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Öst, Anita
Publications (10 of 17) Show all publications
Öst, A. & Pospisilik, J. A. (2015). Epigenetic modulation of metabolic decisions.. Current Opinion in Cell Biology, 33, 88-94
Open this publication in new window or tab >>Epigenetic modulation of metabolic decisions.
2015 (English)In: Current Opinion in Cell Biology, ISSN 0955-0674, E-ISSN 1879-0410, Vol. 33, p. 88-94Article, review/survey (Refereed) Published
Abstract [en]

In the recent years there has been a tremendous increase in our understanding of chromatin, transcription and the importance of metabolites in their regulation. This review highlights what is currently sparse information that suggest existence of a refined system integrating metabolic and chromatin control. We indicate possible regulatory modes, such as feed forward amplification, that may help effect and stabilize long-lasting phenotypic decisions within and even across generations using adipogenesis as the primary context.

National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-115725 (URN)10.1016/j.ceb.2014.12.005 (DOI)000352226700014 ()25588618 (PubMedID)
Available from: 2015-03-18 Created: 2015-03-18 Last updated: 2017-12-04
Öst, A., Lempradl, A., Casas, E., Weigert, M., Tiko, T., Deniz, M., . . . Pospisilik, J. A. (2014). Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity. Cell, 159(6), 1352-1364
Open this publication in new window or tab >>Paternal Diet Defines Offspring Chromatin State and Intergenerational Obesity
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2014 (English)In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 159, no 6, p. 1352-1364Article in journal (Refereed) Published
Abstract [en]

The global rise in obesity has revitalized a search for genetic and epigenetic factors underlying the disease. We present a Drosophila model of paternal-diet-induced intergenerational metabolic reprogramming (IGMR) and identify genes required for its encoding in offspring. Intriguingly, we find that as little as 2 days of dietary intervention in fathers elicits obesity in offspring. Paternal sugar acts as a physiological suppressor of variegation, desilencing chromatin-state-defined domains in both mature sperm and in offspring embryos. We identify requirements for H3K9/K27me3-dependent reprogramming of metabolic genes in two distinct germline and zygotic windows. Critically, we find evidence that a similar system may regulate obesity susceptibility and phenotype variation in mice and humans. The findings provide insight into the mechanisms underlying intergenerational metabolic reprogramming and carry profound implications for our understanding of phenotypic variation and evolution.

Place, publisher, year, edition, pages
Elsevier (Cell Press), 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113500 (URN)10.1016/j.cell.2014.11.005 (DOI)000346652900014 ()25480298 (PubMedID)
Note

Funding Agencies|Max-Planck Society; EU (NoE Epigenesys); ERC [281641]; Swedish VR [K2011-78PK-21893-01-2]; SSMF grants; Spanish Ministry grant [BFU2011-30246, RYC-2010-07114]; Marie Curie European Reintegration Grant "Evo-Chromo; IMPPC; Champalimaud Foundation; Human Frontiers Program Project Grant [RGP0022/2012]; Portuguese Foundation for Science and Technology (FCT) grant [PTDC/BIA-BCM/118684/2010]; Foundation for Science and Technology [SFRH/BPD/79325/2011]

Available from: 2015-01-19 Created: 2015-01-19 Last updated: 2017-12-05
Östh, M., Öst, A., Kjölhede, P. & Strålfors, P. (2014). The Concentration of beta-Carotene in Human Adipocytes, but Not the Whole-Body Adipocyte Stores, Is Reduced in Obesity. PLoS ONE, 9(1), 85610
Open this publication in new window or tab >>The Concentration of beta-Carotene in Human Adipocytes, but Not the Whole-Body Adipocyte Stores, Is Reduced in Obesity
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 1, p. 85610-Article in journal (Refereed) Published
Abstract [en]

We have examined the concentration of beta-carotene in the fat of isolated abdominal subcutaneous adipocytes obtained from lean (BMIless than23 kg/m(2)), non-obese with higher BMI (23 less than= BMIless than28 kg/m(2)), obese (BMI greater than= 28 kg/m(2)), and from a group of obese subjects with type 2 diabetes. The concentration of b-carotene was 50% lower in the adipocytes from the obese and obese/diabetic groups compared with the lean and non-obese groups. Interestingly, the total amount of beta-carotene in the adipocyte stores of each subject was constant among all groups. Triacylglycerol constituted 92 +/- 1% (by weight) of the adipocyte lipids in the lean group and this was increased to 99 +/- 2% in the obese group with diabetes (pless than0.05). The concentration of cholesteryl esters was in all cases less than0.1 g per 100 g of total lipids, demonstrating that mature human adipocytes have negligible stores of cholesteryl ester. Our findings demonstrate that adipocyte concentrations of beta-carotene are reduced in obese subjects. The lower concentrations in adipocytes from subjects with type 2 diabetes apparently reflect subjects obesity. Our finding that whole-body stores of beta-carotene in adipocytes are constant raises new questions regarding what function it serves, as well as the mechanisms for maintaining constant levels in the face of varied adipose tissue mass among individuals over a period of time.

Place, publisher, year, edition, pages
Public Library of Science, 2014
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104290 (URN)10.1371/journal.pone.0085610 (DOI)000329862500259 ()
Available from: 2014-02-17 Created: 2014-02-14 Last updated: 2019-06-28
Alkhori, L., Öst, A. & Alenius, M. (2014). The corepressor Atrophin specifies odorant receptor expression in Drosophila. The FASEB Journal, 28(3), 1355-1364
Open this publication in new window or tab >>The corepressor Atrophin specifies odorant receptor expression in Drosophila
2014 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 3, p. 1355-1364Article in journal (Refereed) Published
Abstract [en]

In both insects and vertebrates, each olfactory sensory neuron (OSN) expresses one odorant receptor (OR) from a large genomic repertoire. How a receptor is specified is a tantalizing question addressing fundamental aspects of cell differentiation. Here, we demonstrate that the corepressor Atrophin (Atro) segregates OR gene expression between OSN classes in Drosophila. We show that the knockdown of Atro result in either loss or gain of a broad set of ORs. Each OR phenotypic group correlated with one of two opposing Notch fates, Notch responding, Nba (N(on)), and nonresponding, Nab (N(off)) OSNs. Our data show that Atro segregates ORs expressed in the Nba OSN classes and helps establish the Nab fate during OSN development. Consistent with a role in recruiting histone deacetylates, immunohistochemistry revealed that Atro regulates global histone 3 acetylation (H3ac) in OSNs and requires Hdac3 to segregate OR gene expression. We further found that Nba OSN classes exhibit variable but higher H3ac levels than the Nab OSNs. Together, these data suggest that Atro determines the level of H3ac, which ensures correct OR gene expression within the Nba OSNs. We propose a mechanism by which a single corepressor can specify a large number of neuron classes.-Alkhori, L., Öst, A., Alenius, M. The corepressor Atrophin specifies odorant receptor expression in Drosophila.

Place, publisher, year, edition, pages
Federation of American Societies for Experimental Biology, 2014
Keywords
HDAC, Notch, epigenetic, neuronal differentiation, olfactory system
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-104702 (URN)10.1096/fj.13-240325 (DOI)000335324800027 ()24334704 (PubMedID)
Available from: 2014-02-24 Created: 2014-02-24 Last updated: 2017-12-05Bibliographically approved
Öst, A., Svensson, K., Ruishalme, I., Brännmark, C., Franck, N., Krook, H., . . . Strålfors, P. (2010). Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes. Molecular medicine (Cambridge, Mass. Print), 16(07-Aug), 235-246
Open this publication in new window or tab >>Attenuated mTOR signaling and enhanced autophagy in adipocytes from obese patients with type 2 diabetes
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2010 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 16, no 07-Aug, p. 235-246Article in journal (Refereed) Published
Abstract [en]

The protein kinase mammalian target of rapamycin (mTOR) mediates insulin control ofprotein synthesis, autophagy, mitochondrial function, and, through feedback signaling tophosphorylation of IRS1 at serine residues, mTOR directly controls insulin signaling. Weshow that in adipocytes from patients with type 2 diabetes (T2D) insulin activation of mTORis attenuated and that the resultant phenotype is compatible with, and can be mimicked by,loss of mTOR activation. In T2D adipocytes mitochondrial function is impaired andautophagy strongly upregulated, with concomitant increased autophagic destruction ofmitochondria and lipofuscin particles, and a dependence on autophagy for ATP production.Conversely, mitochondrial dysfunction attenuates insulin activation of mTOR, enhancesautophagy and attenuates feedback to IRS1. Our findings put mTOR in the driver´s seat of aninsulin resistance that in adipocytes can be fuelled by mitochondrial dysfunction,inflammation, ER-stress, or hypoxia.

Place, publisher, year, edition, pages
Feinstein Institute for Medical Research, 2010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20655 (URN)10.2119/molmed.2010.00023 (DOI)000280048100001 ()20386866 (PubMedID)
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2019-06-28Bibliographically approved
Ahmad, F., Lindh, R., Tang, Y., Ruishalme, I., Öst, A., Sahachartsiri, B., . . . C Manganiello, V. (2009). Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta(3)-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes. BIOCHEMICAL JOURNAL, 424(3), 399-410
Open this publication in new window or tab >>Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta(3)-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes
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2009 (English)In: BIOCHEMICAL JOURNAL, ISSN 0264-6021, Vol. 424, no 3, p. 399-410Article in journal (Refereed) Published
Abstract [en]

In adipocytes, PDE3B (phosphodiesterase 3B) is an important regulatory effector in signalling pathways controlled by insulin and cAMP-increasing hormones. Stimulation of 3T3-L1 adipocytes with insulin or the beta(3)-adrenergic receptor agonist CL316243 (termed CL) indicated that insulin preferentially phosphorylated/activated PDE3B associated with internal membranes (endoplasmic reticulum/Golgi), whereas CL preferentially phosphorylated/activated PDE3B associated with caveolae. siRNA (small interfering RNA)-mediated KD (knockdown) of CAV-1 (caveolin-1) in 3T3-L1 adipocytes resulted in down-regulation of expression of membrane-associated PDE3B. Insulin-induced activation of PDE3B was reduced, whereas CL-mediated activation was almost totally abolished. Similar results were obtained in adipocytes from Cav-1-deficient mice. siRNA-mediated KID of CAV-1 in 3T3-L1 adipocytes also resulted in inhibition of CL-stimulated phosphorylation of HSL (hormone-sensitive lipase) and perilipin A, and of lipolysis. Superose 6 gel-filtration chromatography of solubilized membrane proteins from adipocytes stimulated with insulin or CL demonstrated the reversible assembly of distinct macromolecular complexes that contained P-32-phosphorylated PDE3B and signalling molecules thought to be involved in its activation. Insulin- and CL-induced macromolecular complexes were enriched in cholesterol, and contained certain common signalling proteins [14-3-3, PP2A (protein phosphatase 2A) and cav-1]. The complexes present in insulin-stimulated cells contained tyrosine-phosphorylated IRS-1 (insulin receptor substrate 1) and its downstream signalling proteins, whereas CL-activated complexes contained beta(3)-adrenergic receptor, PKA-RII [PKA (cAMP-dependent protein kinase)-regulatory subunit] and HSL. Insulin- and CL-mediated macromolecular complex formation was significantly inhibited by CAV-1 KID. These results suggest that cav-1 acts as a molecular chaperone or scaffolding molecule in cholesterol-rich lipid rafts that may be necessary for the proper stabilization and activation of PDE3B in response to CL and insulin.

Keywords
adipocyte, beta(3)-adrenergic receptor, caveolin-1, insulin, protein kinase A (PKA), phosphodiesterase 3 (PDE3)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-53067 (URN)10.1042/BJ20090842 (DOI)
Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2010-05-20
Öst, A. (2009). Lipid Metabolism andInsulin Signalling in Adipocytes: enhanced autophagy in type 2 diabetes. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Lipid Metabolism andInsulin Signalling in Adipocytes: enhanced autophagy in type 2 diabetes
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Energy storage in the adipose tissue, to an extent leading to obesity, is associated with local as well assystemic insulin resistance. When insulin-producing beta-cells in the pancreas gradually fail tocompensate, plasma levels of glucose rise and overt type 2 diabetes is diagnosed. Adipocytes are largecells, mostly consisting of one big central lipid droplet, with the surrounding plasma membrane full ofsmall invaginations called caveolae. As caveolae contain the insulin receptor and several other insulinsignallingproteins, we have investigated several aspects of caveolae. We have also mapped mechanismsand defects in the insulin-signalling network in adipocytes from type 2 diabetic patients.

In paper I, we show that a subtype of caveolae has the capability to synthesize triglycerides from fattyacids and glycerol-3-phosphate. The triglyceride-synthesizing caveolae subtype also contains perilipin,suggesting the existence of a mechanism to protect newly made triglycerides from hydrolysis.

In paper II, we demonstrate that adipocytes from patients with type 2 diabetes have an attenuated insulinstimulatedphosphorylation of IRS-1 at Ser-307 (human sequence), which correlates with reduced insulinstimulatedphosphorylation of IRS-1 at tyrosine residues. Insulin-stimulated phosphorylation of IRS-1 atSer-307 is dependent on the nutrient sensor TORC1. This finding indicates that adipocytes from type 2diabetic patients have reduced TORC1 activity.

In paper III, we focus on the mechanisms for RBP4-induced insulin resistance. We also continue ourmapping of insulin-resistance in adipocytes from type 2 diabetes. These cells exhibit, in addition toimpaired insulin-stimulated glucose uptake and the defects presented in paper I, impaired insulinstimulatedphosphorylation of ERK. We do, however, not see any defects in PKB signalling. Neither dowe se any enhanced insulin-stimulated phosphorylation of IRS-1 at Ser-312 (human sequence), a site thatin mice is hyper-stimulated in response to high-fat feeding. Incubation with RBP4 recapitulates all defectswe so far have seen in type 2 diabetes except reduced insulin-stimulated glucose uptake. These results aremirrored by blockade of endogenously produced RBP4 in the incubations with adipocytes from type 2diabetic patients. In other words, RBP4-blocking antibodies restore all insulin-signalling defects we havefound in adipocytes from type 2 diabetic patients, except insulin-stimulated glucose uptake.

In paper IV we show by several approaches that TORC1 activation is down-regulated in adipocytes fromtype 2 diabetic patients. The main finding is that there is enhanced autophagy in those adipocytes.Interestingly, autophagy may be a mechanism to enhance the breakdown of stored triglycerides in theadipocyte.

In conclusion, our data suggest that caveolae, in addition to being micro-domains for insulin-signallingare metabolic platforms. We describe defects in insulin-signalling in adipocytes from type 2 diabeticpatients where the main finding is enhanced autophagy in these obese patients. The perceived starvationin adipose tissue might via secretion of adipokines, such as RBP4, have implications for local as well assystemic insulin-resistance.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. p. 71
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1138
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20656 (URN)978-91-7393-575-3 (ISBN)
Public defence
2009-10-09, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-09-16 Created: 2009-09-16 Last updated: 2009-09-17Bibliographically approved
Danielsson, A., Fagerholm, S., Öst, A., Franck, N., Kjölhede, P., Nyström, F. H. & Strålfors, P. (2009). Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects. Molecular medicine (Cambridge, Mass. Print), 15(7-8), 228-234
Open this publication in new window or tab >>Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects
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2009 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 15, no 7-8, p. 228-234Article in journal (Refereed) Published
Abstract [en]

Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m2) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-20893 (URN)10.2119/molmed.2009.00037 (DOI)000276043800004 ()
Available from: 2009-09-24 Created: 2009-09-24 Last updated: 2019-06-28
Örtegren, U., Aboulaich, N., Öst, A. & Strålfors, P. (2007). A new role for caveolae as metabolic platforms. Trends in endocrinology and metabolism, 18(9), 344-349
Open this publication in new window or tab >>A new role for caveolae as metabolic platforms
2007 (English)In: Trends in endocrinology and metabolism, ISSN 1043-2760, E-ISSN 1879-3061, Vol. 18, no 9, p. 344-349Article in journal (Refereed) Published
Abstract [en]

The plasma membrane of cells functions as a barrier to the environment. Caveolae are minute invaginations of the membrane that selectively carry out the exchange of information and materials with the environment, by functioning as organizers of signal transduction and through endocytosis. Recent findings of uptake of different metabolites and of lipid metabolism occurring in caveolae, point to a new general function of caveolae. As gateways for the uptake of nutrients across the plasma membrane, and as platforms for the metabolic conversion of nutrients, especially in adipocytes, caveolae are now emerging as active centers for many aspects of intermediary metabolism, with implications for our understanding of obesity, diabetes and other metabolic disorders.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40914 (URN)10.1016/j.tem.2007.08.007 (DOI)54533 (Local ID)54533 (Archive number)54533 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
Franck, N., Stenkula, K. G., Lindström, T., Strålfors, P., Nyström, F. H. & Öst, A. (2007). Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual. Diabetologia, 50(8), 1716-1722
Open this publication in new window or tab >>Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
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2007 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 8, p. 1716-1722Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Several studies have suggested that large fat cells are less responsive to insulin than small fat cells. However, in these studies, large fat cells from obese individuals were compared with smaller fat cells from leaner participants, in effect making it impossible to draw conclusions about whether there is a causal relationship between fat cell size and insulin sensitivity. We hypothesised that small fat cells might be more insulin-responsive than large adipocytes when obtained from the same individual.

Materials and methods: We developed a method of sorting isolated primary human fat cells by using nylon filters of two different pore sizes. The cells were stained to visualise DNA, which allowed discrimination from artefacts such as lipid droplets. The sorted cells were left to recover overnight, since we had previously demonstrated that this is necessary for correct assessment of insulin response.

Results: We found similar amounts of the insulin receptor (IR), IRS-1 and GLUT4 when we compared small and large adipocytes from the same volunteer by immunoblotting experiments using the same total cell volume from both cell populations. Activation of IR, IRS-1 and Akt1 (also known as protein kinase B) by insulin was similar in the two cell populations. However, immunofluorescence confocal microscopy of plasma membrane sheets did not reveal any increase in the amount of GLUT4 in the plasma membrane following insulin stimulation in the large fat cells, whereas we saw a twofold increase in the amount of GLUT4 in the small fat cells.

Conclusions/interpretation: Our results support a causal relationship between the accumulation of large fat cells in obese individuals and reduced insulin responsiveness.

Keywords
Adipocyte, GLUT4, Human, Insulin, Insulin receptor, Insulin resistance, IRS-1, Primary fat cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14541 (URN)10.1007/s00125-007-0713-1 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2017-12-13Bibliographically approved
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