriksson U. Endothelial fatty acid transport: role of vascular endothelial growth factor B.

Physiology 28;2 125-34, 2013 (*equal contribution) Link

Mehlem A, Hagberg CE, Muhl L, Eriksson U, Falkevall A. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease.

Nature protocols 8;6 1149-54, 2013 Link

Hagberg CE*, Mehlem A*, Falkevall A, Muhl L, Fam BC, Ortsater H, Scotney P, Nyqvist D, Samen E, Lu L, Stone-Elander S, Proietto J, Andrikopoulos S, Sjoholm A, Nash A, Eriksson U. Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.

Nature 490;7420 426-30, 2012 (*equal contribution) Link

Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Yla-Herttuala S, Lindahl P, Eriksson U. Vascular endothelial growth factor B controls endothelial fatty acid uptake.

Nature 464;7290 917-U136, 2010 Link

Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, Lorentz P, Jeltsch M, Alitalo K, Eriksson U, Christofori G, Pietras K. Suppressive Effects of Vascular Endothelial Growth Factor-B on Tumor Growth in a Mouse Model of Pancreatic Neuroendocrine Tumorigenesis.

PLOS ONE 5;11 e14109, 2010 Link

Lahteenvuo JE, Lahteenvuo MT, Kivela A, Rosenlew C, Falkevall A, Klar J, Heikura T, Rissanen TT, Vahakangas E, Korpisalo P, Enholm B, Carmeliet P, Alitalo K, Eriksson U, Yla-Herttuala S. Vascular Endothelial Growth Factor-B Induces Myocardium-Specific Angiogenesis and Arteriogenesis via Vascular Endothelial Growth Factor Receptor-1-and Neuropilin Receptor-1-Dependent Mechanisms.

Circulation 119;6 845-U134, 2009 Link

Published under maiden name Rosenlew

2004

Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B, Dobyns WB, Dieguez J, Valanne L, Joensuu T, Lehesjoki AE. POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease.

Journal Of Medical Genetics 41;10, 2004 Link

Published under maiden name Rosenlew.