Publications by authors named "Tarja Niemi"

16 Publications

  • Page 1 of 1

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

Adenosine/A2B Receptor Signaling Ameliorates the Effects of Aging and Counteracts Obesity.

Cell Metab 2020 Jul 25;32(1):56-70.e7. Epub 2020 Jun 25.

Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany. Electronic address:

The combination of aging populations with the obesity pandemic results in an alarming rise in non-communicable diseases. Here, we show that the enigmatic adenosine A2B receptor (A2B) is abundantly expressed in skeletal muscle (SKM) as well as brown adipose tissue (BAT) and might be targeted to counteract age-related muscle atrophy (sarcopenia) as well as obesity. Mice with SKM-specific deletion of A2B exhibited sarcopenia, diminished muscle strength, and reduced energy expenditure (EE), whereas pharmacological A2B activation counteracted these processes. Adipose tissue-specific ablation of A2B exacerbated age-related processes and reduced BAT EE, whereas A2B stimulation ameliorated obesity. In humans, A2B expression correlated with EE in SKM, BAT activity, and abundance of thermogenic adipocytes in white fat. Moreover, A2B agonist treatment increased EE from human adipocytes, myocytes, and muscle explants. Mechanistically, A2B forms heterodimers required for adenosine signaling. Overall, adenosine/A2B signaling links muscle and BAT and has both anti-aging and anti-obesity potential.
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http://dx.doi.org/10.1016/j.cmet.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437516PMC
July 2020

BATLAS: Deconvoluting Brown Adipose Tissue.

Cell Rep 2018 10;25(3):784-797.e4

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. Electronic address:

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
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http://dx.doi.org/10.1016/j.celrep.2018.09.044DOI Listing
October 2018

Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue.

Diabetes 2018 07 12;67(7):1226-1236. Epub 2018 Apr 12.

Turku PET Centre, University of Turku, Turku, Finland

Activating brown adipose tissue (BAT) could provide a potential approach for the treatment of obesity and metabolic disease in humans. Obesity is associated with upregulation of the endocannabinoid system, and blocking the cannabinoid type 1 receptor (CB1R) has been shown to cause weight loss and to decrease cardiometabolic risk factors. These effects may be mediated partly via increased BAT metabolism, since there is evidence that CB1R antagonism activates BAT in rodents. To investigate the significance of CB1R in BAT function, we quantified the density of CB1R in human and rodent BAT using the positron emission tomography radioligand [F]FMPEP- and measured BAT activation in parallel with the glucose analog [F]fluorodeoxyglucose. Activation by cold exposure markedly increased CB1R density and glucose uptake in the BAT of lean men. Similarly, β3-receptor agonism increased CB1R density in the BAT of rats. In contrast, overweight men with reduced BAT activity exhibited decreased CB1R in BAT, reflecting impaired endocannabinoid regulation. Image-guided biopsies confirmed CB1R mRNA expression in human BAT. Furthermore, CB1R blockade increased glucose uptake and lipolysis of brown adipocytes. Our results highlight that CB1Rs are significant for human BAT activity, and the CB1Rs provide a novel therapeutic target for BAT activation in humans.
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http://dx.doi.org/10.2337/db17-1366DOI Listing
July 2018

miR-125b affects mitochondrial biogenesis and impairs brite adipocyte formation and function.

Mol Metab 2016 Aug 15;5(8):615-625. Epub 2016 Jun 15.

Univ. Nice Sophia Antipolis, CNRS, Inserm, iBV, 06100 Nice, France. Electronic address:

Objective: In rodents and humans, besides brown adipose tissue (BAT), islands of thermogenic adipocytes, termed "brite" (brown-in-white) or beige adipocytes, emerge within white adipose tissue (WAT) after cold exposure or β3-adrenoceptor stimulation, which may protect from obesity and associated diseases. microRNAs are novel modulators of adipose tissue development and function. The purpose of this work was to characterize the role of microRNAs in the control of brite adipocyte formation.

Methods/results: Using human multipotent adipose derived stem cells, we identified miR-125b-5p as downregulated upon brite adipocyte formation. In humans and rodents, miR-125b-5p expression was lower in BAT than in WAT. In vitro, overexpression and knockdown of miR-125b-5p decreased and increased mitochondrial biogenesis, respectively. In vivo, miR-125b-5p levels were downregulated in subcutaneous WAT and interscapular BAT upon β3-adrenergic receptor stimulation. Injections of an miR-125b-5p mimic and LNA inhibitor directly into WAT inhibited and increased β3-adrenoceptor-mediated induction of UCP1, respectively, and mitochondrial brite adipocyte marker expression and mitochondriogenesis.

Conclusion: Collectively, our results demonstrate that miR-125b-5p plays an important role in the repression of brite adipocyte function by modulating oxygen consumption and mitochondrial gene expression.
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http://dx.doi.org/10.1016/j.molmet.2016.06.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021678PMC
August 2016

Visfatin expression analysis in association with recruitment and activation of human and rodent brown and brite adipocytes.

Adipocyte 2016 Apr-Jun;5(2):186-95. Epub 2015 Dec 9.

Univ. Nice-Sophia Antipolis, UFR Medecine, Nice, France; CNRS, iBV, UMR, 7277, Nice, France; INSERM, iBV, U1091, Nice, France.

Human brown adipocytes are able to burn fat and glucose and are now considered as a potential strategy to treat obesity, type 2 diabetes and metabolic disorders. Besides their thermogenic function, brown adipocytes are able to secrete adipokines. One of these is visfatin, a nicotinamide phosphoribosyltransferase involved in nicotinamide dinucleotide synthesis, which is known to participate in the synthesis of insulin by pancreatic β cells. In a therapeutic context, it is of interest to establish whether a potential correlation exists between brown adipocyte activation and/or brite adipocyte recruitment, and adipokine expression. We analyzed visfatin expression, as a pre-requisite to its secretion, in rodent and human biopsies and cell models of brown/brite adipocytes. We found that visfatin was preferentially expressed in mature adipocytes and that this expression was higher in brown adipose tissue of rodents compared to other fat depots. However, using various rodent models we were unable to find any correlation between visfatin expression and brown or brite adipocyte activation or recruitment. Interestingly, the situation is different in humans where visfatin expression was found to be equivalent between white and brown or brite adipocytes in vivo and in vitro. In conclusion, visfatin can be considered only as a rodent brown adipocyte biomarker, independently of tissue activation.
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http://dx.doi.org/10.1080/21623945.2015.1122854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916889PMC
July 2016

Let-7i-5p represses brite adipocyte function in mice and humans.

Sci Rep 2016 06 27;6:28613. Epub 2016 Jun 27.

Univ. Nice Sophia Antipolis, iBV, UMR 7277, Nice, 06100, France.

In response to cold or β3-adrenoreceptor stimulation brown adipose tissue (BAT) promotes non-shivering thermogenesis, leading to energy dissipation. BAT has long been thought to be absent or scarce in adult humans. The recent discovery of thermogenic brite/beige adipocytes has opened the way to development of novel innovative strategies to combat overweight/obesity and associated diseases. Thus it is of great interest to identify regulatory factors that govern the brite adipogenic program. Here, we carried out global microRNA (miRNA) expression profiling on human adipocytes to identify miRNAs that are regulated upon the conversion from white to brite adipocytes. Among the miRNAs that were differentially expressed, we found that Let-7i-5p was down regulated in brite adipocytes. A detailed analysis of the Let-7i-5p levels showed an inverse expression of UCP1 in murine and human brite adipocytes both in vivo and in vitro. Functional studies with Let-7i-5p mimic in human brite adipocytes in vitro revealed a decrease in the expression of UCP1 and in the oxygen consumption rate. Moreover, the Let-7i-5p mimic when injected into murine sub-cutaneous white adipose tissue inhibited partially β3-adrenergic activation of the browning process. These results suggest that the miRNAs Let-7i-5p participates in the recruitment and the function of brite adipocytes.
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http://dx.doi.org/10.1038/srep28613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921928PMC
June 2016

Microvascular breast reconstruction and lymph node transfer for postmastectomy lymphedema patients.

Ann Surg 2012 Mar;255(3):468-73

Department of Plastic Surgery, Turku University Central Hospital, Turku, Finland.

Objective: Postoperative lymphedema after breast cancer surgery is a challenging problem. Recently, a novel microvascular lymph node transfer technique provided a fresh hope for patients with lymphedema. We aimed to combine this new method with the standard breast reconstruction.

Methods: During 2008-2010, we performed free lower abdominal flap breast reconstruction in 87 patients. For all patients with lymphedema symptoms (n = 9), we used a modified lower abdominal reconstruction flap containing lymph nodes and lymphatic vessels surrounding the superficial circumflex vessel pedicle. Operation time, donor site morbidity, and postoperative recovery between the 2 groups (lymphedema breast reconstruction and breast reconstruction) were compared. The effect on the postoperative lymphatic vessel function was examined.

Results: The average operation time was 426 minutes in the lymphedema breast reconstruction group and 391 minutes in the breast reconstruction group. The postoperative abdominal seroma formation was increased in patients with lymphedema. Postoperative lymphoscintigraphy demonstrated at least some improvement in lymphatic vessel function in 5 of 6 patients with lymphedema. The upper limb perimeter decreased in 7 of 9 patients. Physiotherapy and compression was no longer needed in 3 of 9 patients. Importantly, we found that human lymph nodes express high levels of endogenous lymphatic vessel growth factors. Transfer of the lymph nodes and the resulting endogenous growth factor expression may thereby induce the regrowth of lymphatic network in the axilla. No edema problems were detected in the lymph node donor area.

Conclusion: Simultaneous breast and lymphatic reconstruction is an ideal option for patients who suffer from lymphedema after mastectomy and axillary dissection.
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http://dx.doi.org/10.1097/SLA.0b013e3182426757DOI Listing
March 2012

Different metabolic responses of human brown adipose tissue to activation by cold and insulin.

Cell Metab 2011 Aug;14(2):272-9

Turku PET Centre, University of Turku, Turku, Finland.

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner.
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http://dx.doi.org/10.1016/j.cmet.2011.06.012DOI Listing
August 2011

Perfusion in free breast reconstruction flap zones assessed with positron emission tomography.

Microsurgery 2010 Sep;30(6):430-6

Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Hospital, Turku, Finland.

The aim of this pilot study was to determine the postoperative blood perfusion (BF(PET)) and perfusion heterogeneity (BF(PET) HG) in free microvascular breast reconstruction flap zones with positron emission tomography (PET). Regional BF(PET) and BF(PET) HG of the adipose tissue in medial, central, and lateral parts of 13 free flaps were assessed on the first postoperative morning with PET using oxygen-15-labeled water ([(15)O]H(2)O) in 12 patients undergoing breast reconstruction with a deep inferior epigastric perforator (DIEP) or a transverse rectus abdominis muscle (TRAM) flap. The mean BF(PET) values did not differ between DIEP and TRAM flaps (P = 0.791). The mean BF(PET) values were higher in zone III compared with zone I (P = 0.024). During follow-up, fat necrosis was identified in three patients in the medial part (zone II) of the flap. However, the adipose tissue BF(PET) assessed on the first postoperative day from all zones of the flap using PET with radiowater was normal. The BF(PET) HG was higher in the control side (i.e., in the healthy breast tissue) compared with the flap (P = 0.042). The BF(PET) HG was lower in zone III than in zone I (P = 0.03) and in zone II (P < 0.001). In this pilot study, PET was used for the first time for studying the adipose tissue perfusion in different zones in free flaps in a clinical setup, finding that the mean BF(PET) values did not differ between DIEP and TRAM flaps, and that zone II was sometimes not as well perfused as zone III supporting revisited zone division.
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http://dx.doi.org/10.1002/micr.20770DOI Listing
September 2010

Functional brown adipose tissue in healthy adults.

N Engl J Med 2009 Apr;360(15):1518-25

Turku PET Center, University of Turku, Finland.

Using positron-emission tomography (PET), we found that cold-induced glucose uptake was increased by a factor of 15 in paracervical and supraclavicular adipose tissue in five healthy subjects. We obtained biopsy specimens of this tissue from the first three consecutive subjects and documented messenger RNA (mRNA) and protein levels of the brown-adipocyte marker, uncoupling protein 1 (UCP1). Together with morphologic assessment, which showed numerous multilocular, intracellular lipid droplets, and with the results of biochemical analysis, these findings document the presence of substantial amounts of metabolically active brown adipose tissue in healthy adult humans.
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http://dx.doi.org/10.1056/NEJMoa0808949DOI Listing
April 2009

The limitations of tissue-oxygen measurement and positron emission tomography as additional methods for postoperative breast reconstruction free-flap monitoring.

J Plast Reconstr Aesthet Surg 2010 Feb 6;63(2):314-21. Epub 2008 Dec 6.

Department of Otorhinolaryngology-Head and Neck Surgery, Turku University Central Hospital, FIN-20521, Turku, Finland.

Twelve patients who underwent breast reconstruction with a microvascular flap were monitored postoperatively with continuous partial tissue oxygenation (p(ti)O(2)) measurement. The regional blood flow (BF) of the entire flap was evaluated with positron emission tomography (PET) using oxygen-15-labelled water on the first postoperative (POP) morning to achieve data of the perfusion of the entire flap. A re-exploration was carried out if the p(ti)O(2) value remained lower than 15 mmHg for over 30 min. The mean p(ti)O(2) value of the flaps was 52.9+/-5.5 mmHg, whereas the mean BF values were 3.3+/-1.0 ml per 100 g min(-1). One false-positive result was detected by p(ti)O(2) measurement, resulting in an unnecessary re-exploration. Another re-operation suggested by the low p(ti)O(2) results was avoided due to the normal BF results assessed with PET. Totally, three flaps were re-explored. This prospective study suggests that continuous tissue-oxygen measurement with a polarographic needle probe is reliable for monitoring free breast flaps from one part of the flap, but assessing perfusion of the entire flap requires more complex monitoring methods, for example, PET. Clinical examination by experienced personnel remains important in free-breast-flap monitoring. PET could be useful in assessing free-flap perfusion in selected high-risk patients as an alternative to a re-operation when clinical examination and evaluation by other means are unreliable or present controversial results.
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http://dx.doi.org/10.1016/j.bjps.2008.09.029DOI Listing
February 2010

[Not Available].

Duodecim 2007 ;123(8):979-85

HYKS:n plastiikkakirurgian klinikka, HUS.

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April 2008

Free latissimus dorsi perforator flap for reconstruction of hemifacial atrophy: case report.

Microsurgery 2007 ;27(5):369-71

Department of Surgery, Turku University Central Hospital, Finland.

Progressive hemifacial atrophy (PHA) is characterized by slow and progressive atrophy usually of one side of the face. PHA affects primarily the subcutaneous fat and muscle tissues, but may involve the bone. The cause is unknown. The treatment is symptomatic and directed at augmentation of the deficient soft-tissue volume. The reconstructive procedures may combine fat grafts, dermis fat grafts, pedicle flaps, bone grafts, microvascular free flaps, and alloplastic implants. We report a patient with of PHA whose condition was treated with a free latissimus dorsi (LD) perforator flap. The LD perforator flap was suitable for the large defect of the patient. It could easily be tailored and thinned to follow the facial contour. Minor revisions were needed for esthetic reasons. There was neither significant downward gravitation nor wasting of the flap. 23 months later, the natural appearance of the face was maintained.
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http://dx.doi.org/10.1002/micr.20373DOI Listing
December 2007