| 1. |
- Betz, Mattias J., et al.
(författare)
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Human Brown Adipose Tissue: What We Have Learned So Far
- 2015
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:7, s. 2352-2360
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Betz, M. J., et al.
(författare)
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Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease
- 2018
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Ingår i: Nature Reviews Endocrinology. - : Springer Science and Business Media LLC. - 1759-5029 .- 1759-5037. ; 14:2, s. 77-87
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Forskningsöversikt (refereegranskat)abstract
- 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.
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| 3. |
- Chen, K. Y., et al.
(författare)
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Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans
- 2016
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 24:2, s. 210-222
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Enerbäck, Sven, 1958, et al.
(författare)
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Acidosis and Deafness in Patients with Recessive Mutations in FOXI1
- 2018
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Ingår i: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 29:3, s. 1041-1048
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Tidskriftsartikel (refereegranskat)abstract
- 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 FOXI1 (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.
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| 5. |
- Enerbäck, Sven, 1958
(författare)
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Casein Kinase 2 - A Kinase that Inhibits Brown Fat Formation
- 2015
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Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:6, s. 958-959
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Tidskriftsartikel (refereegranskat)abstract
- 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. © 2015 Elsevier Inc.
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| 6. |
- Klepac, K., et al.
(författare)
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The G(q) signalling pathway inhibits brown and beige adipose tissue
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- 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 G(q) family, and inhibition of G(q) signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of G(q) signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of G(q) signalling in brown adipocytes. Expression of a constitutively active G(q) 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 G(q) in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that G(q) signalling regulates brown/beige adipocytes and inhibition of G(q) signalling may be a novel therapeutic approach to combat obesity.
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| 7. |
- Koffert, J. P., et al.
(författare)
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Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial
- 2017
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Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 0168-8227 .- 1872-8227. ; 131, s. 208-216
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Tidskriftsartikel (refereegranskat)abstract
- Aims Metformin therapy is associated with diffuse intestinal 18F-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 © 2017 The Authors
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| 8. |
- Lasar, D., et al.
(författare)
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Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase
- 2018
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 22:3, s. 760-773
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Tidskriftsartikel (refereegranskat)abstract
- 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 PPAR alpha, beta/delta, and gamma, respectively. We found that both PPARa and beta/delta are dispensable for brown fat function. In contrast, we could show that ablation of PPAR gamma in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by beta-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 PPAR gamma 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 PPAR gamma-mediated regulation of brown fat function and activation by b-adrenergic signaling.
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| 9. |
- Nilsson, Daniel, 1975, et al.
(författare)
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Foxc2 is essential for podocyte function.
- 2019
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Ingår i: Physiological reports. - : Wiley. - 2051-817X. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- 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 invitro, 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.
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| 10. |
- Omar, B. A., et al.
(författare)
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Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice
- 2016
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 310:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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