Publications by authors named "Sven Enerbäck"

76 Publications

ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes.

J Biol Chem 2021 Jan 25:100332. Epub 2021 Jan 25.

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE 40530 Gothenburg, Sweden. Electronic address:

Traditionally, lipolysis has been regarded as an enzymatic activity that liberates fatty acids as metabolic fuel. However, recent work has shown that novel substrates, including a variety of lipid compounds such as fatty acids and their derivatives, release "lipolysis products" that act as signaling molecules and transcriptional modulators. While these studies have expanded the role of lipolysis, the mechanisms underpinning lipolysis signaling are not fully defined. Here, we uncover a new mechanism regulating glucose uptake whereby activation of lipolysis, in response to elevated cAMP, leads to the stimulation of Thioredoxin Interacting Protein (TXNIP) degradation. This, in turn, selectively induces GLUT1 surface localization and glucose uptake in 3T3-L1 adipocytes, and increases lactate production. Interestingly, cAMP-induced glucose uptake via degradation of TXNIP is largely dependent upon adipose triglyceride lipase (ATGL), and not hormone-sensitive lipase (HSL) or monoacylglycerol lipase (MGL). Pharmacological inhibition or knockdown of ATGL alone prevents cAMP-dependent TXNIP degradation and thus significantly decreases glucose uptake and lactate secretion. Conversely, overexpression of ATGL amplifies the cAMP response, yielding increased glucose uptake and lactate production. Similarly, knockdown of TXNIP elicits enhanced basal glucose uptake and lactate secretion and increased cAMP further amplifies this phenotype. Overexpression of TXNIP reduces basal and cAMP-stimulated glucose uptake and lactate secretion. As a proof of concept, we replicated these findings in human primary adipocytes and observed TXNIP degradation and increased glucose uptake and lactate secretion upon elevated cAMP signaling. Taken together, our results suggest a crosstalk between ATGL-mediated lipolysis and glucose uptake.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbc.2021.100332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949114PMC
January 2021

Lactate: the ugly duckling of energy metabolism.

Nat Metab 2020 07 20;2(7):566-571. Epub 2020 Jul 20.

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Lactate, perhaps the best-known metabolic waste product, was first isolated from sour milk, in which it is produced by lactobacilli. Whereas microbes also generate other fermentation products, such as ethanol or acetone, lactate dominates in mammals. Lactate production increases when the demand for ATP and oxygen exceeds supply, as occurs during intense exercise and ischaemia. The build-up of lactate in stressed muscle and ischaemic tissues has established lactate's reputation as a deleterious waste product. In this Perspective, we summarize emerging evidence that, in mammals, lactate also serves as a major circulating carbohydrate fuel. By providing mammalian cells with both a convenient source and sink for three-carbon compounds, circulating lactate enables the uncoupling of carbohydrate-driven mitochondrial energy generation from glycolysis. Lactate and pyruvate together serve as a circulating redox buffer that equilibrates the NADH/NAD ratio across cells and tissues. This reconceptualization of lactate as a fuel-analogous to how Hans Christian Andersen's ugly duckling is actually a beautiful swan-has the potential to reshape the field of energy metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-020-0243-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983055PMC
July 2020

Human Bone Marrow Adipose Tissue is a Metabolically Active and Insulin-Sensitive Distinct Fat Depot.

J Clin Endocrinol Metab 2020 07;105(7)

Institute of Biomedicine, University of Turku, Turku, Finland.

Context: Bone marrow (BM) in adult long bones is rich in adipose tissue, but the functions of BM adipocytes are largely unknown. We set out to elucidate the metabolic and molecular characteristics of BM adipose tissue (BMAT) in humans.

Objective: Our aim was to determine if BMAT is an insulin-sensitive tissue, and whether the insulin sensitivity is altered in obesity or type 2 diabetes (T2DM).

Design: This was a cross-sectional and longitudinal study.

Setting: The study was conducted in a clinical research center.

Patients Or Other Participants: Bone marrow adipose tissue glucose uptake (GU) was assessed in 23 morbidly obese subjects (9 with T2DM) and 9 healthy controls with normal body weight. In addition, GU was assessed in another 11 controls during cold exposure. Bone marrow adipose tissue samples for molecular analyses were collected from non-DM patients undergoing knee arthroplasty.

Intervention(s): Obese subjects were assessed before and 6 months after bariatric surgery and controls at 1 time point.

Main Outcome Measure: We used positron emission tomography imaging with 2-[18F]fluoro-2-deoxy-D-glucose tracer to characterize GU in femoral and vertebral BMAT. Bone marrow adipose tissue molecular profile was assessed using quantitative RT-PCR.

Results: Insulin enhances GU in human BMAT. Femoral BMAT insulin sensitivity was impaired in obese patients with T2DM compared to controls, but it improved after bariatric surgery. Furthermore, gene expression analysis revealed that BMAT was distinct from brown and white adipose tissue.

Conclusions: Bone marrow adipose tissue is a metabolically active, insulin-sensitive and molecularly distinct fat depot that may play a role in whole body energy metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247553PMC
July 2020

The generation of immune-induced fever and emotional stress-induced hyperthermia in mice does not involve brown adipose tissue thermogenesis.

FASEB J 2020 04 6;34(4):5863-5876. Epub 2020 Mar 6.

Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.

We examined the role of brown adipose tissue (BAT) for fever and emotional stress-induced hyperthermia. Wild-type and uncoupling protein-1 (UCP-1) knockout mice were injected with lipopolysaccharide intraperitoneally or intravenously, or subjected to cage exchange, and body temperature monitored by telemetry. Both genotypes showed similar febrile responses to immune challenge and both displayed hyperthermia to emotional stress. Neither procedure resulted in the activation of BAT, such as the induction of UCP-1 or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA, or reduced BAT weight and triglyceride content. In contrast, in mice injected with a β agonist, UCP-1 and PGC-1α were strongly induced, and BAT weight and triglyceride content reduced. Both lipopolysaccharide and the β agonist, and emotional stress, induced UCP-3 mRNA in skeletal muscle. A β antagonist did not attenuate lipopolysaccharide-induced fever, but augmented body temperature decrease and inhibited BAT activation when mice were exposed to cold. An α /α antagonist or a 5HT agonist, which inhibit vasoconstriction, abolished lipopolysaccharide-induced fever, but had no effect on emotional stress-induced hyperthermia. These findings demonstrate that in mice, UCP-1-mediated BAT thermogenesis does not take part in inflammation-induced fever, which is dependent on peripheral vasoconstriction, nor in stress-induced hyperthermia. However, both phenomena may involve UCP-3-mediated muscle thermogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1096/fj.201902945RDOI Listing
April 2020

Foxc2 is essential for podocyte function.

Physiol Rep 2019 05;7(9):e14083

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Foxc2 is one of the earliest podocyte markers during glomerular development. To circumvent embryonic lethal effects of global deletion of Foxc2, and to specifically investigate the role of Foxc2 in podocytes, we generated mice with a podocyte-specific Foxc2 deletion. Mice carrying the homozygous deletion developed early proteinuria which progressed rapidly into end stage kidney failure and death around postnatal day 10. Conditional loss of Foxc2 in podocytes caused typical characteristics of podocyte injury, such as podocyte foot process effacement and podocyte microvillus transformation, probably caused by disruption of the slit diaphragm. These effects were accompanied by a redistribution of several proteins known to be necessary for correct podocyte structure. One target gene that showed reduced glomerular expression was Nrp1, the gene encoding neuropilin 1, a protein that has been linked to diabetic nephropathy and proteinuria. We could show that NRP1 was regulated by Foxc2 in vitro, but podocyte-specific ablation of Nrp1 in mice did not generate any phenotype in terms of proteinuria, suggesting that the gene might have more important roles in endothelial cells than in podocytes. Taken together, this study highlights a critical role for Foxc2 as an important gene for podocyte function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.14083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503019PMC
May 2019

FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism.

Nat Commun 2019 04 5;10(1):1582. Epub 2019 Apr 5.

Sections of Integrative Physiology and Metabolism and Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Boston, MA, 02215, USA.

A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09418-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450906PMC
April 2019

FOXK1 and FOXK2 regulate aerobic glycolysis.

Nature 2019 02 30;566(7743):279-283. Epub 2019 Jan 30.

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.

Adaptation to the environment and extraction of energy are essential for survival. Some species have found niches and specialized in using a particular source of energy, whereas others-including humans and several other mammals-have developed a high degree of flexibility. A lot is known about the general metabolic fates of different substrates but we still lack a detailed mechanistic understanding of how cells adapt in their use of basic nutrients. Here we show that the closely related fasting/starvation-induced forkhead transcription factors FOXK1 and FOXK2 induce aerobic glycolysis by upregulating the enzymatic machinery required for this (for example, hexokinase-2, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase), while at the same time suppressing further oxidation of pyruvate in the mitochondria by increasing the activity of pyruvate dehydrogenase kinases 1 and 4. Together with suppression of the catalytic subunit of pyruvate dehydrogenase phosphatase 1 this leads to increased phosphorylation of the E1α regulatory subunit of the pyruvate dehydrogenase complex, which in turn inhibits further oxidation of pyruvate in the mitochondria-instead, pyruvate is reduced to lactate. Suppression of FOXK1 and FOXK2 induce the opposite phenotype. Both in vitro and in vivo experiments, including studies of primary human cells, show how FOXK1 and/or FOXK2 are likely to act as important regulators that reprogram cellular metabolism to induce aerobic glycolysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-019-0900-5DOI Listing
February 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2018.09.044DOI Listing
October 2018

STK25 regulates oxidative capacity and metabolic efficiency in adipose tissue.

J Endocrinol 2018 09 24;238(3):187-202. Epub 2018 May 24.

Lundberg Laboratory for Diabetes ResearchDepartment of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden

Whole-body energy homeostasis at over-nutrition critically depends on how well adipose tissue remodels in response to excess calories. We recently identified serine/threonine protein kinase (STK)25 as a critical regulator of ectopic lipid storage in non-adipose tissue and systemic insulin resistance in the context of nutritional stress. Here, we investigated the role of STK25 in regulation of adipose tissue dysfunction in mice challenged with a high-fat diet. We found that overexpression of STK25 in high-fat-fed mice resulted in impaired mitochondrial function and aggravated hypertrophy, inflammatory infiltration and fibrosis in adipose depots. Reciprocally, knockout mice displayed improved mitochondrial function and were protected against diet-induced excessive fat storage, meta-inflammation and fibrosis in brown and white adipose tissues. Furthermore, in rodent HIB-1B cell line, STK25 depletion resulted in enhanced mitochondrial activity and consequently, reduced lipid droplet size, demonstrating an autonomous action for STK25 within adipocytes. In summary, we provide the first evidence for a key function of STK25 in controlling the metabolic balance of lipid utilization vs lipid storage in brown and white adipose depots, suggesting that repression of STK25 activity offers a potential strategy for establishing healthier adipose tissue in the context of chronic exposure to dietary lipids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JOE-18-0182DOI Listing
September 2018

Elevated Glucose Levels Preserve Glucose Uptake, Hyaluronan Production, and Low Glutamate Release Following Interleukin-1β Stimulation of Differentiated Chondrocytes.

Cartilage 2019 10 27;10(4):491-503. Epub 2018 Apr 27.

Department of Clinical Chemistry and Transfusion Medicine, University of Gothenburg, Gothenburg, Sweden.

Objective: Chondrocytes are responsible for remodeling and maintaining the structural and functional integrity of the cartilage extracellular matrix. Because of the absence of a vascular supply, chondrocytes survive in a relatively hypoxic environment and thus have limited regenerative capacity during conditions of cellular stress associated with inflammation and matrix degradation, such as osteoarthritis (OA). Glucose is essential to sustain chondrocyte metabolism and is a precursor for key matrix components. In this study, we investigated the importance of glucose as a fuel source for matrix repair during inflammation as well as the effect of glucose on inflammatory mediators associated with osteoarthritis.

Design: To create an OA model, we used equine chondrocytes from 4 individual horses that were differentiated into cartilage pellets followed by interleukin-1β (IL-1β) stimulation for 72 hours. The cells were kept at either normoglycemic conditions (5 mM glucose) or supraphysiological glucose concentrations (25 mM glucose) during the stimulation with IL-1β.

Results: We found that elevated glucose levels preserve glucose uptake, hyaluronan synthesis, and matrix integrity, as well as induce anti-inflammatory actions by maintaining low expression of Toll-like receptor-4 and low secretion of glutamate.

Conclusions: Adequate supply of glucose to chondrocytes during conditions of inflammation and matrix degradation interrupts the detrimental inflammatory cycle and induces synthesis of hyaluronan, thereby promoting cartilage repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1947603518770256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755873PMC
October 2019

Adipose Tissue Flexes Its Muscles.

Authors:
Sven Enerbäck

Cell Metab 2018 04;27(4):712-713

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, PO Box 440, 405 30 Göteborg, Sweden. Electronic address:

How brown and beige adipocytes activate UCP1-dependent thermogenesis has been studied in great detail. In Cell Metabolism, Tharp et al. (2018) have recently added another interesting dimension to this by demonstrating that actinomyosin-mediated elasticity regulates the thermogenic capacity of UCP1+ adipocytes, opening up new ways by which UCP1-dependent thermogenesis can be stimulated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.03.010DOI Listing
April 2018

Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.

Cell Rep 2018 01;22(3):760-773

Institute of Food, Nutrition and Health, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. Electronic address:

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.12.067DOI Listing
January 2018

Acidosis and Deafness in Patients with Recessive Mutations in FOXI1.

J Am Soc Nephrol 2018 03 14;29(3):1041-1048. Epub 2017 Dec 14.

Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.

Maintenance of the composition of inner ear fluid and regulation of electrolytes and acid-base homeostasis in the collecting duct system of the kidney require an overlapping set of membrane transport proteins regulated by the forkhead transcription factor FOXI1. In two unrelated consanguineous families, we identified three patients with novel homozygous missense mutations in (p.L146F and p.R213P) predicted to affect the highly conserved DNA binding domain. Patients presented with early-onset sensorineural deafness and distal renal tubular acidosis. In cultured cells, the mutations reduced the DNA binding affinity of FOXI1, which hence, failed to adequately activate genes crucial for normal inner ear function and acid-base regulation in the kidney. A substantial proportion of patients with a clinical diagnosis of inherited distal renal tubular acidosis has no identified causative mutations in currently known disease genes. Our data suggest that recessive mutations in FOXI1 can explain the disease in a subset of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2017080840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5827603PMC
March 2018

Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease.

Nat Rev Endocrinol 2018 02 23;14(2):77-87. Epub 2017 Oct 23.

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Medicinaregatan 9A, SE-405 30 Gothenburg, Sweden.

Brown fat is emerging as an interesting and promising target for therapeutic intervention in obesity and metabolic disease. Activation of brown fat in humans is associated with marked improvement in metabolic parameters such as levels of free fatty acids and insulin sensitivity. Skeletal muscle is another important organ for thermogenesis, with the capacity to induce energy-consuming futile cycles. In this Review, we focus on how these two major thermogenic organs - brown fat and muscle - act and cooperate to maintain normal body temperature. Moreover, in the light of disease-relevant mechanisms, we explore the molecular pathways that regulate thermogenesis in brown fat and muscle. Brown adipocytes possess a unique cellular mechanism to convert chemical energy into heat: uncoupling protein 1 (UCP1), which can short-circuit the mitochondrial proton gradient. However, recent research demonstrates the existence of several other energy-expending 'futile' cycles in both adipocytes and muscle, such as creatine and calcium cycling. These mechanisms can complement or even substitute for UCP1-mediated thermogenesis. Moreover, they expand our view of cold-induced thermogenesis from a special feature of brown adipocytes to a more general physiological principle. Finally, we discuss how thermogenic mechanisms can be exploited to expend energy and hence offer new therapeutic opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nrendo.2017.132DOI Listing
February 2018

Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial.

Diabetes Res Clin Pract 2017 Sep 20;131:208-216. Epub 2017 Jul 20.

Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland. Electronic address:

Aims: Metformin therapy is associated with diffuse intestinal F-fluoro-deoxyglucose (FDG) accumulation in clinical diagnostics using routine FDG-PET imaging. We aimed to study whether metformin induced glucose uptake in intestine is associated with the improved glycaemic control in patients with type 2 diabetes. Therefore, we compared the effects of metformin and rosiglitazone on intestinal glucose metabolism in patients with type 2 diabetes in a randomized placebo controlled clinical trial, and further, to understand the underlying mechanism, evaluated the effect of metformin in rats.

Methods: Forty-one patients with newly diagnosed type 2 diabetes were randomized to metformin (1g, b.i.d), rosiglitazone (4mg, b.i.d), or placebo in a 26-week double-blind trial. Tissue specific intestinal glucose uptake was measured before and after the treatment period using FDG-PET during euglycemic hyperinsulinemia. In addition, rats were treated with metformin or vehicle for 12weeks, and intestinal FDG uptake was measured in vivo and with autoradiography.

Results: Glucose uptake increased 2-fold in the small intestine and 3-fold in the colon for the metformin group and associated with improved glycemic control. Rosiglitazone increased only slightly intestinal glucose uptake. In rodents, metformin treatment enhanced intestinal FDG retention (P=0.002), which was localized in the mucosal enterocytes of the small intestine.

Conclusions: Metformin treatment significantly enhances intestinal glucose uptake from the circulation of patients with type 2 diabetes. This intestine-specific effect is associated with improved glycemic control and localized to mucosal layer. These human findings demonstrate directs effect of metformin on intestinal metabolism and elucidate the actions of metformin. Clinical trial number NCT02526615.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diabres.2017.07.015DOI Listing
September 2017

Foxc2 influences alveolar epithelial cell differentiation during lung development.

Dev Growth Differ 2017 Aug 4;59(6):501-514. Epub 2017 Jul 4.

First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan.

FOXC2, a forkhead transcriptional factor, is a candidate gene for congenital heart diseases and lymphedema-distichiasis syndrome and yellow nail syndrome; however, there are no reports on Foxc2 and the development of the lung. We have identified lung abnormalities in Foxc2-knockout embryos during investigation of cardiac development. The aim of this study was to clarify the morphological characteristics during lung development using ICR-Foxc2 knockout lungs. Mutant fetuses at embryonic days 10.5-18.5 were obtained from mating of Foxc2 mice and then analyzed. Notably, Foxc2-knockout lungs appeared parenchymatous and much smaller than those of the wild-type littermates. In the Foxc2 knockout lungs, the capillary beds remained distant from the alveolar epithelium until the late stages, the number of type2 alveolar cells per alveolar progenitor cell was lower and the type1 alveolar cells were thicker in Foxc2 knockout mice. In contrast, Foxc2 expression was only detected in the mesenchyme of the lung buds at E10.5, and it disappeared at E11.5 in Foxc2-LacZ knockin mice. Furthermore, the expression of Lef1 was significantly inhibited in E11.5 lungs. All of these results suggest that the abnormalities in Foxc2 knockout mice may involve maldifferentiation of alveolar epithelial cells and capillary vessel endothelial-alveolar epithelial approach as well as lymph vessel malformation. This is the first report about relationship between Foxc2 and lung development. This animal model might provide an important clue for elucidating the mechanism of lung development and the cause of respiratory diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dgd.12368DOI Listing
August 2017

Beige Communication through Gap Junctions and Adaption by Autophagy.

Authors:
Sven Enerbäck

Cell Metab 2016 09;24(3):370-371

Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, P.O. Box 440, 405 30 Göteborg, Sweden. Electronic address:

How thermogenic stimuli activate and control beige adipocytes is not fully understood. In this issue, Zhu et al. (2016) and Altshuler-Keylin et al. (2016) provide insights into these important issues by demonstrating roles for connexin 43 (Cx43) atg5 and atg12 in signal propagation and phenotypic adaptation in beige adipocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2016.08.024DOI Listing
September 2016

Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans.

Cell Metab 2016 08;24(2):210-22

Washington University School of Medicine, Mallinckrodt Institute of Radiology, Saint Louis, MO 63110, USA.

Human brown adipose tissue (BAT) presence, metabolic activity, and estimated mass are typically measured by imaging [18F]fluorodeoxyglucose (FDG) uptake in response to cold exposure in regions of the body expected to contain BAT, using positron emission tomography combined with X-ray computed tomography (FDG-PET/CT). Efforts to describe the epidemiology and biology of human BAT are hampered by diverse experimental practices, making it difficult to directly compare results among laboratories. An expert panel was assembled by the National Institute of Diabetes and Digestive and Kidney Diseases on November 4, 2014 to discuss minimal requirements for conducting FDG-PET/CT experiments of human BAT, data analysis, and publication of results. This resulted in Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0). Since there are no fully validated best practices at this time, panel recommendations are meant to enhance comparability across experiments, but not to constrain experimental design or the questions that can be asked.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2016.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981083PMC
August 2016

A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans.

Metabolism 2016 Jun 1;65(6):926-34. Epub 2016 Apr 1.

Department of Medical and Health Sciences, Faculty of Medicine and Health Sciences, Linköping University. Electronic address:

Objective: To study if repeated cold-exposure increases metabolic rate and/or brown adipose tissue (BAT) volume in humans when compared with avoiding to freeze.

Design: Randomized, open, parallel-group trial.

Methods: Healthy non-selected participants were randomized to achieve cold-exposure 1hour/day, or to avoid any sense of feeling cold, for 6weeks. Metabolic rate (MR) was measured by indirect calorimetry before and after acute cold-exposure with cold vests and ingestion of cold water. The BAT volumes in the supraclavicular region were measured with magnetic resonance imaging (MRI).

Results: Twenty-eight participants were recruited, 12 were allocated to controls and 16 to cold-exposure. Two participants in the cold group dropped out and one was excluded. Both the non-stimulated and the cold-stimulated MR were lowered within the group randomized to avoid cold (MR at room temperature from 1841±199 kCal/24h to 1795±213 kCal/24h, p=0.047 cold-activated MR from 1900±150 kCal/24h to 1793±215 kCal/24h, p=0.028). There was a trend towards increased MR at room temperature following the intervention in the cold-group (p=0.052). The difference between MR changes by the interventions between groups was statistically significant (p=0.008 at room temperature, p=0.032 after cold-activation). In an on-treatment analysis after exclusion of two participants that reported ≥8days without cold-exposure, supraclavicular BAT volume had increased in the cold-exposure group (from 0.0175±0.015l to 0.0216±0.014l, p=0.049).

Conclusions: We found evidence for plasticity in metabolic rate by avoiding to freeze compared with cold-exposure in a randomized setting in non-selected humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.metabol.2016.03.012DOI Listing
June 2016

The Gq signalling pathway inhibits brown and beige adipose tissue.

Nat Commun 2016 Mar 9;7:10895. Epub 2016 Mar 9.

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

Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786868PMC
March 2016

Casein Kinase 2--A Kinase that Inhibits Brown Fat Formation.

Authors:
Sven Enerbäck

Cell Metab 2015 Dec;22(6):958-9

Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, P.O. Box 440, 405 30 Göteborg, Sweden. Electronic address:

In adipose tissue, there is a delicate balance between storing and expending energy. In this issue, Shinoda et al. (2015) use phosphoproteomics to identify casein kinase 2 (CK2) as a suppressor of brown adipocyte formation, providing insights into how adipose tissue regulates its composition of white versus brown adipocytes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2015.11.007DOI Listing
December 2015

Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

Am J Physiol Endocrinol Metab 2016 Jan 3;310(1):E81-90. Epub 2015 Nov 3.

Department of Clinical Sciences, Lund University, Lund, Sweden; and.

Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpendo.00296.2015DOI Listing
January 2016

Human Brown Adipose Tissue: What We Have Learned So Far.

Diabetes 2015 Jul 7;64(7):2352-60. Epub 2015 Jun 7.

Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Brown adipose tissue (BAT) is a unique tissue that is able to convert chemical energy directly into heat when activated by the sympathetic nervous system. While initially believed to be of relevance only in human newborns and infants, research during recent years provided unequivocal evidence of active BAT in human adults. Moreover, it has become clear that BAT plays an important role in insulin sensitivity in rodents and humans. This has opened the possibility for exciting new therapies for obesity and diabetes. This review summarizes the current state of research with a special focus on recent advances regarding BAT and insulin resistance in human adults. Additionally, we provide an outlook on possible future therapeutic uses of BAT in the treatment of obesity and diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db15-0146DOI Listing
July 2015

Characterization of brown adipose tissue by water-fat separated magnetic resonance imaging.

J Magn Reson Imaging 2015 Dec 25;42(6):1639-45. Epub 2015 Apr 25.

Department of Biomedical Engineering, Linköping University, Linköping, Sweden.

Background: To evaluate the possibility of quantifying brown adipose tissue (BAT) volume and fat concentration with a high resolution, long echo time, dual-echo Dixon imaging protocol.

Methods: A 0.42 mm isotropic resolution water-fat separated MRI protocol was implemented by using the second opposite-phase echo and third in-phase echo. Fat images were calibrated with regard to the intensity of nearby white adipose tissue (WAT) to form relative fat content (RFC) images. To evaluate the ability to measure BAT volume and RFC contrast dynamics, rats were divided into two groups that were kept at 4° or 22°C for 5 days. The rats were then scanned in a 70 cm bore 3.0 Tesla MRI scanner and a human dual energy CT. Interscapular, paraaortal, and perirenal BAT (i/pa/pr-BAT) depots as well as WAT and muscle were segmented in the MRI and CT images. Biopsies were collected from the identified BAT depots.

Results: The biopsies confirmed that the three depots identified with the RFC images consisted of BAT. There was a significant linear correlation (P < 0.001) between the measured RFC and the Hounsfield units from DECT. Significantly lower iBAT RFC (P = 0.0064) and significantly larger iBAT and prBAT volumes (P = 0.0017) were observed in the cold stimulated rats.

Conclusion: The calibrated Dixon images with RFC scaling can depict BAT and be used to measure differences in volume, and fat concentration, induced by cold stimulation. The high correlation between RFC and HU suggests that the fat concentration is the main RFC image contrast mechanism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.24931DOI Listing
December 2015

Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors.

Nature 2014 Dec 15;516(7531):395-9. Epub 2014 Oct 15.

1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Pharma Center, University of Bonn, 53127 Bonn, Germany.

Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature13816DOI Listing
December 2014

Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans.

Diabetes 2014 Dec 23;63(12):4089-99. Epub 2014 Jul 23.

Metabolism Unit, Shriners Hospital for Children, Galveston, TX Department of Nutrition and Metabolism, Division of Rehabilitation Sciences, University of Texas Medical Branch, Galveston, TX Department of Nutrition and Dietetics, Harokopio University of Athens, Athens, Greece Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX Sealy Center on Aging, University of Texas Medical Branch, Galveston, TX Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX

Brown adipose tissue (BAT) has attracted scientific interest as an antidiabetic tissue owing to its ability to dissipate energy as heat. Despite a plethora of data concerning the role of BAT in glucose metabolism in rodents, the role of BAT (if any) in glucose metabolism in humans remains unclear. To investigate whether BAT activation alters whole-body glucose homeostasis and insulin sensitivity in humans, we studied seven BAT-positive (BAT(+)) men and five BAT-negative (BAT(-)) men under thermoneutral conditions and after prolonged (5-8 h) cold exposure (CE). The two groups were similar in age, BMI, and adiposity. CE significantly increased resting energy expenditure, whole-body glucose disposal, plasma glucose oxidation, and insulin sensitivity in the BAT(+) group only. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose homeostasis, and insulin sensitivity in humans, and support the notion that BAT may function as an antidiabetic tissue in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db14-0746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4238005PMC
December 2014

Two types of brown adipose tissue in humans.

Adipocyte 2014 Jan 28;3(1):63-6. Epub 2013 Oct 28.

Department of Medical and Clinical Genetics; Institute of Biomedicine; The Sahlgrenska Academy; University of Gothenburg; Gothenburg, Sweden.

During the last years the existence of metabolically active brown adipose tissue in adult humans has been widely accepted by the research community. Its unique ability to dissipate chemical energy stored in triglycerides as heat makes it an attractive target for new drugs against obesity and its related diseases. Hence the tissue is now subject to intense research, the hypothesis being that an expansion and/or activation of the tissue is associated with a healthy metabolic phenotype. Animal studies provide evidence for the existence of at least two types of brown adipocytes. Apart from the classical brown adipocyte that is found primarily in the interscapular region where it constitutes a thermogenic organ, a second type of brown adipocyte, the so-called beige adipocyte, can appear within white adipose tissue depots. The fact that the two cell types develop from different precursors suggests that they might be recruited and stimulated by different cues and therefore represent two distinct targets for therapeutic intervention. The aim of this commentary is to discuss recent work addressing the question whether also humans possess two types of brown adipocytes and to highlight some issues when looking for molecular markers for such cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/adip.26896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917936PMC
January 2014

Brown adipose tissue in humans: detection and functional analysis using PET (positron emission tomography), MRI (magnetic resonance imaging), and DECT (dual energy computed tomography).

Methods Enzymol 2014 ;537:141-59

Department of Clinical and Medical Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. Electronic address:

If the beneficial effects of brown adipose tissue (BAT) on whole body metabolism, as observed in nonhuman experimental models, are to be translated to humans, tools that accurately measure how BAT influences human metabolism will be required. This chapter discusses such techniques, how they can be used, what they can measure and also some of their limitations. The focus is on detection and functional analysis of human BAT and how this can be facilitated by applying advanced imaging technology such as positron emission tomography, magnetic resonance imaging, and dual energy computed tomography.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/B978-0-12-411619-1.00008-2DOI Listing
September 2014

An enzymatic chromatin switch that directs formation of active brown fat.

Authors:
Sven Enerbäck

Cell Metab 2014 Jan;19(1):3-4

Department of Medical and Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Medicinaregatan 9A, P.O. Box 440, 405 30 Göteborg, Sweden. Electronic address:

How is the recruitment of brown adipocytes regulated? Ohno et al. (2013) show that the euchromatic histone-lysine N-metyltransferase 1 (EHMT1) is essential for the specification of the brown adipocyte fate, a finding with important implications for the pathophysiology of obesity and obesity-related maladies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2013.12.011DOI Listing
January 2014

Hyperthyroidism increases brown fat metabolism in humans.

J Clin Endocrinol Metab 2014 Jan 20;99(1):E28-35. Epub 2013 Dec 20.

Turku PET Centre (M.L., J.O., M.S., J.C.H., A.K., K.A.V., P.N.), University of Turku, 20520 Turku, Finland; Division of Endocrinology (C.S.-J.), Department of Medicine, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland; Department of Endocrinology (M.S., P.J.) and Department of Nuclear Medicine (T.N.), Turku University Hospital, 20520 Turku, Finland; Department of Investigative Radiology (H.I.), National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan; Department of Medical Physics (N.K.), Faculty of Medicine, Kagawa University, Kagawa 760-0016, Japan; and Medical Genetics (S.E.), Department of Medical Biochemistry, University of Gothenburg, 411 37 Gothenburg, Sweden.

Context: Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones.

Objective: The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans.

Design: This was a follow-up study using positron emission tomography imaging.

Main Outcome Measures: Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry.

Results: Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (P<.005), 45% higher EE (P<.005), and a 70% higher lipid oxidation rate (P=.001). These changes were reversible after restoration of euthyroidism. During hyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (P<.001). TSH correlated inversely with BAT and skeletal muscle glucose metabolism (P<.001). Hyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects.

Conclusions: Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2013-2312DOI Listing
January 2014