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Team Carolina Hagberg

The Hagberg team aims to elucidate early cellular mechanisms in our white adipose tissue that contribute to the development of obesity-induced metabolic disorders, focusing on nutrient biochemistry.

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

Research focus

Investigating early cellular mechanisms in the white adipose tissue contributing to adipose tissue dysfunction, lipid leakage and peripheral insulin resistance.

Introduction

The Hagberg team integrates vascular biology with nutrient biochemistry to study how and why white adipose tissue dysfunction develops during obesity, with the aim of identifying new clinical treatment options that can prevent or reverse the emergence of obesity-associated diseases. Our research is focused on the interaction between adipocytes and the vasculature, which we study using in vitro culture models and combine with in vivo research to mechanistically test our findings.

Major lines of Research

- What are the vascular signalling 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, and dysregulation can lead to serious metabolic disease (Hagberg et al., Nature 2012). However unlike for muscle, the pathways working within the adipose (fat) tissue vasculature to govern nutrient uptake are still poorly understood. Recently it was demonstrated that loss-of-function mutations in the gene coding for a key lipogenic protein localized to the adipose tissue vascular wall in humans greatly impaired lipid uptake to the adipose tissue and predisposed patients to cardio-metabolic disease(Lotta et al., Nature Genetic, 2017). These results show that further unbiased studies of vascular nutrient transport pathways in the adipose tissue are needed to understand how and when different types of nutrients are taken up for storage, and hence the fundamental pathways governing how adipose tissue expands and obesity develops. Our lab studies these pathways on a broad basis looking both at nutrient preference and molecular changes in the adipose tissue vasculature.

- Impact of obesity-induced endothelial hypertrophy on adipose tissue nutrient transport and vascular function-

Compensatory hypertrophy develops to make up for cellular or functional loss, and is a major pathogenic mechanism in a multitude of tissues, including heart cardiomyocytes, kidney podocytes or pancreatic beta-cells. It involves enlargement of the cellular mass that can have great consequences on both function and metabolism of the cells. However, the initiating cues and driving pathways differ greatly between cell types and are in some cell types still poorly characterized and understood. The vascular endothelium is highly heterogenous between organs, reflecting its organ-specific functions, and the impact of endothelial hypertrophy on the function of the adipose tissue vascular bed, which is in charge of all nutrient exchange to and from the tissue in both the fed and fasted stated, remains poorly characterized. The project aims to study the influence of endothelial hypertrophy on whole tissue function and if limiting endothelial hypertrophy can have positive effects on metabolic health.

Team members

Carolina Hagberg, PhD, Assistant Professor

Shemim Alatar, MSc-student

Contact

Carolina Hagberg

Employee
Integrated Cardio Metabolic Centre
Department of Medicine, Solna (MedS), K2

Mobile: +46 (0) 707572204

Publications

Mature Human White Adipocytes Cultured under Membranes Maintain Identity, Function, and Can Transdifferentiate into Brown-like Adipocytes.
Harms MJ, Li Q, Lee S, Zhang C, Kull B, Hallen S, et al
Cell Rep 2019 Apr;27(1):213-225.e5

Hagberg C. Understanding obesity one adipocyte at a time. Oct.26th 2018. Science Trends.

Flow Cytometry of Mouse and Human Adipocytes for the Analysis of Browning and Cellular Heterogeneity.
Hagberg CE, Li Q, Kutschke M, Bhowmick D, Kiss E, Shabalina IG, et al
Cell Rep 2018 Sep;24(10):2746-2756.e5

PGC-1α Coordinates Mitochondrial Respiratory Capacity and Muscular Fatty Acid Uptake via Regulation of VEGF-B.
Mehlem A, Palombo I, Wang X, Hagberg CE, Eriksson U, Falkevall A
Diabetes 2016 04;65(4):861-73

Expression of vascular endothelial growth factor (VEGF)-B and its receptor (VEGFR1) in murine heart, lung and kidney.
Muhl L, Moessinger C, Adzemovic MZ, Dijkstra MH, Nilsson I, Zeitelhofer M, et al
Cell Tissue Res. 2016 07;365(1):51-63

Adrenergically stimulated blood flow in brown adipose tissue is not dependent on thermogenesis.
Abreu-Vieira G, Hagberg CE, Spalding KL, Cannon B, Nedergaard J
Am. J. Physiol. Endocrinol. Metab. 2015 May;308(9):E822-9

Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.
Pirinen E, Cantó C, Jo YS, Morato L, Zhang H, Menzies KJ, et al
Cell Metab. 2014 Jun;19(6):1034-41

Endothelial fatty acid transport: role of vascular endothelial growth factor B.
Hagberg C, Mehlem A, Falkevall A, Muhl L, Eriksson U
Physiology (Bethesda) 2013 Mar;28(2):125-34

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

Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.
Hagberg CE, Mehlem A, Falkevall A, Muhl L, Fam BC, Ortsäter H, et al
Nature 2012 Oct;490(7420):426-30

Vascular endothelial growth factor B controls endothelial fatty acid uptake.
Hagberg CE, Falkevall A, Wang X, Larsson E, Huusko J, Nilsson I, et al
Nature 2010 Apr;464(7290):917-21

Suppressive effects of vascular endothelial growth factor-B on tumor growth in a mouse model of pancreatic neuroendocrine tumorigenesis.
Albrecht I, Kopfstein L, Strittmatter K, Schomber T, Falkevall A, Hagberg CE, et al
PLoS ONE 2010 Nov;5(11):e14109

Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.
Lähteenvuo JE, Lähteenvuo MT, Kivelä A, Rosenlew C, Falkevall A, Klar J, et al
Circulation 2009 Feb;119(6):845-56

POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease.
Diesen C, Saarinen A, Pihko H, Rosenlew C, Cormand B, Dobyns WB, et al
J. Med. Genet. 2004 Oct;41(10):e115