| 1. |
- Nilsson, Anders, 1958, et al.
(author)
-
Expression of functional growth hormone receptors in cultured human osteoblast-like cells.
- 1995
-
In: The Journal of clinical endocrinology and metabolism. - 0021-972X. ; 80:12, s. 3483-8
-
Journal article (peer-reviewed)abstract
- Recent clinical studies indicate that GH is important for bone remodeling. Patients with GH deficiency exhibit decreased bone density, and GH substitution increases bone density in these patients. The aim of the present study was to investigate the presence of GH receptors and the effects of GH on cultured human osteoblast-like cells. Primary cultures of human osteoblast-like cells were established from trabecular bone. Northern blot analysis, using a probe recognizing exon 10 of the human GH receptor, revealed a 4.7-kilobase transcript corresponding to the human GH receptor. Cultured osteoblast-like cells expressed, as determined by RNase protection assay, approximately one fourth of the GH receptor messenger RNA levels found in liver. Binding studies using 125I-labeled GH revealed a single class of receptors with approximately 2000 binding sites per cell and an association constant (Ka) of 2.6 x 10(9) M-1. GH stimulation of the cultured cells resulted in increased [3H]thymidine incorporation, suggesting that the GH receptors are functional. In summary, the present study shows that cultured human osteoblast-like cells express functional GH receptors.
|
|
| 2. |
- Pall, Marita E., 1959, et al.
(author)
-
The transcription factor C/EBP-b and its role in ovarian function; evidence for direct involvement in the ovulatory process
- 1997
-
In: The EMBO Journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 16:17, s. 5273-5279
-
Journal article (peer-reviewed)abstract
- Gonadotropins are responsible for maturation of the ovarian follicle and the oocyte. Ovulation is the ultimate step in this process and involves disintegration of the follicular wall and subsequent release of an oocyte into the oviduct. These events are triggered by a surge of luteinizing hormone (LH), Genes expressed in the ovary, that respond to LH, are likely to be involved in the biochemical pathways that regulate ovulation, The transcription factor C/EBP-beta is induced promptly in the ovary, as a response to an ovulatory dose of gonadotropins. We used an ex vivo perfusion system to demonstrate that a specific reduction in ovarian C/EBP-beta expression inhibits ovulation, In such ovaries the oocytes appeared to be entrapped within the follicle. We have found a correlation between the expression level of the activating isoform of C/EBP-beta and the number of oocytes ovulated in response to gonadotropins, Since a reduction in C/EBP-beta expression does not affect the level of the ovulatory mediator prostaglandin endoperoxide synthase-2 (PGS-2), these findings support the view of C/EBP-beta as an important factor in the ovulatory process and highlight a C/EBP-beta-dependent and PGS-2-independent pathway that takes part in regulation of ovulation.
|
|
| 3. |
- Sundfeldt, Karin, 1962, et al.
(author)
-
E-cadherin expression in human epithelial ovarian cancer and normal ovary.
- 1997
-
In: International journal of cancer. - 0020-7136. ; 74:3, s. 275-80
-
Journal article (peer-reviewed)abstract
- The ovarian surface epithelium (OSE) is the origin of the majority of human ovarian cancers. These adenocarcinomas are characterized by initial local growth followed by spreading into the peritoneal cavity at later stages of tumor progression. The cell-adhesion molecule E-cadherin (E-cad) plays an important role in maintaining tissue integrity. Disappearance or impaired function of E-cad have often been associated with tumor formation and invasion in vivo and in vitro. The cell-specific expression of E-cad was investigated in normal human ovaries (n = 12), in benign (n = 5) and borderline (n = 4) ovarian epithelial tumors and in adenocarcinomas of different stages and histological grades (n = 18), by immunohistochemistry and immunoblotting. An ovarian cancer cell line (NIH-OVCAR3) was used as a reference. The epithelial origin of the cells was confirmed with cytokeratin (AE1/AE3) staining. In normal ovaries, the expression of E-cad was limited to inclusion cysts or deep clefts lined with OSE, whereas no staining of the OSE could be demonstrated at the surface of the ovary. In contrast, benign and borderline tumors uniformly expressed E-cad. This was observed in malignant tumors of all stages despite their degree of differentiation. E-cad was also present in metastasis from such tumors. The cell-specific expression of E-cad in inclusion cysts of normal ovaries and in epithelial layers of borderline tumors indicates a role for E-cad in the early events of the progression to a malignant phenotype. E-cad was not downregulated in later stages of ovarian cancer progression.
|
|
| 4. |
- Sundfeldt, Karin, 1962, et al.
(author)
-
The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPbeta during epithelial tumour progression.
- 1999
-
In: British journal of cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 79:7-8, s. 1240-8
-
Journal article (peer-reviewed)abstract
- The CCAAT/enhancer binding protein (C/EBP) family of transcription factors is involved in metabolism and differentiation of cells, especially in rodent liver cells and adipocytes. Their roles in vivo and in particular during pathophysiological conditions in humans are largely unknown. We have investigated the presence of C/EBPalpha, -beta, -delta and -zeta in normal ovaries and in epithelial ovarian tumours of different stages. Immunohistochemical experiments demonstrated that C/EBPalpha and C/EBPbeta were preferentially expressed in epithelial/tumour cells irrespective of stage or grade of the tumour. C/EBPbeta was located in the nuclei of the cells, in contrast to C/EBPalpha, which was present only in the cytoplasm of these cells. The nuclear localization of C/EBPbeta indicates an active role of this transcription factor in tumour cells, whereas the cytoplasmic distribution suggests a more passive function of C/EBPalpha. C/EBPdelta and -zeta demonstrated a more diverse distribution with predominant localization to epithelial cells, but stromal distribution was also noted. The intracellular distribution was confined to both the nucleus and the cytoplasm for C/EBPdelta and -zeta. Western blotting demonstrated that C/EBPalpha, -beta, -delta and -zeta were present in a majority of the samples. The amount of C/EBPbeta increased markedly with malignancy, i.e. with degree of dedifferentiation, while the other members of the C/EBP family displayed a more constant expression level. These results demonstrate an association between the expression of members of the C/EBP family and the formation of epithelial ovarian tumours, with C/EBPbeta as a potential marker for these tumours. As C/EBPbeta is known to be expressed during proliferation of cells in vitro, it may participate in the proliferative process of ovarian epithelial tumour cells in vivo and play a central role in tumour progression.
|
|
| 5. |
- Allu, P. K. R., et al.
(author)
-
FoxK1 associated gene regulatory network in hepatic insulin action and its relationship to FoxO1 and insulin receptor mediated transcriptional regulation
- 2023
-
In: Molecular Metabolism. - 2212-8778. ; 78
-
Journal article (peer-reviewed)abstract
- Objective: Insulin acts on the liver via changes in gene expression to maintain glucose and lipid homeostasis. This study aimed to the Forkhead box protein K1 (FOXK1) associated gene regulatory network as a transcriptional regulator of hepatic insulin action and to determine its role versus FoxO1 and possible actions of the insulin receptor at the DNA level.Methods: Genome-wide analysis of FoxK1 binding were studied by chromatin immunoprecipitation sequencing and compared to those for IR and FoxO1. These were validated by knockdown experiments and gene expression analysis.Results: Chromatin immunoprecipitation (ChIP) sequencing shows that FoxK1 binds to the proximal promoters and enhancers of over 4000 genes, and insulin enhances this interaction for about 75% of them. These include genes involved in cell cycle, senescence, steroid biosynthesis, autophagy, and metabolic regulation, including glucose metabolism and mitochondrial function and are enriched in a TGTTTAC consensus motif. Some of these genes are also bound by FoxO1. Comparing this FoxK1 ChIP-seq data to that of the insulin receptor (IR) reveals that FoxK1 may act as the transcription factor partner for some of the previously reported roles of IR in gene regulation, including for LARS1 and TIMM22, which are involved in rRNA processing and cell cycle.Conclusion: These data demonstrate that FoxK1 is an important regulator of gene expression in response to insulin in liver and may act in concert with FoxO1 and IR in regulation of genes in metabolism and other important biological pathways.(c) 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
|
|
| 6. |
- Beg, Muheeb, et al.
(author)
-
ATGL activity regulates GLUT1-mediated glucose uptake and lactate production via TXNIP stability in adipocytes
- 2021
-
In: Journal of Biological Chemistry. - : Elsevier BV. - 0021-9258 .- 1083-351X. ; 296
-
Journal article (peer-reviewed)abstract
- 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 glucose transporter 1 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 or monoacylglycerol lipase. 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.
|
|
| 7. |
- Betz, Mattias J., et al.
(author)
-
Human Brown Adipose Tissue: What We Have Learned So Far
- 2015
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 64:7, s. 2352-2360
-
Journal article (peer-reviewed)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.
|
|
| 8. |
- Betz, Mattias J., et al.
(author)
-
Presence of Brown Adipocytes in Retroperitoneal Fat From Patients With Benign Adrenal Tumors: Relationship With Outdoor Temperature
- 2013
-
In: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 98:10, s. 4097-4104
-
Journal article (peer-reviewed)abstract
- Context: Brown adipose tissue (BAT) is a metabolically highly active organ with increased thermogenic activity in rodents exposed to cold temperature. Recently its presence in the cervical adipose tissue of human adults and its association with a favorable metabolic phenotype have been reported. Objective: The objective of the study was to determine the prevalence of retroperitoneal BAT in human adults. Patients: Fifty-seven patients who underwent surgery for benign adrenal tumors were included in this study. Main Outcome Measures: Prevalence of retroperitoneal BAT adjacent to the removed adrenal tumor as determined by uncoupling protein 1 (UCP1) protein and mRNA expression was measured. Results: Using protein and mRNA expression analysis, we detected UCP1 protein in 26 of 57 patients (45.6%) as well as high mRNA expression of genes characteristic for brown adipocytes, independent of the adrenal tumor type. The presence of brown adipocytes within the retroperitoneal fat was associated with a significantly lower outdoor temperature during the month prior to surgery. Importantly, UCP1 expression on both mRNA and protein level was inversely correlated to outdoor temperature, whereas body mass index, sex, age, and diabetes status were not. Conclusions: These findings suggest that human retroperitoneal adipose tissue can acquire a BAT phenotype, thereby adapting to environmental challenges. These adaptive processes might provide a valuable therapeutic target in the treatment of obesity and insulin resistance.
|
|
| 9. |
- Betz, M. J., et al.
(author)
-
Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease
- 2018
-
In: Nature Reviews Endocrinology. - : Springer Science and Business Media LLC. - 1759-5029 .- 1759-5037. ; 14:2, s. 77-87
-
Research review (peer-reviewed)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.
|
|
| 10. |
- Blomqvist, Sandra Rodrigo, 1974, et al.
(author)
-
Epididymal expression of the forkhead transcription factor Foxi1 is required for male fertility.
- 2006
-
In: The EMBO journal. - : Wiley. - 0261-4189 .- 1460-2075. ; 25:17, s. 4131-41
-
Journal article (peer-reviewed)abstract
- An essential aspect of male reproductive capacity is the immediate availability of fertilization-ready spermatozoa. To ensure this, most mammals rely on post-testicular sperm maturation. In epididymis, germ cells are matured and stored in a quiescent state that readily can be altered to produce active spermatozoa. This depends on active proton secretion into the epididymal lumen. We have identified Foxi1 as an important regulator of gene expression in narrow and clear cells-the major proton secretory cells of epididymal epithelia. Foxi1 appears to be required for the expression of the B1-subunit of the vacuolar H+ -ATPase proton pump and for carbonic anhydrase II as well as the chloride/bicarbonate transporter pendrin. Using transfection experiments, we have identified a Foxi1 binding cis-element in the ATP6V1B1 (encoding the B1-subunit) promoter that is critical for reporter gene activation. When this site is mutated to eliminate Foxi1 binding, activation is also abolished. As a consequence of defect Foxi1-dependent epididymal sperm maturation, we demonstrate that spermatozoa from Foxi1 null males fail to reach the female genital tract in sufficient number to allow fertilization.
|
|
| 11. |
- Borga, Magnus, et al.
(author)
-
Brown adipose tissue in humans: detection and functional analysis using PET (positron emission tomography), MRI (magnetic resonance imaging), and DECT (dual energy computed tomography).
- 2014
-
In: Methods in enzymology. - : Elsevier. - 1557-7988. ; 537, s. 141-59, s. 141-159
-
Journal article (peer-reviewed)abstract
- 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.
|
|
| 12. |
- Cederberg, Anna, 1972, et al.
(author)
-
In vitro differentiated adipocytes from a Foxc2 reporter knock-in mouse as screening tool.
- 2009
-
In: Transgenic research. - : Springer Science and Business Media LLC. - 1573-9368 .- 0962-8819. ; 18:6, s. 889-97
-
Journal article (peer-reviewed)abstract
- We have developed a generic model for in vitro high-throughput screening for agents regulating transcription of genes in the mouse genome here exemplified by Foxc2, a forkhead transcription factor involved in regulation of adipocyte metabolism. We made a Foxc2-LacZ reporter "knock-in" mouse in which one of the two Foxc2 alleles has been inactivated and replaced by a LacZ reporter gene. Mouse embryonic fibroblasts, derived from such mice, were differentiated in vitro to adipocytes and used in cell-based screens. Forskolin as well as 12-O-tetradecanoylphorbol-13-acetate (TPA) increased levels of Foxc2nLacZ fusion protein. We could also demonstrate that this was paralleled by an increase in Foxc2 mRNA, transcribed from the wild type allele. This generic method offers a novel way of identifying both positive and negative upstream regulators of a gene, using high-throughput screening methodology. In a cell-based screen using such methodology we demonstrate efficacy by identifying NKH477 as a Foxc2 activating compound.
|
|
| 13. |
- Chen, K. Y., et al.
(author)
-
Brown Adipose Reporting Criteria in Imaging STudies (BARCIST 1.0): Recommendations for Standardized FDG-PET/CT Experiments in Humans
- 2016
-
In: Cell Metabolism. - : Elsevier BV. - 1550-4131. ; 24:2, s. 210-222
-
Journal article (peer-reviewed)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.
|
|
| 14. |
- Chondronikola, M., et al.
(author)
-
Brown Adipose Tissue Improves Whole-Body Glucose Homeostasis and Insulin Sensitivity in Humans
- 2014
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:12, s. 4089-4099
-
Journal article (peer-reviewed)abstract
- 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.
|
|
| 15. |
- Cornier, Marc-Andre, et al.
(author)
-
Insulin sensitivity determines the effectiveness of dietary macronutrient composition on weight loss in obese women.
- 2005
-
In: Obesity research. - 1071-7323. ; 13:4, s. 703-9
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: To determine whether macronutrient composition of a hypocaloric diet can enhance its effectiveness and whether insulin sensitivity (Si) affects the response to hypocaloric diets. RESEARCH METHODS AND PROCEDURES: Obese nondiabetic insulin-sensitive (fasting insulin < 10 microU/mL; n = 12) and obese nondiabetic insulin-resistant (fasting insulin > 15 microU/mL; n = 9) women (23 to 53 years old) were randomized to either a high carbohydrate (CHO) (HC)/low fat (LF) (60% CHO, 20% fat) or low CHO (LC)/high fat (HF) (40% CHO, 40% fat) hypocaloric diet. Primary outcome measures after a 16-week dietary intervention were: changes in body weight (BW), Si, resting metabolic rate, and fasting lipids. RESULTS: Insulin-sensitive women on the HC/LF diet lost 13.5 +/- 1.2% (p < 0.001) of their initial BW, whereas those on the LC/HF diet lost 6.8 +/- 1.2% (p < 0.001; p < 0.002 between the groups). In contrast, among the insulin-resistant women, those on the LC/HF diet lost 13.4 +/- 1.3% (p < 0.001) of their initial BW as compared with 8.5 +/- 1.4% (p < 0.001) lost by those on the HC/LF diet (p < 0.04 between two groups). These differences could not be explained by changes in resting metabolic rate, activity, or intake. Overall, changes in Si were associated with the degree of weight loss (r = -0.57, p < 0.05). DISCUSSION: The state of Si determines the effectiveness of macronutrient composition of hypocaloric diets in obese women. For maximal benefit, the macronutrient composition of a hypocaloric diet may need to be adjusted to correspond to the state of Si.
|
|
| 16. |
- Di Gregorio, Gina B, et al.
(author)
-
Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity.
- 2004
-
In: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:4
-
Journal article (peer-reviewed)abstract
- FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test (r = -0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA (P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-alpha, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.
|
|
| 17. |
- Enerbäck, Sven, 1958, et al.
(author)
-
Acidosis and Deafness in Patients with Recessive Mutations in FOXI1
- 2018
-
In: Journal of the American Society of Nephrology. - : Ovid Technologies (Wolters Kluwer Health). - 1046-6673 .- 1533-3450. ; 29:3, s. 1041-1048
-
Journal article (peer-reviewed)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.
|
|
| 18. |
|
|
| 19. |
- Enerbäck, Sven, 1958
(author)
-
An enzymatic chromatin switch that directs formation of active brown fat
- 2014
-
In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 19:1, s. 3-4
-
Journal article (peer-reviewed)abstract
- 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. © 2014 Elsevier Inc.
|
|
| 20. |
- Enerbäck, Sven, 1958
(author)
-
Brown adipose tissue in humans
- 2010
-
In: INTERNATIONAL JOURNAL OF OBESITY. - 0307-0565. ; 34
-
Research review (peer-reviewed)abstract
- Obesity is endemic in many regions of the world and a forerunner of several serious and sometimes fatal diseases such as ischemic heart disease, stroke, kidney failure and neoplasia. Although we know its origin—it results when energy intake exceeds energy expenditure—at present, the only proven therapy is bariatric surgery. This is a major abdominal procedure that, for reasons that are largely unknown (it cannot be explained solely by a reduction in ventricular volume), significantly reduces energy intake, but because of cost and limited availability, it will most likely be reserved for only a small fraction of those who stand to gain from effective antiobesity treatment. Clearly, alternative ways to treat obesity are needed. Another way to combat excessive accumulation of white adipose tissue would be to increase energy expenditure. Rodents, hibernators and human infants all have a specialized tissue—brown adipose tissue (BAT)—with the unique capacity to regulate energy expenditure by a process called adaptive thermogenesis. This process depends on the expression of uncoupling protein-1 (UCP1), which is a unique marker for BAT. UCP1 is an inner mitochondrial membrane protein that short circuits the mitochondrial proton gradient, so that oxygen consumption is no longer coupled to adenosine triphosphate synthesis. As a consequence, heat is generated. Mice lacking ucp-1 are severely compromised in their ability to maintain normal body temperature when acutely exposed to cold and they are also prone to become obese. We have shown that, in mice, BAT protects against diet-induced obesity, insulin resistance and type 2 diabetes. This is based on prevention of excessive accumulation of triglyceride in non-adipose tissues such as muscle and liver. Ectopic triglyceride storage at these locations is associated with initiation of insulin resistance and, ultimately, development of type 2 diabetes.
|
|
| 21. |
- Enerbäck, Sven, 1958
(author)
-
Casein Kinase 2 - A Kinase that Inhibits Brown Fat Formation
- 2015
-
In: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 22:6, s. 958-959
-
Journal article (peer-reviewed)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.
|
|
| 22. |
|
|
| 23. |
- Enerbäck, Sven, 1958
(author)
-
Human brown adipose tissue.
- 2010
-
In: Cell metabolism. - : Elsevier BV. - 1932-7420 .- 1550-4131. ; 11:4, s. 248-52
-
Journal article (peer-reviewed)abstract
- The BAT organ is unique in that it has evolved to safely dissipate large amounts of chemical energy--a quality that might be harnessed to help humans deal with a dangerously hypercaloric environment and still remain in good health.
|
|
| 24. |
|
|
| 25. |
|
|
