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NO. 3 2018 VOLUME 20
DANISH SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY – WWW.BIOKEMI.ORG
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RedaktionHelene Halkjær JensenPostdoc Department of Chemistry and BioscienceBiotechnology Aalborg UniversityFredrik Bajers Vej 7HDK-9220 AalborgE-mail: [email protected]
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THEME: BROWN ADIPOSE TISSUE
Brown fat: the biological furnace that could burn away obesityJENS LUND, JULIA PEICS, ZACHARY GERHART-HINES. NOVO NORDISK FOUNDATION CENTER
FOR BASIC METABOLIC RESEARCH, UNIVERSITY OF COPENHAGEN; DEPARTMENT OF
BIOCHEMISTRY AND MOLECULAR BIOLOGY, UNIVERSITY OF SOUTHERN DENMARK;
NOVO NORDISK A/S, DENMARK. [email protected] 4Brown fat cells in adult humansCAMILLA SCHÉELE, NOVO NORDISK FOUNDATION CENTER FOR BASIC METABOLIC RESEARCH,
UNIVERSITY OF COPENHAGEN AND CENTRE FOR PHYSICAL ACTIVITY RESEARCH,
RIGSHOSPITALET, DENMARK. [email protected] 7Plasticity of Thermogenic AdipocytesLASSE K. MARKUSSEN, MAJA W. ANDERSEN, SUSANNE MANDRUP, CENTER FOR FUNCTIONAL
GENOMICS AND TISSUE PLASTICITY (ATLAS), FUNCTIONAL GENOMICS & METABOLISM
RESEARCH UNIT, UNIVERSITY OF SOUTHERN DENMARK. [email protected] 10Down the drain – Brown adipose tissue as a metabolic sinkSALLY WINTHER, NOVO NORDISK FOUNDATION POSTDOCTORAL FELLOW, DANA FARBER
CANCER INSTITUTE AND HARVARD MEDICAL SCHOOL, BOSTON, USA.
[email protected] 13News from Danish Society for Biochemistry and Molecular BiologyMETTE VIXØ VISTESEN, CHAIRMAN OF THE BOARD FOR DANISH SOCIETY FOR BIOCHEMISTRY
AND MOLECULAR BIOLOGY, PH.D.-STUDENT, CELL DEATH AND METABOLISM, CENTER FOR
AUTOPHAGY, RECYCLING AND DISEASE, DANISH CANCER SOCIETY RESEARCH CENTER.
FRONT PAGE:
Brown bears (Ursus arctos) hibernate for 5–7 months without eating, drinking, urinating, and defecating. Nonetheless, they emerge healthy and alert in spring. Important physiological responses in hibernating bears include reduction in body temperature, cardiac output and metabolic rate (oxygen consumption), compared with those of active bears. Winter hibernators repeatedly cycle between cold torpor and rewarming, supported by nonshivering thermogenesis in brown adipose tissue. In contrast, summer animals are homeotherms, undergoing reproduction, growth, and fattening. This life history confers variability to brown adipose tissue recruitment and activity.Reference: H.V.Carey, M.T Andrews, S.L. Martin. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature.Physiol Rev. 2003;83:1153–1181.
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Brown fat: the biological furnace that could burn away obesityJENS LUND1, JULIA PEICS2,3, ZACHARY GERHART-HINES1
1NOVO NORDISK FOUNDATION CENTER FOR BASIC METABOLIC RESEARCH, UNIVERSITY OF COPENHAGEN, DENMARK;2DEPARTMENT OF BIOCHEMISTRY AND MOLECULAR BIOLOGY, UNIVERSITY OF SOUTHERN DENMARK;3NOVO NORDISK A/S, 2760 MÅLØV, DENMARK. E-MAIL: [email protected]
It is believed that brown adipose tissue (BAT) arose in mammals about 100 million years ago. This thermogenic (also known as heat-producing) organ likely pro-vided a selective advantage that allowed our placental ancestors to leave the dark underground and enter surface habitats which used to be merely dominated by large predators up until the last mass extinction 65 million years ago [1]. For modern humans, harnessing the thermogenic, calorie-burning power of brown fat may now hold the key to battling metabolic dis-ease.
Perfect timing: why is brown fat research all of a sudden so hot?
Although the gross anatomy of BAT was first described as early as 1551 and more detailed morphological depictions were published in the early 1900s, our understanding of BAT physiology did not really evolve until the latter half of the 20th century. Intense research efforts in the 1960s-1980s revealed that this organ mediates both non-shivering and diet-induced thermogenesis [1, 2]. In fact, its potent ability to generate heat is not just utilized in the febrile response to pathogen infections, it also allows for periodic arousal during hibernation, ensures survival of neonates, and makes it possible for larger mammals to thrive in cold conditions [2].
While these revelations represent landmark discoveries to our field, it should be pointed out that the more classical biochemical and molecular biological tools available at that time were quite restrictive factors in early brown fat investigation. In light of novel multi-omic approaches and other mod-ern methodologies, one could view these scientific endeavors as an explora-tion of the darkness guided only by the dim light of an oil lantern. Nevertheless, the seminal work of these pioneering BAT researchers still revealed some of the most significant features of brown fat. These include 1) multiple lipid droplets and enormous amounts of un-coupling protein 1 (UCP1)-containing mitochondria in brown adipocytes, 2) extensive vasculature and sympathetic innervation of this organ and, impor-
tantly, 3) the ability of brown fat to at-tenuate adiposity in rodents.
Despite of these findings, the ini-tial enlightening era of BAT research eventually waned. This stagnation was a result of the prevailing public view that human brown fat was only pres-ent in appreciable amounts in infants. Fortunately, this changed with the new millennium. Using a common cancer diagnostic tool called the PET-scan, radiologists noticed symmetrical regions in the upper-body areas of patients that consumed significant amounts of glucose. Prominent BAT biologists spec-ulated that these observed phenomena could mark the existence of brown fat in human adults.
However, it was not until 2009, when several simultaneous investigations combined imaging technology with his-tological staining to confirm that the pre-viously detected patches of these glu-cose-consuming regions were indeed UCP1-positive brown adipocytes. The fact that three out of the five key papers were published in the same issue of The New England Journal of Medicine gal-vanized the re-ignited interest in brown fat research, as clearly evidenced by the subsequent explosion in publicat ions (Figure 1).
Given that the period between 1960 and 1980 can be seen as the brown adipose ‘Age of Enlightenment’, one could infer that the last decade marks a renaissance in brown fat research. However, we would like to emphasize that this renaissance, in contrast to the one in European history, will not take another three centuries. The field of
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adipose research is virtually exploding as a result of technological advances that are continuously generating major leaps forward. We are able to increas-ingly delve deeper into the metabolic machinery and unravel the innermost cellular complexities of this fascinating organ that clearly does much more than just keeping us warm.
Fueling the engine: what does brown fat burn to create heat?
One of the central tenets of brown fat biology is that when mammals are ex-posed to cold temperature, activated brown adipocytes liberate fatty acids from intracellular lipid droplets to fuel UCP1-dependent thermogenesis [2]. Yet several recent studies have over-turned this long-held dogma using newly developed lipidomic techniques and tissue-specific genetic knockout mouse models. Contrary to previous belief, we now know that brown fat is capable of consuming enormous amounts of circulating lipids (Figure 2) derived from both the intestines (in the fed state) and white adipose depots (in the fasted state) and this appears to bypass the need for lipid reserves within the brown adipocyte itself.
Moreover, white fat-derived lipids can apparently travel towards brown fat via several routes in the form of both triglycerides and acylcarnitines. Another characteristic feature of brown fat is its capacity to consume glucose from the blood. In fact, this is the trait for which the presence of brown fat in adult humans was definitively shown
in 2009. While some of it is converted into lactate (Figure 2), the role of this in-creased glucose uptake in thermogenic function still largely remains a mystery.
Although intracellular and extra-cellular sugar and lipid substrates likely supply the majority of combustibles required for brown fat metabolism, alternative sources of energy could be utilized under certain conditions. Skel-etal muscle shivering is differentially fueled by amino acids when glycogen stores are depleted. Could a similar transition in substrate utilization occur in BAT over the course of long-term cold exposure? Moreover, what helped sustain brown fat when our mammalian ancestors had to survive times of both
prolonged cold exposure and shortage of food? A deeper understanding of how brown fat metabolism is driven will be indispensable in designing strategies to exploit its function therapeutically.
Running the engine: how is brown fat activity controlled?
We have known for decades now that the “fight or flight” sympathetic nervous system is a predominant regula-tor of brown fat function. It induces non-shivering thermogenesis by activating β3-adrenergic receptors and hampers heat production via α2-adreno-ceptor agonism [2]. These basic adren-ergic mechanisms are crucial for rapidly
Figure 1. The emergence of research on brown adipose tissue.
Figure 2. The evolving understanding of brown adipose regulation and its biological impact.
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switching thermogenesis ON or OFF in response to acute changes in ambient temperature. However, other cellular systems refine brown fat responses according to more predictable environ-mental changes that occur on a seasonal and daily basis. These programs are responsible for the expansion of brown fat depots that takes place during winter and its subsequent shrinkage during summer as well as oscillation of brown fat activity throughout the day and night (Figure 2).
The 24-hour rotation of our planet has shaped evolution and provided mammals with sophisticated cellular clockworks that are fine-tuned accord-ing to the length of day. Like a molec-ular metronome, an internal system of interlocked transcription-translation feedback loops generates rhythms for regulating physiological tempos of var-ious tissues in order to match environ-mental cues and hence favor survival. In brown fat, these pendulum swings also dictate diurnal fluctuations in meta-bolic activity, as evidenced by reduced
fuel intake and thermogenesis prior to the onset of sleep [3]. It is unknown why the system is set like this, but one feasible explanation could be that it served to spare calories when most ancient mammals clustered together in a warm and safe nest. Furthermore, the fact that brown fat activity peaks just before dawn highly suggests that it is involved in arousal. Pushing the ther-mogenic throttle at this critical time of the day may have helped our ancestors to, so to say, gather both attention and muscle strength before entering harsh and cold environments for hunting prey.
The holy grail: can brown fat be exploited for biomedical gain?
Besides its role as a defender of mam-malian core body temperature, brown fat is also an important regulator of hu-man metabolic homeostasis (Figure 2). The beneficial effects of activated BAT can be attributed to its direct ability to consume circulating glucose and lipids
in addition to indirect effects such as its secretion of cytokines, also known as batokines [4]. Various techniques examining molecules secreted from fat cells have recently been employed to identify several cold-induced fac-tors. The way these substances affect whole-body metabolism is currently still under investigation. Another po-tentially fruitful area of research aims at identifying non-adrenergic receptors able to trigger brown fat thermogen-esis. This is of special importance because stimulation of such recep-tors could circumvent the adverse cardiovascular effects associated with systemic administration of β-adrenergic receptor agonists. Several cell-surface receptors have already been identified [5], but the entire brown adipocyte ‘receptor skyline’ has yet to be con-structed (Figure 2).
Despite all that has been explored, we believe that the vast body of knowledge, collectively acquired over decades of research, combined with the newest technological develop-ments have uniquely poised brown fat biologists to make unprecedented leaps over the next decade. We hope that these insights will reveal how scientists can take what was once an evolutionary advantage to ancestral mammals and exploit it as a powerful pharmacological weapon in the battle against metabolic disorders that critically threaten the health of our species.
References
[1] Jastroch M, Oelkrug R, Keipert S. Insights into brown adipose tissue evolution and function from non-model organ-isms. Journal of Experimental Biology 2018;221:March 7.
[2] Cannon B, Nedergaard J. Brown adipose tissue: function and physiological signifi-cance 2004; 84:277–359.
[3] Ninel Hansen S, Peics J, Gerhart-Hines Z. Keeping fat on time: circadian control of adipose tissue. Experimental Cell Research 2017;360:31–34.
[4] Villarroya F, Gavaldà-Navarro A, Peyrou M, Villarroya J, Giralt M. The lives and times of brown adipokines. Trends in Endocrinology and Metabolism 2017;28:855–867.
[5] Braun K, Oeckl J, Westermeier J, Li Y, Klingenspor M. Non-adrenergic control of lipolysis and thermogenesis in adipose tissues. Journal of Experimental Biology 2018;221:March 7.
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Brown fat cells in adult humansCAMILLA SCHÉELE, NOVO NORDISK FOUNDATION CENTER FOR BASIC METABOLIC RESEARCH, UNIVERSITY OF COPENHAGEN AND CENTRE FOR PHYSICAL
ACTIVITY RESEARCH, RIGSHOSPITALET, DENMARK. [email protected]
Brown fat is a thermogenic organ in mammals, which is activated by cold exposure. Brown fat cells use lipids as fuel in the mitochondria to produce heat. In humans, brown adipose tissue is present in infants and children playing an important role in thermoregulation. Recently, the presence of brown fat was discovered in human adults rais-ing promises for understanding its role in health and disease. The first challenge is how to detect and measure activation of brown fat cells. Next, to describe the physio-logical role of brown fat during life in young and old individuals. Third, to investigate the brown adipose tissue in pathological con-ditions like obesity.
A fat cell that consumes energy sounds contradictive. It is nevertheless true for the heat-producing, mitochondria-rich brown fat cell. A sympathetic response to cold stimulates brown fat cells to burn stored lipids as fuel in the mitochondria, which uncouple through uncoupling protein 1 (UCP1), allowing the energy to dissipate as heat. This activation is associated with a simultaneous uptake of glucose and lipids from the blood stream to rebuild the lost lipid storages (Figure 1).
Thus, whereas brown fat primarily evolved as a thermogenic organ in mam-mals, it has the potential for counteract-ing obesity and its associated diseases. The discovery of cold-responsive brown fat cells in adult humans a decade ago further raised the expectations on iden-tifying factors that could enhance brown fat cell activity in humans (1). Since then, research on human brown fat function and physiological relevance, as well as tools for investigating brown fat activity has exploded.
How to study brown fat in humans
A challenge in brown fat research in adult humans is the difficulty of obtain-ing brown fat needle biopsies. The rea-son for this is that the most accessible brown fat in adult humans appears in the neck region, and biopsies are thus associated with risks of accidentally injuring major blood vessels or even puncturing a lung. Another problem is that the fat tissue in this region is het-erogeneous and only partly contains cold-responsive brown adipose tissue (BAT). Therefore, some laboratories have developed methods to perform PET/CT-scanning following cooling
of the subjects, to find the areas of cold-responsive BAT prior to obtaining a needle biopsy in the neck region. This kind of approach is still risky and resource demanding and not possible for most laboratories. An alternative approach is to collect the tissue biop-sies during unrelated neck surgery, for example during removal of a dys-functional thyroid gland. With surgical approaches, it is also possible to access the deeper brown fat depots, including the tissue around the kidney, called perirenal fat.
Active brown fat cells can be visual-ized in humans by injecting a radioactive glucose tracer, cooling down the subject and subsequently performing a PET/CT or a PET/MRI scan. The cooling initiates a sympathetic response, which activates heat production in the brown fat cells, leading to lipid and glucose uptake. The fat tissue including the glucose tracer therefore represents the active brown fat cells.
An alternative technique is infrared thermography. This is simply a camera, which is sensitive for infrared radia-tion, and therefore detects fluctuations in heat. The camera images the skin temperature and is therefore only use-ful for studying the more superficial brown fat depots, including the one in the neck region. The advantages with this technique are that it is completely non- invasive and that it allows for meas-urements of brown fat heat production to acute stimuli in real-time. Using both techniques is so far preferable as the PET/CT or PET/MRI scans allows for a more precise quantification of the amount of active brown fat compared to infrared thermography.
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Brown fat is reduced in aging and obesity
Brown fat is abundant and important in infants where it like a “thermogenic jacket” covers the back and the neck region as well as part of the arms. Brown fat activity decreases with age and al-though morphological traces of brown fat have been observed at high ages (2), the acute response to cold is decreased (3). Why do we get less active brown fat with age? An early hypothesis was that thermogenic regulation is immature in children while it gradually stabilizes with age. This could be benefi cial for adapta-tion to the environmental conditions of a growing child. Today, most of us live
our lives at thermoneutrality. We have central heating and warm clothes to pro-tect us from cold. This could be a simple explanation to why brown fat activity declines in adult humans.
In obesity, brown fat responsiveness is even more reduced and the increased lipid storage is mainly handled by white fat cells. Interestingly, when obese people were subjected to daily cold treatments for a few weeks, their brown fat became more responsive to acute cold (4), suggesting a fl exibility between an inactive, i.e. dormant, brown fat cell type, and an active brown fat cell type, which directly responds to cold by producing heat. This observation is sup-ported by studies in mice. Here, hous-
ing mice at thermoneutrality results in a more white-like cell type in the brown fat depot.
Dormant brown fat in adult humans
We wanted to investigate the brown fat following the decline in activity in adults. We therefore performed a study on perirenal fat i.e. the fat tissue surround-ing the kidney (5). The perirenal fat is interesting due to its asymmetric access to local sympathetic activity. The upper pole of the kidney is close to the adrenal gland, producing norepinephrine and epinephrine. By comparing different sites of the perirenal fat, we discovered
heatbrown fat cell
batokines
metabolismBAT recruitment
ATP
glucose
NEFAadenylatecyclase
UCP1
lipid
H+
NADHO2
H2O
H+
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Figure 1. Active Brown Fat. β-adrenergic signaling is induced by cold, and the released norepinephrine (NE) binds to β-adrenergic recep-tors at the brown fat cell surface. This induces a lipolysis signaling cascade including activation of adenylyl cyclase to catalyze the conver-sion of ATP into cyclic adenosine monophosphate (cAMP). The increased intracellular concentration of cAMP results in the activation of protein kinase A (PKA). PKA initiates lipolysis for example through activation of hormone sensitive lipase (HSL), resulting in the release of free fatty acids (FFA). These intracellular FFA constitute the main substrate for the active brown fat and allow for acceleration of the mito-chondrial electron transport chain, building up a membrane potential in the mitochondria. The mitochondria are then uncoupled through mitochondrial brown fat uncoupling protein 1 (UCP1), resulting in the dissipation of energy as heat. Active brown fat has an increased plasma uptake of glucose and NEFA, and might thus serve as a “metabolic sink”. There are some reports in the literature that active brown fat also secretes brown fat specifi c adipokines, known as “batokines” that could infl uence metabolism and/or induce recruitment of brown fat precursor cells. Reproduced from Scheele and Nielsen (1).
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a more active BAT phenotype close to the adrenal gland, but also found that the rest of the perirenal fat were mor-phologically similar to white fat (WAT), yet contained brown preadipocytes and expressed some of the brown fat mark-ers. We concluded that rather than disappearing with age, the brown fat surrounding the kidney becomes dormant and this is associated with local sources of sympathetic ac-tivity. This fi nding is important as it means that adult humans actually could increase their amounts of cold-responsive BAT by reactivation of dormant BAT depots.
Future perspectives
If we can identify regulators of brown fat cell recruitment by targeting brown fat progenitor cells or by switching the phenotype of white fat cells into brown-like cells with en-ergy consuming properties, we would have a novel strategy to counteract obesity in humans.
Currently, researchers are putting much effort into in-vestigating factors secreted from brown fat cells, called batokines. Some of these factors might be important for priming brown fat cell differentiation and for providing a reactivation of dormant brown fat cells. Other batokines could be important regulators of appetite and energy ex-penditure. Importantly, by studying the cross-talk between batokines and brain, novel pathways controlling appetite regulation could be identifi ed. Indeed, efforts should focus on identifi cation and neutralisation of brown fat induced energy-saving negative feedback circuits. Allowing the brown fat to be active for a longer time would increase the anti- obesity effect.
Another approach for understanding the regulation of fat cell properties can be provided by studying fat cell progen-itor cells at single cell level. By comparing the gene expres-sion between fat cell precursor cells derived from multiple brown and white fat depots, we hope to identify key regula-tors of brown versus white fat cell types, which then can be used to manipulate white fat progenitors into brown.
In conclusion, the last decade of brown fat research has leveraged our understanding of human brown fat biology and has thereby provided us with new tools and ideas on how to search for alternative anti-obesity strategies.
References
1. Scheele C, Nielsen S. Metabolic regulation and the anti-obesity perspectives of human brown fat. Redox Biol. 2017;12:770-775. doi: 10.1016/j.redox.2017.04.011.
2. Heaton JM. The distribution of brown adipose tissue in the hu-man. J Anat. 1972 May;112(Pt 1):35-9.
3. Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, Miyagawa M, Tsujisaki M, Saito M. Age-related de-crease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring). 2011 Sep;19(9):1755-60. doi: 10.1038/oby.2011.125.
4. Hanssen MJ, van der Lans AA, Brans B, Hoeks J, Jardon KM, Schaart G, Mottaghy FM, Schrauwen P, van Marken Lichtenbelt WD. Short-term Cold Acclimation Recruits Brown Adipose Tis-sue in Obese Humans. Diabetes. 2016 May;65(5):1179-89. doi: 10.2337/db15-1372.
5. Jespersen NJ, Feizi A, Andersen ES, Heywood S, Hattel HB, Daugaard S, Bagi P, Feldt-Rasmussen B, Schultz HS, Hansen NS, Krogh-Madsen R, Pedersen BK, Petrovic N, Nielsen S, Scheele C. Asymmetric perirenal brown adipose dormancy in adult humans is defi ned by local sympathetic activity. Biorxiv. 2018. doi: https://doi.org/10.1101/368621
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Plasticity of Thermogenic AdipocytesLASSE K. MARKUSSEN, MAJA W. ANDERSEN, SUSANNE MANDRUP,
CENTER FOR FUNCTIONAL GENOMICS AND TISSUE PLASTICITY (ATLAS), FUNCTIONAL GENOMICS & METABOLISM RESEARCH UNIT,
UNIVERSITY OF SOUTHERN DENMARK. [email protected]
White and brown adipocytes play different roles in metabolism and physiology. However, both cell types appear to be plastic with an ability to switch between metabolic states in response to changes in the cellular environment. Hence, the separation between brown and white adipocytes is less clear than previously thought.
Adipocytes are mesenchymal cells specialized in storing large quantities of lipids in the cytosol as lipid droplets. They are found in adipose tissues such as those located subcutaneously or intra-abdominally, as well as in many smaller depots within or surrounding organs. Examples include the adipose tissue in the bone marrow and the adi-pose tissue associated with the kidneys and the adrenal gland. In addition, ad-ipocytes can be found interspersed in other tissues, e.g. in muscle fi bers and thymus. While the general biochemical function of all adipocytes is related to lipid storage, the specifi c physiological functions of adipocytes in the different tissues and their cross-talk with other resident cell types are not well under-stood. Interestingly, an increasing body of evidence indicates that adipocytes display a remarkable plasticity in re-sponse to the specifi c tissue niche as well as physiological stresses such as under- and over-nutrition, environmen-tal temperature, exercise, and age.
White and brown adipocytes
Traditionally, adipocytes have been clas-sifi ed as white or brown. White adipo-cytes are large unilocular cells special-ized in storage and release of fatty acids. Endocrine signals derived from these adipocytes provide continuous informa-tion to the brain as well as peripheral tis-sues on the degree of fi lling of adipocyte stores. Brown adipocytes contain many smaller lipid droplets (multilocular) and many mitochondria that are partially uncoupled owing to high expression of the uncoupling protein 1 (UCP1). As a result, these adipocytes are specialized in oxidation rather than release of fatty acids and in conversion of metabolic energy into heat (i.e. non-shivering
thermogenesis). The major activator of non-shivering thermogenesis is be-lieved to be cold exposure, which leads to release of norepinephrine from the sympathetic nervous system (SNS) and activation of β-adrenergic receptors on brown adipocytes.
Brown-like adipocytes – a new cell type?
More recently a third type of adipocyte, the brown-like (or beige, brite) adipo-cyte, has been shown to be induced in certain white adipose tissues (WAT) in rodents in response to physiological stresses such as cold (Figure 1). Similar to brown adipocytes, brown-like adipo-cytes are rich in mitochondria that ex-press UCP1 and can perform non-shiv-ering thermogenesis. During the recent years, these adipocytes have attracted considerable research interest because of their potential to increase WAT en-ergy metabolism, which may increase whole-body energy expenditure and promote clearance of glucose and fatty acids from the plasma. Notably, mice lacking brown adipose tissue (BAT) become obese, while BAT transplan-tation reverses obesity in obese mice, indicating that, at least in rodents, BAT contributes signifi cantly to organismal energy expenditure. Thus, the hope is that by recruiting brown-like adipocytes in humans one could combat obesity or the metabolic consequences thereof.
So far more than hundred signals/factors promoting browning of white adipocytes in rodents have been identi-fi ed (Figure 1). In humans, browning of WAT has been demonstrated in patients with pheochromocytoma, i.e. with chro-nically high levels of norepinephrine, as well as in cancer cachexia. These examples show that browning of human
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WAT is possible; however, the extent to which browning of WAT occurs in hu-mans during non-diseased physiological conditions is currently not clear.
One of the much debated questions in the fi eld is whether brown-like adi-pocytes should be considered brown adipocytes, or whether they represent a distinct cell type. It has been argued that brown-like adipocytes express specifi c brown-like defi ning marker genes; how-ever, none of these marker genes have been linked to important biochemical functions and many appear to derive from anatomical position. Furthermore, no markers are unique for any single adipocyte type (brown, white or brown-like) (1).
Importantly, brown-like adipocytes appear to perform the same biochemical functions as classical brown adipo-cytes and to be activated by the same browning agents. In this respect, it is also worth noting that the sympathetic neuronal pathways stimulating WAT and BAT have identical origins in the brain. Thus, the distinction between brown and brown-like adipocytes appears somewhat artifi cial.
Another controversial question is which cells give rise to the brown-like adipocytes, i.e. do they primarily arise by phenotypic switching of existing white adipocytes into brown-like adipo-cytes (transdifferentiation), or are they recruited by de novo differentiation of progenitors? Lineage-tracing studies, where cells are permanently “labelled” due to their expression of a particular
lineage-specifi c gene, have recently provided evidence that both pathways play a role in browning of rodent WAT and that the relative importance of these pathways depends on the tissue and the environmental challenge. Notably, however, such lineage-tracing studies are inherently biased towards cells that express one particular gene, and further insight into this question awaits future more unbiased approaches such as sin-gle-cell sequencing.
Adipocyte heterogeneity and plasticity
A key question that to date remains unanswered is whether the ability to undergo browning is restricted to a subpopulation(s) of progenitor cells and mature adipocytes in WAT, or whether every white adipocyte has the ability to differentiate into a brown-like adi-pocyte. In support of adipocyte heter-ogeneity, a recent study identifi ed two adipocyte populations in subcutaneous adipose tissue in mice – one brown-like subpopulation that expressed high levels of medium-chain acyl-CoA de-hydrogenase (MCAD) and UCP1 but low levels of fatty acid synthase (FASN), and another white subpopulation that expressed high levels of FASN, and low levels of MCAD and UCP1 (2).
Furthermore, another recent study observed that around 50% of former UCP1-positive brown-like adipocytes became UCP1-positive again when re-exposed to cold after an intermediate
whitening period (3), suggesting that adipocytes that once were brown-like constitute a subpopulation with an epi-genetic memory of being brown.
The above reports clearly support adipocyte heterogeneity of WAT that has been exposed to browning signals. The question is how this heterogeneity arises in the fi rst place. Interestingly, after re-exposure to cold temperatures, brown-like adipocytes primarily local-ize to islands of brown-like adipocytes within the WAT, indicating that the mi-croenvironment is a crucial factor for de-termining adipocyte fate. In particular, the proximity to norepinephrine fi bers might be a determining factor, since these fi bers correlate with the number of brown-like adipocytes, and since the lack of β3-adrenoreceptors depressed browning (4). Thus, the apparent heter-ogeneity may arise as a result of proxim-ity to norepinephrine fi bers.
Interestingly, during conditions of thermoneutrality or chronic positive energy balance, brown and brown-like adipocytes convert to white adipo-cytes, a process called whitening. In addition, in several mammals as well as humans there is a general decrease in the amount of BAT following weaning, and during aging. This indicates that the thermogenic phenotype of brown and brown-like adipocytes is reversible and requires sustained β-adrenergic stimulation to maintain the thermogenic signature.
Thus, depending on how one defi nes a cell type, one could view brown-like
• Cold exposure (norepinephrine)• Hormones (BMP7, T3, FGF21)• Metabolites (lactate, bile acids, FFAs)
White Brown-like
• Warm environment • Aging• Weight gain• Weaning
Stimulatory signals
Inhibitory signals
Figure 1: Physiological signals controlling browning of white adipocytes. Cold exposure which leads to release of norepinephrine from the sympathetic nervous system is the most prominent activator of adipocyte browning; however, numerous circulating hormones and metabolites have also been implicated in browning. By contrast, several physiological conditions, such as warm environment, aging, weight gain and weaning, are known to reduce browning.
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adipocytes as products of cellular plas-ticity of progenitors and mature adipo-cytes, and the interconversion of white to brown-like adipocytes as phenotypic transitions allowing the organism to adapt to physiological stresses. These emerging intricacies call for a revision of the classifi cation of adipocytes.
Progenitor heterogeneity and plasticity
Intriguingly, progenitors isolated from different adipose depots retain their de-
pot-specifi c characteristics in culture (5), suggesting that the microenvironment has preprogrammed the progenitors to a particular adipocyte sub-lineage and that this preprogramming is relatively stable. The question is whether there in a given WAT are distinct populations of white and brown-like progenitor cells, or whether progenitors are mostly bi-potent with cellular fate decisions being determined stochastically or by condi-tional signals.
Subclonal analyses of cells from the subcutaneous WAT suggested
that there are distinct subpopulations of brown-like and white progenitors. Interestingly, however, there is also evidence of bipotent progenitor cells that have the potential to differen-tiate into brown-like adipocytes upon β-adrenergic stimulation and into white adipocytes following feeding with high-fat diet. These results indicate that despite differential preprogramming of progenitor cells in the different adipose tissues, at least some progenitor cells display plasticity in response to the ap-propriate signals.
Interplay between plasticity and heterogeneity
The above discussion highlights that adipocyte phenotype is the result of the balance between fate-conserving and plasticity-inducing mechanisms. According to the more classical model (Figure 2A), dedicated white progenitor cells exclusively differentiate into white adipocytes, brown progenitor cells into brown adipocytes and brown-like pro-genitor cells into brown-like adipocytes. According to this model, brown-like adipocytes convert back to dormant “white” adipocytes when thermogene-sis is no longer a priority. The dormant “white” adipocytes and classical white adipocytes are viewed as different cell types defi ned by specifi c marker genes, as discussed above.
The second model (Figure 2B) pro-poses that although progenitor cells and mature adipocytes are preprogram-med toward a specifi c lineage, they still retain some degree of plasticity and can change this preprogramming in response to physiological signals. At this point none of the models can be ex-cluded, but data to support the second model is accumulating.
Concluding remarks and future perspectives
Thermogenic adipocytes have been intensively studied during the recent years because of their alleged potential to counteract the development or con-sequences of obesity. However, there are still many open questions regarding the origin, plasticity and regulation of these cells. These include questions such as: What drives thermogenic ad-ipocyte plasticity? What niche-specifi c
White Brown-like Brown
Preprogrammed progenitors
White
A
B
Brown
Thermogenic programUCP1, mitochondria, FFA oxidation
Adipocyte size
Figure 2: Adipocyte plasticity. Two competing models explaining the relationship between different types of adipocytes. (A) In the fi rst model, all progenitor cells are preprogrammed to a specifi c lineage (white, brown-like or brown), and only brown-like and dormant white adipocytes have the potential to undergo browning and remain plastic. (B) In the second model, adipocytes and their progenitors constitute a continuum of states. The inherent memory of the state in each cell works to conserve the state, whereas plasticity is induced in response to certain physiological signals. Fortsættes side 15
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Down the drain – Brown adipose tissue as a metabolic sinkSALLY WINTHER,
NOVO NORDISK FOUNDATION POSTDOCTORAL FELLOW, DANA FARBER CANCER INSTITUTE AND HARVARD MEDICAL SCHOOL,
BOSTON, USA. [email protected]
The high metabolic demand of uncoupled respiration in activated brown adipose tissue gives it unique capabilities in combating obesity and metabolic disease. The rich supply of fuels needed to sustain thermogenesis in brown adipocytes requires substantial up-take of glucose and lipids from the blood stream, creating a metabolic sink in the tissue. In this way, ex-cess metabolites are efficiently dis-posed of by using the high energy turn-over in brown adipose tissue as a metabolic drainage system to counteract metabolic dysfunctions such as dyslipidemia and hyper-glycemia.
Increasing body weight is often closely followed by other metabolic disruptions such as abdominal fat accumulation, high blood pressure and increased glu-cose and triglyceride levels in the blood. The clustering of these related condi-tions greatly increases the risk of devel-oping cardiovascular disease and type 2 diabetes. Finding new ways to combat not only obesity, but also alleviating the underlying metabolic dysfunction is of great importance. The unique ability of brown adipose tissue (BAT) to uncou-ple mitochondrial respiration from ATP production creates a futile cycle where energy is wasted at the expense of heat production.
From an obesity perspective this specialized function of BAT holds the potential to increase (resting) energy expenditure providing a much-needed
burning of calories to normalize the weight balance. However, the therapeu-tic promise of BAT activity is not limited to its effect on energy expenditure, but also its ability to counteract dyslipidemia and hyperglycemia by sequestering metabolites from the circulation (Figure 1). On unit weight basis the nutrient consuming properties of BAT are un-matched by any other tissue, at least in mice [1]. From human studies it seems, that at least BAT glucose utilization is of systemic relevance, underlining its potential use as a metabolic sink for cir-culating metabolites.
Fueling thermogenesis – substrate uptake in BAT
The thermogenic process in BAT re-quires a rich supply of substrates. Ox-
Figure 1: Brown adipocytes can serve as a sink for harmful metabolites. Increased intake of triglycerides and glucose leads to obesity and metabolic disease. Uptake and combus-tion of these nutrients in brown adipocytes protect against metabolic disease and obesity by clearing excess metabolites from the circu-lation. Figure adapted from [1].
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idative phosphorylation of fuels such as sugar and lipids in the mitochondria extracts high-energy electrons that are transported by the electron transport chain (ETC) to their ultimate destination, molecular oxygen, which is reduced to water in the last step of the chain. The ETC uses this flow of electrons to establish an electrochemical proton gradient across the inner mitochondrial membrane. Re-entering of protons to the mitochondrial matrix is usually cou-pled to ATP synthesis, but in activated BAT uncoupling protein 1 (UCP1) allows for protons to leak across the inner mi-tochondrial membrane, bypassing ATP production and dissipating the stored energy as heat. Hence, during thermo-genesis fuel oxidation is uncoupled from ADP phosphorylation, resulting in an energy-consuming futile proton cycle.
Initially the brown adipocytes can utilize its internal stores of lipids, but to sustain the high energy demands, substrates from outside the tissue are needed. Cold-activated brown adipo-cytes therefore take up large quantities of lipids and glucose from the blood-stream to use for immediate combus-tion, or to store in lipid droplets or gly-cogen for later use.
In cold-exposed mice it has been shown that following a fatty meal, nearly 50% of the ingested triglycerides ended up in BAT, underlining the magnitude of BAT’s lipid clearing capabilities (Figure 2) [2]. Following cold exposure, the triglycerides are efficiently channeled into BAT by upregulation of specific transporters and enzymes that boost tri-
glyceride availability and uptake. Impor-tantly, it was shown that under patho-physiological conditions thermogenic activation could correct hyperlipidemia and improve the deleterious effects of obesity in mice [2]. Initial reports show that activated human BAT utilizes its internally stored lipids but also take up fatty acids from the circulation, but its contribution to systemic clearance is comparatively small.
Glucose clearance by BAT
Glucose uptake in BAT is at basal condi-tions comparable to the uptake in highly glycolytic tissues such as brain and kidneys and after cold exposure glucose uptake is even further increased. In fact, cold-activated BAT has the highest glu-cose uptake of any tissue in mice (Figure 2) [2]. BAT’s avid uptake of glucose is actually what led to its rediscovery in adult humans 10 years ago, since human brown fat was first noticed by radiologist as symmetrical areas with high glucose uptake in PET scans of cancer patients.
Later it was shown that cold exposure of could increase glucose uptake in human BAT even further, and that this cold-induced BAT activity positively im-pacts whole-body glucose homeostasis and insulin sensitivity. Even in subjects initially classified as BAT negative (based on baseline scans) cooling can induce glucose uptake in BAT, although to a les-ser extent than in BAT positive subjects.
The exact amount of glucose, that activated BAT can clear from the blood stream in humans still remains to be de-
termined, but a conservative estimate is somewhere between 3-9 grams of glu-cose per day depending on BAT volume and activation degree. In a study with lean patients, glucose uptake per gram tissue in BAT was shown to be equal to that of skeletal muscle, and exceed that of insulin-stimulated skeletal muscle when the subjects were cold-exposed [3].
Underscoring the important role of glucose metabolism many genes involved in glucose uptake and catab-olism are upregulated in BAT after cold exposure, and the activity of several key glycolytic enzymes is also increased in cold acclimated rodents. The glucose consumed by activated BAT can be channeled into different catabolic path-ways, it might be used directly as a fuel through glycolytic breakdown to pyru-vate or be turned into triglyceride to replenish intracellular lipids stores [4].
Recent studies showed unaltered glucose uptake in UCP1 knockout (ther-mogenically defect) mice. This obser-vation means that even though most of the time, glucose uptake coincides with thermogenesis, it is not a direct con-sequence hereof. In line with glucose uptake, noradrenaline induced increase in BAT blood flow is also independent of UCP1. Suggesting these processes might not be functionally connected but rather stimulated in parallel by cold-ex-posure.
The clever thing about utilizing BAT as a glucose sink for treatment of diabe-tes is that cold-induced glucose uptake is insulin-independent, making this
Figure 2: Brown adipose tissue substrate uptake. Left panel: relative amounts of different tissues in normal (“lean”) mice. Middle panel: proportions of ingested triglyceride taken up by different tissues following feeding with a fatty meal. Right panel: proportion of ingested glucose taken up by different tissue in obese mice exposed to cold. Figure modified from [7], based on data presented in [2].
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approach viable even in subjects with insulin-resistance. Proof-of-principle studies in mice have actually shown that increasing BAT mass by transplantation can improve glucose tolerance and insulin sensitivity in models of obesity and type I diabetes. Together this makes BAT a desirable target for anti-diabetic treatment.
Sequestering of signaling metabolites in BAT
Lipids and glucose are the classic metab-olites associated with uptake in brown adipocytes, but brown adipocytes also take up other metabolites. This is of particular interest because multiple me-tabolites have been shown to not only function as energy sources and anabolic substrates, but also as intra- and extra-cellular signaling molecules [5].
Recently, we identified that cold-ac-tivated BAT can accumulate substantial amounts of the Krebs cycle metabolite succinate [6]. We showed that activated BAT actively take up succinate from the circulation, a hitherto undescribed phenomenon, which also provides an integrating paradigm for the longstan-ding observation of variable and sub-stantial concentrations of succinate in the blood stream. The source tissue for succinate is still undetermined, but at least under cold conditions BAT acts as a specific sink for circulating succinate.
The uptake and accumulation of a metabolite like succinate is interesting for multiple reasons. First, we observed that succinate in itself was an activator of thermogenesis in brown adipocytes, and that just adding succinate to the drinking water of mice could increase
their energy expenditure and counteract diet-induced obesity. Hence, our find-ings suggest that dietary interventions that involve acute elevation of systemic succinate levels may protect against metabolic disease, but only for individu-als with a sufficient endowment of ther-mogenic adipose tissue.
Furthermore, it has been suggested that chronically elevated succinate can promote an inflammatory response. Therefore, our findings imply that a major anti-inflammatory mechanism of BAT activity may involve sequestration of circulating succinate to antagonize systemic inflammation. Since the met-abolic disruptions coinciding with obe-sity are also associated with a chronic low-grade inflammation, using BAT to sequester potential pro-inflammatory metabolites, like succinate, could be of substantial interest. The discovery that a single mitochondrial metabolite is a molecular driver of adipocyte thermo-genesis opens many interesting avenues of investigation into the selective uptake of metabolites not only in BAT, but also other metabolically active tissues.
Perspectives
Exposure to environmental cold ef-fectively drives BAT activation and im-proves metabolic profiles in both mice and humans. Curiously, it seems that BAT has a unique ability to sequester multiple different metabolites from the circulation, many of which when pres-ent in excess amounts have deleterious effects on health. The sink and drain effect, where activated BAT not only takes up these metabolites, but also has an efficient way of disposing of them via
uncoupled respiration is quite unique. To take advantage of this effect we need to establish efficient ways of boosting BAT activity, and preferably find alter-native ways of activating metabolite uptake besides just letting mice and people freeze. Being able to control the flow of metabolites in the blood stream could pose huge advantages to treating obesity, diabetes, heart disease, inflam-mation, fatty liver disease, and many others.
References
1. Bartelt, A. and J. Heeren, Adipose tissue browning and metabolic health. Nat Rev Endocrinol, 2014;10:24-36.
2. Bartelt, A., et al., Brown adipose tissue activity controls triglyceride clearance. Nat Med, 2011;17:200-205.
3. Peirce, V. and A. Vidal-Puig, Regulation of glucose homoeostasis by brown adi-pose tissue. Lancet Diabetes Endocrinol, 2013;1:353-60.
4. Hankir, M.K., M.A. Cowley, and W.K. Fenske, A BAT-Centric Approach to the Treatment of Diabetes: Turn on the Brain. Cell Metab, 2016;24:31-40.
5. Murphy, M.P. and L.A.J. O’Neill, Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Trans-ducers. Cell, 2018;174:780-784.
6. Mills, E.L., et al., Accumulation of succinate controls activation of adipose tissue ther-mogenesis. Nature, 2018;560:102-106.
7. Nedergaard, J., T. Bengtsson, and B. Can-non, New powers of brown fat: fighting the metabolic syndrome. Cell Metab, 2011;13:238-40.
signals regulate plasticity? And are there fundamental functional differences between the brown and brown-like thermogenic program, or do brown-like adipocytes represent shades of brown? Resolving these fundamental questions will require a combination of the use of intelligent lineage-tracing mouse mod-els, single cell sequencing and advanced molecular studies.
References
1. Roh HC, Tsai LTY, Shao M, Tenen D, Shen Y, Kumari M, et al. Warming Induces Sig-nificant Reprogramming of Beige, but Not Brown, Adipocyte Cellular Identity. Cell metabolism. 2018;27(5):1121-37.e5.
2. Lee YH, Kim SN, Kwon HJ, Granneman JG. Metabolic heterogeneity of activated beige/brite adipocytes in inguinal adipose tissue. Scientific reports. 2017;7:39794.
3. Rosenwald M, Perdikari A, Rulicke T, Wolfrum C. Bi-directional interconversion of brite and white adipocytes. Nature cell biology. 2013;15(6):659-67.
4. Jimenez M, Barbatelli G, Allevi R, Cinti S, Seydoux J, Giacobino JP, et al. Beta 3-adrenoceptor knockout in C57BL/6J mice depresses the occurrence of brown adipocytes in white fat. European journal of biochemistry. 2003;270(4):699-705.
5. Siersbaek MS, Loft A, Aagaard MM, Nielsen R, Schmidt SF, Petrovic N, et al. Genome-wide profiling of peroxisome proliferator-activated receptor gamma in primary epididymal, inguinal, and brown adipocytes reveals depot-selective binding correlated with gene expression. Molecular and cellular biology. 2012;32(17):3452-63.
Fortsat fra side 12
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Besøg
www.cotedor.dk
News from Danish Society for Biochemistry and Molecular BiologyMETTE VIXØ VISTESEN,
CHAIRMAN OF THE BOARD FOR DANISH SOCIETY FOR BIOCHEMISTRY AND MOLECULAR BIOLOGY, PH.D.-STUDENT, CELL DEATH AND METABOLISM,
CENTER FOR AUTOPHAGY, RECYCLING AND DISEASE, DANISH CANCER SOCIETY RESEARCH CENTER. [email protected]
The Danish Society of Biochemistry and Molecular Biology (DSBMB) was represented by Board member Cord Brakebush at the Council Meeting of the Federation of European Biochemical Societies (FEBS), which was held in con-nection with the annual FEBS congres in Prague, July 2018. At the FEBS Council Meeting, reports about the recent activi-ties were given and discussed.
FEBS is a charitable academic organi-zation with the aim to support scientific advances in Life Sciences in Europe. FEBS finances are developing well, and it is expected that in the coming years even more scientific activities can be supported by FEBS. These are besides the annual FEBS Congress (www.febs.org/our-activities/annual-con-gress-forums/), the Advanced Courses (www.febs.org/our-activities/ad-
vanced-courses/), and in particular the Research Fellowships (www.febs.org/our-activities/fellowships/), for which all members of the Danish Society for Biochemistry and Molecular Biology are eligible. Particularly the short-term fellowships have a good funding quota. Taken together, members of DSBMB are encouraged to take advantage of the opportunities, FEBS is offering!
The FEBS Congress 2019, which will be held in Krakow, Poland, is an excel-lent opportunity for young scientists to obtain an overview about all that is currently “hot” in biochemistry and to network with scientists from all over Europe and many oversea countries. https://2019.febscongress.org
DSBMB is also involved in the Dan-ish Bioimaging Meeting in Odense in October and the Host-Pathogen Com-
munication Meeting in Israel in Novem-ber. Read more about these upcoming meetings, and find the sign-up links on our webpage www.biokemi.org. If you are planning to host a meeting within the scope of the society, don’t hesitate to contact us. We have a small budget to participate in covering meeting-related expenses, and a good platform for spreading the word about the event.
Finally, we would like to invite all our members to the annual General Assembly of DSBMB. This year, it will take place on Monday November 12th from 15:00-16:00 at the Biocenter, Ole Maaløes Vej 5, 2200 København.
KEN Hygiene Systems har udviklet en helt ny IQ serie af laboratorieopvaskere, alle tilpasset fremtidens krav til vask og desinfektion. Mød os i Øksnehallen den 12. og 13. september 2018.
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Lille fysisk footprint. Minimalt pladsforbrug og serviceadgang fra maskinens front
Økonomien er i topklasse ved lavt vand-, el- og kemiforbrug.
Miljøet skånes ved det lave vandforbrug, og CO2 udslippet er begrænset
Super funktionalitet med lave procestider, støjsvag drift og brugervenlig touch screen
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Dorte Egelund klarede alle kriser og vil nu udvide sine aktiviteterAF JOURNALIST IB CHRISTENSEN, CYPRESS KOMMUNIKATION
Dorte Egelund grundlagde niche virksomheden Dorte Egelund ApS da finanskrisen brød ud og har overlevet alle kriser i en barsk branche som højt specialiseret leverandør til mikrobiologiske og biotech laboratorier ved at stille høje krav til sig selv, lytte til og turde udfordre kunderne
Bakterier og svampe har været mit speciale hele mit liv. Sådan har det altid været. Jeg beskæftiger mig med det, der skal til for at dyrke bakterier og celler og få dem identificeret, så dette er mit nicheområde.
Noget af det seneste Dorte Egelund har udvidet sin virksomhed med er Poly Chain Reaction, PCR, som er optaget i sortimentet, for at styrke firmaet og give den det et tredje ben at stå på. PCR er det bioteknologibranchen anvender til hurtig diagnosticering.
Dorte Egelund ApS har foruden PCR to ”ben” at stå på, apparatur og for-brugsartikler inden for mikrobiologi til
bioteknisk industri. Virksomheden har tilknyttet nogle af verdens bedste pro-ducenter af mikrobiologiske løsninger og udstyr til procesoptimering indenfor celledyrkning.
– Vi kan ikke udføre analysen for kunderne, vi har intet laboratorium, men kan levere udstyr og viden og hjælpe med at forstå aflæsningerne, teknikkerne og hvorfor der optræder bestemte mikrober lige netop dér – og hvad de skal gøre for at få dem væk.
Startede med finanskrisen
Firmaet har ti års jubilæum den 1. ok-tober i år. Det er meget godt gået i en tid, hvor der har været masser af bryd-ninger, konkurser og alt muligt, mener Dorte Egelund.
– Da jeg startede i 2008 og hen-vendte jeg mig til min bank, hvilket var ugen efter Roskilde Bank var gået konkurs og alle banker var i højeste alarmberedskab. Jeg bad bare om en kassekredit, fik startet op og valgte efter et par år at afskaffe kassekreditten som jeg aldrig brugte.
Dorte Egelund er laboratorieteknikker, merkonom i salg og markedsføring, samt erhvervsøkonomi, foruden at være mor til 4 voksne børn og vant til ”at være utro-lig rationel i min tilgang til tingene”. Jeg kan sagtens sætte mig ind i kundernes dilemmaer og se udveje til at de hurtigt kommer videre med den største gevinst.
Jeg har en mikrobiologisk baggrund og arbejdet i offentlige og private labo-ratorier, med udvikling af nye metoder og især med celledyrkning og udvikling af nye dyrkningsoverflader.
I 2015 fik Dorte Egelund Børsens Gazellepris og har opnået triple A i kre-ditvurderingsinstitut (Bisnode) som er den højeste rating. Det kan godt være vi ikke er store, siger Dorte Egelund, men vi er stabile, har en sund økonomi og vil være at finde på markedet fremadrettet. Vi bygger på langvarige relationer til le-verandører og vore kunder.
Nichevirksomhed og samarbejdspartner
Jeg er en mindre spiller, der går ind i nicher, hvor jeg er alene. Jeg har så vidt muligt valgt at samarbejde med de føren de leverandører i Europa og USA. Vi er ikke bare leverandør, men samar-bejdspartner til kunderne og fokuserer på at skabe øget værdi for dem.
Det er en blanding af produkter til ru-tine samt til forskning og udvikling. Vor kundegruppe er bred. Det er universi-teter, farmaceutiske- og bioteknologiske virksomheder. Hos nogle af dem er vi aktive både på kontrolsiden inden for mikrobiologi og indenfor deres forsk-nings- og udviklingsafdelinger.
Vor opgave er at gå ud og afdække kundens behov og supportere dem ad den vej. Kunderne oplever gennem vort samarbejde, at vi kommer ud og vi ser, hvilke udfordringer de har. Når vi ken-der dem, kan vi byde ind med løsninger.
Formuer at hente på bundlinjen
Et af de helt store emner for tiden er, at vi har en del produktionsvirksomheder som bruger levende mikroorganismer som led i deres produktudvikling. For 4-5 år siden mente de, at de havde den nødvendige viden.Vi spurgte, hvordan de kunne være sikre på at bakterierne har optimale vækstbetingelser og ikke har ændret egenskaber.
Det, der nu er sket er, at man er nødt til også at se på, hvordan mikroberne har det omkring respirationsmekanis-Dorte Egelund
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Kontakt Anne-Mette Storm for yderligere info på 23 37 25 76 eller [email protected] Egelund ApS. Vestre Hedevej 15. 4000 Roskilde. www.dorteegelund.dkKontakt Dorte Egelund for yderligere info på tlf. 40202576 eller [email protected] Egelund ApS. Vestre Hedevej 15. 4000 Roskilde. www.dorteegelund.dk
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Biolog introduces Mitoplates™
mer. Vi har en leverandør der har udstyr til det. Så vi ser ikke kun på sekvente-ring, men også på fænotype karakterise-ring. Kan vi hjælpe produktionsvirksom-heder med at få 1 pct. større udbytte ud af en fermentering, er der formuer at hente på bundlinjen.
Nu har man fundet ud af se på forgæ-ringsmønstre rendyrkninger og respira-tion. Vi kan hjælpe med at levere udstyr, viden og med at forstå afl æsningerne og teknikkerne.
Projekt til hurtig screening
Vi har udliciteret al service til eksterne samarbejdspartnere, der er uddannet i vort apparatur. Vore leverandører som vi samarbejder med i farmaceutisk indu-stri, arbejder inden for den lovgivning og de regelsæt der eksisterer på områ-derne som PH.EUR som er european pharmacupe og FDA. Vore kunder ved, at når vi kan levere, har de deres ryg fri, når der kommer inspektion. Når de ind-leder samarbejde med os er baglandet i
orden med hensyn til guidelines der skal overholdes.
Vi har bidraget med knowhow i et EU-projekt, hvor vi gik ind og var med til at udvikle high trueput technology i forbindelse med udvælgelse af mam-male cellelinjer i forbindelse med kræft-behandling. Der har vi været med i hele processen i samarbejde med fi rmaer fra lrland, Tyskland og Sheffi eld Universitet.
Der var behov i industrien for at få udviklet en teknik, hvor man lynhurtigt kunne screene mange cellelinjer.
Det skal være sjovt
Jeg beskæftiger mig med det, der er sjovt og har brug for sparring. Jeg er ikke en rygklapper, når jeg tager ud. Det udvikler hverken mig eller kunden. Jeg skal udfordre dem og de skal udfordre mig, så vi gensidigt udvikler hinanden.
Masser af forberedelse, hårdt arbejde og at lære af sine fejl er de tre regler bag en succes. Så kommer man videre. Jeg er god til at strukturere. Dette bliver al-
drig nogensinde et one-stop-shop fi rma, hvor du kan købe alt. Vi er et nichef-irma, der har fået succes.
Vi uddanner os løbende ved at lytte til kunderne, tage på kurser, internationale udstillinger m.m. Der har været masser af fravalg i leverandørbasen. Dem, der kommer gennem nåleøjet, er de, der le-ver op til mine krav til leverandører.
Der er nye, spændende projekter i støbeskeen:
– Jeg er i dialog med Københavns Universitet omkring udvikling af et nyt medie til dyrkning af Borelia ved hjælp af min phenotype microarray teknik fra Biolog.
Det er et samarbejde med Svenske Landbrugs Universitet om en teknik til måling af bluelight påvirkning af mikro-organismer i forbindelse med påvisning af, hvilke ændringer vi kan opleve mi-krobielt i væksthuse nu, hvor lyskilderne er udskiftet til LED lys. Og sidst har jeg introduceret et mindre fi rma i indførelse af hygiejne kontrol og brug af agarskåle hertil, siger Dorte Egelund.
YOUR RESEARCH PARTNERHolm & Halby forhandler nu Tecan mikropladelæsere og vaskere.
Du er derfor sikret både rigtige og holdbare løsninger i fremtiden.
Multimode microplate readers - microplate washersTecan har et bredt program – der giver dig mulighed for at vælge den rigtige løsning til netop din applikation
Rådgivning Et sikkert valg – vores erfarne specialister har mange års erfaring i rådgivning af netop mikropladelæsere og vaskere – det er din sikkerhed for det rigtige valg.
ServiceVores teknikere er alle certificeret hos voresleverandører – det er din sikkerhed for korrekte resultater – og lang levetid for dit instrument.
Vallensbækvej 35 DK-2605 BrøndbyTelefon: (+45) 4326 9400 www.holm-halby.dk [email protected]
Tilmeld dig på:www.seminarplan.dkEller kontakt: Karina Back [email protected]. 4326 9421
Info uden støj:
YOUR RESEARCH PARTNERHolm & Halby forhandler nu Tecan
Du er derfor sikret både rigtige og
at vælge den rigtige løsning til netop din applikation
Vivi BrammerProduktspecialistTlf. 4326 [email protected]
Aske Bech RasmussenProduktspecialist Tlf. 4326 9475 [email protected]