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Steneberg, Pär
Publications (10 of 10) Show all publications
Ericsson, M., Steneberg, P., Nyrén, R. & Edlund, H. (2021). AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice. Communications Biology, 4(1), Article ID 1306.
Open this publication in new window or tab >>AMPK activator O304 improves metabolic and cardiac function, and exercise capacity in aged mice
2021 (English)In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1306Article in journal (Refereed) Published
Abstract [en]

Age is associated with progressively impaired, metabolic, cardiac and vascular function, as well as reduced work/exercise capacity, mobility, and hence quality of life. Exercise exhibit positive effects on age-related dysfunctions and diseases. However, for a variety of reasons many aged individuals are unable to engage in regular physical activity, making the development of pharmacological treatments that mimics the beneficial effects of exercise highly desirable. Here we show that the pan-AMPK activator O304, which is well tolerated in humans, prevented and reverted age-associated hyperinsulinemia and insulin resistance, and improved cardiac function and exercise capacity in aged mice. These results provide preclinical evidence that O304 mimics the beneficial effects of exercise. Thus, as an exercise mimetic in clinical development, AMPK activator O304 holds great potential to mitigate metabolic dysfunction, and to improve cardiac function and exercise capacity, and hence quality of life in aged individuals.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Cell and Molecular Biology Physiology
Identifiers
urn:nbn:se:umu:diva-189961 (URN)10.1038/s42003-021-02837-0 (DOI)000720447400003 ()34795407 (PubMedID)2-s2.0-85119445550 (Scopus ID)
Funder
Swedish Research Council, 2018-02999Knut and Alice Wallenberg Foundation, KAW 2015.0278
Available from: 2021-12-07 Created: 2021-12-07 Last updated: 2023-03-23Bibliographically approved
López-Pérez, A. R., Norlin, S., Steneberg, P., Remeseiro, S., Edlund, H. & Hörnblad, A. (2021). Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice. Scientific Reports, 11(1), Article ID 24410.
Open this publication in new window or tab >>Pan-AMPK activator O304 prevents gene expression changes and remobilisation of histone marks in islets of diet-induced obese mice
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2021 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 11, no 1, article id 24410Article in journal (Refereed) Published
Abstract [en]

AMP-activated protein kinase (AMPK) has an important role in cellular energy homeostasis and has emerged as a promising target for treatment of Type 2 Diabetes (T2D) due to its beneficial effects on insulin sensitivity and glucose homeostasis. O304 is a pan-AMPK activator that has been shown to improve glucose homeostasis in both mouse models of diabetes and in human T2D subjects. Here, we describe the genome-wide transcriptional profile and chromatin landscape of pancreatic islets following O304 treatment of mice fed high-fat diet (HFD). O304 largely prevented genome-wide gene expression changes associated with HFD feeding in CBA mice and these changes were associated with remodelling of active and repressive chromatin marks. In particular, the increased expression of the β-cell stress marker Aldh1a3 in islets from HFD-mice is completely abrogated following O304 treatment, which is accompanied by loss of active chromatin marks in the promoter as well as distant non-coding regions upstream of the Aldh1a3 gene. Moreover, O304 treatment restored dysfunctional glucose homeostasis as well as expression of key markers associated with β-cell function in mice with already established obesity. Our findings provide preclinical evidence that O304 is a promising therapeutic compound not only for T2D remission but also for restoration of β-cell function following remission of T2D diabetes.

Place, publisher, year, edition, pages
Nature Publishing Group, 2021
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-190971 (URN)10.1038/s41598-021-03567-3 (DOI)000734163400004 ()34949756 (PubMedID)2-s2.0-85121738771 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2015.0278Swedish Research Council, 2018-05973The Kempe Foundations, SMK-1863
Available from: 2022-01-04 Created: 2022-01-04 Last updated: 2022-09-15Bibliographically approved
Mucibabic, M., Steneberg, P., Lidh, E., Straseviciene, J., Ziolkowska, A., Dahl, U., . . . Edlund, H. (2020). alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice. Scientific Reports, 10(1), Article ID 20438.
Open this publication in new window or tab >>alpha-Synuclein promotes IAPP fibril formation in vitro and beta-cell amyloid formation in vivo in mice
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2020 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 20438Article in journal (Refereed) Published
Abstract [en]

Type 2 diabetes (T2D), alike Parkinson's disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in beta -cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (alpha Syn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in beta -cells. Here we show that alpha Syn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, alpha Syn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of alpha Syn in hIAPPtg mice enhanced beta -cell amyloid formation in vivo whereas beta -cell amyloid formation was reduced in hIAPPtg mice on a Snca (-/-) background. Taken together, our findings provide evidence that alpha Syn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for alpha Syn in beta -cell amyloid formation.

Place, publisher, year, edition, pages
Nature Publishing Group, 2020
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-178308 (URN)10.1038/s41598-020-77409-z (DOI)000596280500007 ()33235246 (PubMedID)2-s2.0-85096611352 (Scopus ID)
Available from: 2021-01-11 Created: 2021-01-11 Last updated: 2023-03-23Bibliographically approved
Steneberg, P., Lindahl, E., Dahl, U., Lidh, E., Straseviciene, J., Backlund, F., . . . Edlund, H. (2018). PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients. JCI INSIGHT, 3(12), Article ID e99114.
Open this publication in new window or tab >>PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
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2018 (English)In: JCI INSIGHT, ISSN 2379-3708, Vol. 3, no 12, article id e99114Article in journal (Refereed) Published
Abstract [en]

AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.

Place, publisher, year, edition, pages
American Society for Clinical Investigation, 2018
National Category
Endocrinology and Diabetes Physiology
Identifiers
urn:nbn:se:umu:diva-150778 (URN)10.1172/jci.insight.99114 (DOI)000436144100013 ()29925691 (PubMedID)2-s2.0-85061843820 (Scopus ID)
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2023-03-23Bibliographically approved
Steneberg, P., Sykaras, A. G., Backlund, F., Straseviciene, J., Söderström, I. & Edlund, H. (2015). Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance. Journal of Biological Chemistry, 290(31), 19034-19043
Open this publication in new window or tab >>Hyperinsulinemia Enhances Hepatic Expression of the Fatty Acid Transporter Cd36 and Provokes Hepatosteatosis and Hepatic Insulin Resistance
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2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 290, no 31, p. 19034-19043Article in journal (Refereed) Published
Abstract [en]

Hepatosteatosis is associated with the development of both hepatic insulin resistance and Type 2 diabetes. Hepatic expression of Cd36, a fatty acid transporter, is enhanced in obese and diabetic murine models and human nonalcoholic fatty liver disease, and thus it correlates with hyperinsulinemia, steatosis, and insulin resistance. Here, we have explored the effect of hyperinsulinemia on hepatic Cd36 expression, development of hepatosteatosis, insulin resistance, and dysglycemia. A 3-week sucrose-enriched diet was sufficient to provoke hyperinsulinemia, hepatosteatosis, hepatic insulin resistance, and dysglycemia in CBA/J mice. The development of hepatic steatosis and insulin resistance in CBA/J mice on a sucrose-enriched diet was paralleled by increased hepatic expression of the transcription factor Ppar gamma and its target gene Cd36 whereas that of genes implicated in lipogenesis, fatty acid oxidation, and VLDL secretion was unaltered. Additionally, we demonstrate that insulin, in a Ppar gamma-dependent manner, is sufficient to directly increase Cd36 expression in perfused livers and isolated hepatocytes. Mouse strains that display low insulin levels, i.e. C57BL6/J, and/or lack hepatic Ppar gamma, i.e. C3H/HeN, do not develop hepatic steatosis, insulin resistance, or dysglycemia on a sucrose-enriched diet, suggesting that elevated insulin levels, via enhanced CD36 expression, provoke fatty liver development that in turn leads to hepatic insulin resistance and dysglycemia. Thus, our data provide evidence for a direct role for hyperinsulinemia in stimulating hepatic Cd36 expression and thus the development of hepatosteatosis, hepatic insulin resistance, and dysglycemia.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-107866 (URN)10.1074/jbc.M115.640292 (DOI)000358781100021 ()26085100 (PubMedID)2-s2.0-84940532511 (Scopus ID)
Available from: 2015-09-16 Created: 2015-08-28 Last updated: 2023-03-24Bibliographically approved
Sharma, S. K., Chorell, E., Steneberg, P., Vernersson-Lindahl, E., Edlund, H. & Wittung-Stafshede, P. (2015). Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner. Scientific Reports, 5, Article ID 12531.
Open this publication in new window or tab >>Insulin-degrading enzyme prevents alpha-synuclein fibril formation in a nonproteolytical manner
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2015 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 12531Article in journal (Refereed) Published
Abstract [en]

The insulin-degrading enzyme (IDE) degrades amyloidogenic proteins such as Amyloid β (Aβ) and Islet Amyloid Polypeptide (IAPP), i.e. peptides associated with Alzheimer's disease and type 2 diabetes, respectively. In addition to the protease activity normally associated with IDE function an additional activity involving the formation of stable, irreversible complexes with both Aβ and α-synuclein, an amyloidogenic protein involved in Parkinson's disease, was recently proposed. Here, we have investigated the functional consequences of IDE-α-synuclein interactions in vitro. We demonstrate that IDE in a nonproteolytic manner and at sub-stoichiometric ratios efficiently inhibits α-synuclein fibril formation by binding to α-synuclein oligomers making them inert to amyloid formation. Moreover, we show that, within a defined range of α-synuclein concentrations, interaction with α-synuclein oligomers increases IDE's proteolytic activity on a fluorogenic substrate. We propose that the outcomes of IDE-α-synuclein interactions, i.e. protection against α-synuclein amyloid formation and stimulated IDE protease activity, may be protective in vivo.

Place, publisher, year, edition, pages
Nature Publishing Group, 2015
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-107289 (URN)10.1038/srep12531 (DOI)000358773300001 ()26228656 (PubMedID)2-s2.0-84938523810 (Scopus ID)
Available from: 2015-08-31 Created: 2015-08-21 Last updated: 2023-03-24Bibliographically approved
Steneberg, P., Bernardo, L., Edfalk, S., Lundberg, L., Backlund, F., Ostenson, C.-G. & Edlund, H. (2013). The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells. Diabetes, 62(6), 2004-2014
Open this publication in new window or tab >>The Type 2 Diabetes-Associated Gene Ide Is Required for Insulin Secretion and Suppression of alpha-Synuclein Levels in beta-Cells
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2013 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 62, no 6, p. 2004-2014Article in journal (Refereed) Published
Abstract [en]

Genome-wide association studies have identified several type 2 diabetes (T2D) risk loci linked to impaired beta-cell function. The identity and function of the causal genes in these susceptibility loci remain, however, elusive. The HHEX/IDE T2D locus is associated with decreased insulin secretion in response to oral glucose stimulation in humans. Here we have assessed beta-cell function in Ide knockout (KO) mice. We find that glucose-stimulated insulin secretion (GSIS) is decreased in Ide KO mice due to impaired replenishment of the releasable pool of granules and that the Ide gene is haploinsufficient. We also show that autophagic flux and microtubule content are reduced in beta-cells of Ide KO mice. One important cellular role for IDE involves the neutralization of amyloidogenic proteins, and we find that a-synuclein and IDE levels are inversely correlated in beta-cells of Ide KO mice and T2D patients. Moreover, we provide evidence that both gain and loss of function of a-synuclein in beta-cells in vivo impair not only GSIS but also autophagy. Together, these data identify the Ide gene as a regulator of GSIS, suggest a molecular mechanism for beta-cell degeneration as a consequence of Ide deficiency, and corroborate and extend a previously established important role for a-synuclein in beta-cell function.

National Category
Cell and Molecular Biology Endocrinology and Diabetes
Identifiers
urn:nbn:se:umu:diva-76787 (URN)10.2337/db12-1045 (DOI)000319845000030 ()2-s2.0-84878253079 (Scopus ID)
Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2023-03-24Bibliographically approved
Edfalk, S., Steneberg, P. & Edlund, H. (2008). Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.. Diabetes, 57(9), 2280-7
Open this publication in new window or tab >>Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion.
2008 (English)In: Diabetes, ISSN 1939-327X, Vol. 57, no 9, p. 2280-7Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: The G-protein-coupled receptor Gpr40 is expressed in beta-cells where it contributes to free fatty acid (FFA) enhancement of glucose-stimulated insulin secretion. However, other sites of Gpr40 expression, including the intestine, have been suggested. The transcription factor IPF1/PDX1 was recently shown to bind to an enhancer element within the 5'-flanking region of Gpr40, implying that IPF1/PDX1 might regulate Gpr40 expression. Here, we addressed whether 1) Gpr40 is expressed in the intestine and 2) Ipf1/Pdx1 function is required for Gpr40 expression. RESEARCH DESIGN AND METHODS: In the present study, Gpr40 expression was monitored by X-gal staining using Gpr40 reporter mice and by in situ hybridization. Ipf1/Pdx1-null and beta-cell specific mutants were used to investigate whether Ipf1/Pdx1 controls Gpr40 expression. Plasma insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucose levels in response to acute oral fat diet were determined in Gpr40 mutant and control mice. RESULTS: Here, we show that Gpr40 is expressed in endocrine cells of the gastrointestinal tract, including cells expressing the incretin hormones GLP-1 and GIP, and that Gpr40 mediates FFA-stimulated incretin secretion. We also show that Ipf1/Pdx1 is required for expression of Gpr40 in beta-cells and endocrine cells of the anterior gastrointestinal tract. CONCLUSIONS: Together, our data provide evidence that Gpr40 modulates FFA-stimulated insulin secretion from beta-cells not only directly but also indirectly via regulation of incretin secretion. Moreover, our data suggest a conserved role for Ipf1/Pdx1 and Gpr40 in FFA-mediated secretion of hormones that regulate glucose and overall energy homeostasis.

Identifiers
urn:nbn:se:umu:diva-23321 (URN)10.2337/db08-0307 (DOI)18519800 (PubMedID)2-s2.0-52749098923 (Scopus ID)
Available from: 2009-06-10 Created: 2009-06-10 Last updated: 2023-03-24
Steneberg, P., Rubins, N., Bartoov-Shifman, R., Walker, M. D. & Edlund, H. (2005). The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.. Cell Metabolism, 1(4), 245-58
Open this publication in new window or tab >>The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse.
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2005 (English)In: Cell Metabolism, ISSN 1550-4131, Vol. 1, no 4, p. 245-58Article in journal (Refereed) Published
Keywords
Animals, Diabetes Mellitus; Type 2/genetics/*metabolism/physiopathology, Fatty Liver/*metabolism, Glucose/*physiology, Glucose Intolerance/genetics/metabolism, Homeostasis/*physiology, Hyperinsulinism/*metabolism, Hypertriglyceridemia/genetics/metabolism, Insulin/secretion, Islets of Langerhans/metabolism, Mice, Receptors; G-Protein-Coupled/deficiency/genetics/*metabolism
Identifiers
urn:nbn:se:umu:diva-5927 (URN)16054069 (PubMedID)2-s2.0-20944433543 (Scopus ID)
Available from: 2007-12-03 Created: 2007-12-03 Last updated: 2023-03-23Bibliographically approved
Lundström, A., Gallio, M., Englund, C., Steneberg, P., Hemphälä, J., Aspenström, P., . . . Samakovlis, C. (2004). Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons. Genes & Development, 18(17), 2161-71
Open this publication in new window or tab >>Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons
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2004 (English)In: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 18, no 17, p. 2161-71Article in journal (Refereed) Published
Abstract [en]

Slit proteins steer the migration of many cell types through their binding to Robo receptors, but how Robo controls cell motility is not clear. We describe the functional analysis of vilse, a Drosophila gene required for Robo repulsion in epithelial cells and axons. Vilse defines a conserved family of RhoGAPs (Rho GTPase-activating proteins), with representatives in flies and vertebrates. The phenotypes of vilse mutants resemble the tracheal and axonal phenotypes of Slit and Robo mutants at the CNS midline. Dosage-sensitive genetic interactions between vilse, slit, and robo mutants suggest that vilse is a component of robo signaling. Moreover, overexpression of Vilse in the trachea of robo mutants ameliorates the phenotypes of robo, indicating that Vilse acts downstream of Robo to mediate midline repulsion. Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP and, less efficiently, of Cdc42GTP. These results together with genetic interaction experiments with robo, vilse, and rac mutants suggest a mechanism whereby Robo repulsion is mediated by the localized inactivation of Rac through Vilse.

Identifiers
urn:nbn:se:umu:diva-30131 (URN)10.1101/gad.310204 (DOI)15342493 (PubMedID)2-s2.0-4444379134 (Scopus ID)
Available from: 2009-12-08 Created: 2009-12-08 Last updated: 2023-03-24Bibliographically approved
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