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Bauzá-Thorbrügge, M., Vujičić, M., Chanclón, B., Palsdottir, V., Pillon, N. J., Benrick, A. & Wernstedt Asterholm, I. (2024). Adiponectin stimulates Sca1+CD34−-adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue. Metabolism: Clinical and Experimental, 151, Article ID 155716.
Open this publication in new window or tab >>Adiponectin stimulates Sca1+CD34-adipocyte precursor cells associated with hyperplastic expansion and beiging of brown and white adipose tissue
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2024 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 151, article id 155716Article in journal (Refereed) Published
Abstract [en]

Background: The adipocyte hormone adiponectin improves insulin sensitivity and there is an inverse correlation between adiponectin levels and type-2 diabetes risk. Previous research shows that adiponectin remodels the adipose tissue into a more efficient metabolic sink. For instance, mice that overexpress adiponectin show increased capacity for hyperplastic adipose tissue expansion as evident from smaller and metabolically more active white adipocytes. In contrast, the brown adipose tissue (BAT) of these mice looks “whiter” possibly indicating reduced metabolic activity. Here, we aimed to further establish the effect of adiponectin on adipose tissue expansion and adipocyte mitochondrial function as well as to unravel mechanistic aspects in this area. Methods: Brown and white adipose tissues from adiponectin overexpressing (APN tg) mice and littermate wildtype controls, housed at room and cold temperature, were studied by histological, gene/protein expression and flow cytometry analyses. Metabolic and mitochondrial functions were studied by radiotracers and Seahorse-based technology. In addition, mitochondrial function was assessed in cultured adiponectin deficient adipocytes from APN knockout and heterozygote mice. Results: APN tg BAT displayed increased proliferation prenatally leading to enlarged BAT. Postnatally, APN tg BAT turned whiter than control BAT, confirming previous reports. Furthermore, elevated adiponectin augmented the sympathetic innervation/activation within adipose tissue. APN tg BAT displayed reduced metabolic activity and reduced mitochondrial oxygen consumption rate (OCR). In contrast, APN tg inguinal white adipose tissue (IWAT) displayed enhanced metabolic activity. These metabolic differences between genotypes were apparent also in cultured adipocytes differentiated from BAT and IWAT stroma vascular fraction, and the OCR was reduced in both brown and white APN heterozygote adipocytes. In both APN tg BAT and IWAT, the mesenchymal stem cell-related genes were upregulated along with an increased abundance of Lineage−Sca1+CD34− “beige-like” adipocyte precursor cells. In vitro, the adiponectin receptor agonist Adiporon increased the expression of the proliferation marker Pcna and decreased the expression of Cd34 in Sca1+ mesenchymal stem cells. Conclusions: We propose that the seemingly opposite effect of adiponectin on BAT and IWAT is mediated by a common mechanism; while reduced adiponectin levels are linked to lower adipocyte OCR, elevated adiponectin levels stimulate expansion of adipocyte precursor cells that produce adipocytes with intrinsically higher metabolic rate than classical white but lower metabolic rate than classical brown adipocytes. Moreover, adiponectin can modify the adipocytes' metabolic activity directly and by enhancing the sympathetic innervation within a fat depot. 

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Adipocyte, Adipocyte precursor cell, Adiponectin, Brown adipose tissue, Mitochondria, White adipose tissue
National Category
Cell and Molecular Biology Physiology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-23470 (URN)10.1016/j.metabol.2023.155716 (DOI)001128761900001 ()37918793 (PubMedID)2-s2.0-85178627618 (Scopus ID)
Note

CC BY 4.0 DEED

© 2023 The Authors

Correspondence Address: I. Wernstedt Asterholm; Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Medicinaregatan 11, PO Box 432, SE-405 30, Sweden; email: IWA@neuro.gu.se; CODEN: METAA

Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2024-04-15Bibliographically approved
Samad, M., Ek, J., Börchers, S., Krieger, J.-P., Stener-Victorin, E., Skibicka, K. P., . . . Benrick, A. (2024). Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model. Scientific Reports, 14(1), Article ID 563.
Open this publication in new window or tab >>Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model
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2024 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 14, no 1, article id 563Article in journal (Refereed) Published
Abstract [en]

Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects. 

Place, publisher, year, edition, pages
Springer Nature, 2024
Keywords
Adiponectin, Androgens, Animals, Anti-Anxiety Agents, Anxiety, Female, Humans, Mice, Polycystic Ovary Syndrome, Pregnancy, Prenatal Exposure Delayed Effects, androgen, anxiolytic agent, animal, human, metabolism, mouse, ovary polycystic disease, prenatal exposure
National Category
Physiology Endocrinology and Diabetes Neurosciences Obstetrics, Gynecology and Reproductive Medicine
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-23545 (URN)10.1038/s41598-023-50503-8 (DOI)001136960700018 ()38177175 (PubMedID)2-s2.0-85181457736 (Scopus ID)
Funder
University of GothenburgSwedish Research Council, 2020-02485Magnus Bergvall Foundation, 2022-082Hjalmar Svensson's Research Foundation, 2022-291Swedish Research Council, 2021-01549Swedish Research Council, 2022-00550Novo Nordisk Foundation, NNF22OC0072904Swedish Research Council, 2018-00660NIH (National Institutes of Health), R01DK129321Swedish Research Council, 2020-01463Insamlingsstiftelsen Diabetes Wellness
Note

CC BY 4.0 DEED

© 2024, The Author(s)

Correspondence Address: A. Benrick; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Box 423, 40530, Sweden; email: anna.benrick@gu.se

Open access funding provided by University of Gothenburg. AB holds funding from the Swedish Research Council (2020-02485), Magnus Bergvalls Foundation (2022-082), Tore Nilssons Foundation (2022-033), and Hjalmars Svenssons Foundation (2022-291). JPK holds funding from the Swedish Research Council (2021-01549), the Swiss Cancer Research Foundation (KFS-5745-02-2023-R), and Boehringer Ingelheim. ESV holds funding from the Swedish Research Council (2022-00550), the Novo Nordisk Foundation (NNF22OC0072904), KPS is funded by the Swedish Research Council (2018-00660), and the National Institutes of Health R01DK129321, and IWA. holds funding from the Swedish Research Council (2020-01463), Mary von Sydow Foundation (5022), EFSD//European Research Program on ‘New Targets for Diabetes or Obesity-related Metabolic Diseases’ supported by MSD 2022, and Diabetes Wellness Sverige. The funding bodies did not have a role in the study design and had no role in the implementation of the study.

Available from: 2024-01-18 Created: 2024-01-18 Last updated: 2024-04-15Bibliographically approved
Stener-Victorin, E., Eriksson, G., Shrestha, M. M., Rodriguez Paris, V., Lu, H., Banks, J., . . . Benrick, A. (2024). Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS. eLife, 12
Open this publication in new window or tab >>Proteomic analysis shows decreased Type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS
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2024 (English)In: eLife, ISSN 2050-084X, Vol. 12Article in journal (Refereed) Published
Abstract [en]

Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation. Results: Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.

Place, publisher, year, edition, pages
eLife Sciences Publications Ltd, 2024
Keywords
PCOS, adipose tissue, genetics, genomics, human, medicine, methylation, mouse, proteomics, skeletal muscle, transcriptomics
National Category
Physiology Obstetrics, Gynecology and Reproductive Medicine Endocrinology and Diabetes Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-23514 (URN)10.7554/eLife.87592 (DOI)001137149700001 ()38180081 (PubMedID)2-s2.0-85181630677 (Scopus ID)
Funder
Swedish Research Council, 2020-02485Swedish Research Council, 2022-00550Novo Nordisk Foundation, NNF22OC0072904Swedish Research Council, 2020-01463Insamlingsstiftelsen Diabetes WellnessIngaBritt and Arne Lundberg’s Research Foundation
Note

CC BY 4.0 DEED

5 January 2024

Corresponding author: Anna Benrick, University of Gothenburg, Institute of Neuroscience and Physiology, Department of Physiology, Box 432, 405 30 Gothenburg, Sweden. Phone: +46 (0)709490148. E-mail: anna.benrick@gu.se

Funding: A.B. holds funding from the Swedish Research Council (2020-02485), E.SV. holds funding from the Swedish Research Council (2022-00550), the Novo Nordisk Foundation (NNF22OC0072904), and I.W.A. holds funding from the Swedish Research Council (2020-01463), Mary von Sydow Foundation, Diabetes Wellness Sverige, and EFSD//European Research Programme on ‘New Targets for Diabetes or Obesity-related Metabolic Diseases’ supported by MSD 2022, and J.N. holds funding from IngaBritt and Arne Lundberg Research Foundation.

Manuskript i medRxiv: DOI: 10.1101/2023.03.08.23286896

Available from: 2024-01-08 Created: 2024-01-08 Last updated: 2024-04-15Bibliographically approved
Bauzá-Thorbrügge, M., Peris, E., Zamani, S., Micallef, P., Paul, A., Bartesaghi, S., . . . Wernstedt Asterholm, I. (2023). NRF2 is essential for adaptative browning of white adipocytes. Redox Biology, 68, Article ID 102951.
Open this publication in new window or tab >>NRF2 is essential for adaptative browning of white adipocytes
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2023 (English)In: Redox Biology, E-ISSN 2213-2317, Vol. 68, article id 102951Article in journal (Refereed) Published
Abstract [en]

White adipose tissue browning, defined by accelerated mitochondrial metabolism and biogenesis, is considered a promising mean to treat or prevent obesity-associated metabolic disturbances. We hypothesize that redox stress acutely leads to increased production of reactive oxygen species (ROS), which activate electrophile sensor nuclear factor erythroid 2-Related Factor 2 (NRF2) that over time results in an adaptive adipose tissue browning process. To test this, we have exploited adipocyte-specific NRF2 knockout mice and cultured adipocytes and analyzed time- and dose-dependent effect of NAC and lactate treatment on antioxidant expression and browning-like processes. We found that short-term antioxidant treatment with N-acetylcysteine (NAC) induced reductive stress as evident from increased intracellular NADH levels, increased ROS-production, reduced oxygen consumption rate (OCR), and increased NRF2 levels in white adipocytes. In contrast, and in line with our hypothesis, longer-term NAC treatment led to a NRF2-dependent browning response. Lactate treatment elicited similar effects as NAC, and mechanistically, these NRF2-dependent adipocyte browning responses in vitro were mediated by increased heme oxygenase-1 (HMOX1) activity. Moreover, this NRF2-HMOX1 axis was also important for β3-adrenergic receptor activation-induced adipose tissue browning in vivo. In conclusion, our findings show that administration of exogenous antioxidants can affect biological function not solely through ROS neutralization, but also through reductive stress. We also demonstrate that NRF2 is essential for white adipose tissue browning processes. 

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Adipose tissue, Lactate, N-acetylcysteine, NRF2, Redox stress
National Category
Physiology Endocrinology and Diabetes Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-23363 (URN)10.1016/j.redox.2023.102951 (DOI)001110673000001 ()37931470 (PubMedID)2-s2.0-85175560964 (Scopus ID)
Note

CC BY 4.0 DEED

© 2023 The Authors

Correspondence Address: I. Wernstedt Asterholm; Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Medicinaregatan 11, PO Box 432, SE, 405 30, Sweden; email: IWA@neuro.gu.se

Available from: 2023-11-16 Created: 2023-11-16 Last updated: 2024-04-15Bibliographically approved
Risal, S., Li, C., Luo, Q., Fornes, R., Lu, H., Eriksson, G., . . . Stener-Victorin, E. (2023). Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome. Cell Reports Medicine, 4(5), Article ID 101035.
Open this publication in new window or tab >>Transgenerational transmission of reproductive and metabolic dysfunction in the male progeny of polycystic ovary syndrome
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2023 (English)In: Cell Reports Medicine, E-ISSN 2666-3791 , Vol. 4, no 5, article id 101035Article in journal (Refereed) Published
Abstract [en]

The transgenerational maternal effects of polycystic ovary syndrome (PCOS) in female progeny are being revealed. As there is evidence that a male equivalent of PCOS may exists, we ask whether sons born to mothers with PCOS (PCOS-sons) transmit reproductive and metabolic phenotypes to their male progeny. Here, in a register-based cohort and a clinical case-control study, we find that PCOS-sons are more often obese and dyslipidemic. Our prenatal androgenized PCOS-like mouse model with or without diet-induced obesity confirmed that reproductive and metabolic dysfunctions in first-generation (F1) male offspring are passed down to F3. Sequencing of F1–F3 sperm reveals distinct differentially expressed (DE) small non-coding RNAs (sncRNAs) across generations in each lineage. Notably, common targets between transgenerational DEsncRNAs in mouse sperm and in PCOS-sons serum indicate similar effects of maternal hyperandrogenism, strengthening the translational relevance and highlighting a previously underappreciated risk of transmission of reproductive and metabolic dysfunction via the male germline. 

Place, publisher, year, edition, pages
Cell Press, 2023
Keywords
adipose tissue, male offspring, male offspring to male germline, maternal hyperandrogenism, maternal obesity, polycystic ovary syndrome, small non-coding RNAs, sperm, transgenerational transmission, Animals, Case-Control Studies, Female, Humans, Male, Mice, Obesity, Pregnancy, Reproduction, Semen, small untranslated RNA, animal experiment, animal model, animal tissue, Article, case control study, childhood obesity, cohort analysis, controlled study, differential gene expression, dyslipidemia, fetus outcome, fetus risk, gene locus, genetic risk, genital system disease, germ line, high risk infant, high risk patient, human, hyperandrogenism, maternal fetal transmission, metabolic disorder, mouse, nonhuman, ovary polycystic disease, prenatal exposure, progeny, risk assessment, RNA analysis, vertical transmission, animal, genetics
National Category
Obstetrics, Gynecology and Reproductive Medicine Physiology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-22630 (URN)10.1016/j.xcrm.2023.101035 (DOI)001001951100001 ()37148878 (PubMedID)2-s2.0-85159450311 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2019.0211Novo Nordisk Foundation, NNF18OC0033992, NNF19OC0056647Adlerbertska Research Foundation, GU 2019/86O.E. och Edla Johanssons vetenskapliga stiftelse, 2021Magnus Bergvall Foundation, 2020-03808, 2021-04329H.R.H. Crown Princess Lovisa's Association for Child CareAxel Tielmans minnesfond
Note

CC BY 4.0

© 2023 The Author(s)

Correspondence: qiaolin.deng@ki.se (Q.D.), elisabet.stener-victorin@ki.se (E.S.-V.)

We thank Zhiyi Zhao, Jacob Victorin, Sonja Edström, and Sara Pilström for technical assistance during animal work and molecular analysis; TSE Systems and the Metabolic Phenotyping Center at the Strategic Research program in Diabetes at the Karolinska Institutet; and the electron microscopy unit Emil at Huddinge University Hospital at the Karolinska Institutet. This work is supported by the Swedish Medical Research Council: project nos. 2018-02435 and 2022-00550 (E.S.-V.) and 2018-02557 and 2020-00253 (Q.D.); the Knut and Alice Wallenberg Foundation: 2019.0211 (Q.D.); Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation: NNF22OC0072904 (E.S.-V.); the Diabetes Foundation:DIA2021-633 (E.S.-V.); the Novo Nordisk Foundation: NNF18OC0033992 and NNF19OC0056647 (E.S.-V.); the Strategic Research Program in Diabetes at the Karolinska Institutet (E.S.-V.); the Adlerbertska Research Foundation: GU 2019/86 (E.S.-V.); Karolinska Institutet KID funding: 2020-00990 (E.S.-V.); a Karolinska Instiutet faculty funded position (Q.D.); the Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet: 20190079 (E.S.-V.); O.E. och Edla Johanssons Stiftelse 2021 (S.R.); the Karolinska Institutet China scholarship council program (Q.L.); Magnus Bergvalls Stiftelse: 2020-03808 and 2021-04329 (S.R.); the Karolinska Institutet: 2020-02026 (S.R.); the National Fund for Scientific and Technological Development (FONDECYT): project no. 1151531 (T.S.P.); the FONDECYT: project no. 1201483 (B.E.); the National Commission for Scientific and Technological Research (CONICYT) (R.F.); HKH Kronprinsessan Lovisas förening för barnasjukvård (R.F.); and Stiftelsen Axel Tielmans minnesfond (R.F.)

Available from: 2023-06-01 Created: 2023-06-01 Last updated: 2023-07-14Bibliographically approved
Shrestha, M. M., Wermelin, S., Stener-Victorin, E., Asterholm, I. W. & Benrick, A. (2022). Adiponectin Deficiency Alters Placenta Function but Does Not Affect Fetal Growth in Mice. International Journal of Molecular Sciences, 23(9), Article ID 4939.
Open this publication in new window or tab >>Adiponectin Deficiency Alters Placenta Function but Does Not Affect Fetal Growth in Mice
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2022 (English)In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 9, article id 4939Article in journal (Refereed) Published
Abstract [en]

Adiponectin administration to pregnant mice decreases nutrient transport and fetal growth. An adiponectin deficiency, on the other hand, as seen in obese women during pregnancy, alters fetal growth; however, the mechanism is unclear. To determine the role of adiponectin on placenta function and fetal growth, we used adiponectin knockout, adiponectin heterozygote that displays reduced adiponectin levels, and wild-type mice on a control diet or high fat/high sucrose (HF/HS) diet. Triglycerides (TGs) in the serum, liver, and placenta were measured using colorimetric assays. Gene expression was measured using quantitative RT-PCR. Adiponectin levels did not affect fetal weight, but it reduced adiponectin levels, increased fetal serum and placenta TG content. Wildtype dams on a HF/HS diet protected the fetuses from fatty acid overload as judged by increased liver TGs in dams and normal serum and liver TG levels in fetuses, while low adiponectin was associated with increased fetal liver TGs. Low maternal adiponectin increased the expression of genes involved in fatty acid transport; Lpl and Cd36 in the placenta. Adiponectin deficiency does not affect fetal growth but induces placental dysfunction and increases fetal TG load, which is enhanced with obesity. This could lead to imprinting effects on the fetus and the development of metabolic dysfunction in the offspring. 

Place, publisher, year, edition, pages
MDPI, 2022
Keywords
adiponectin, fetal growth, placenta, triglycerides
National Category
Medical and Health Sciences Basic Medicine Physiology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-21132 (URN)10.3390/ijms23094939 (DOI)000795395700001 ()35563332 (PubMedID)2-s2.0-85129085040 (Scopus ID)
Funder
Swedish Research Council, 2013-07107Swedish Research Council, 2020-02485Swedish Research Council, 2020-01463Diabetesfonden, DIA2019-419Magnus Bergvall Foundation, 2018-02891Åke Wiberg Foundation, M17-0113Adlerbertska Research Foundation, E 2017/26Hjalmar Svensson's Research Foundation, HJSV2017070
Note

CC BY 4.0

Attribution 4.0 International (CC BY 4.0)

© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Correspondence: anna.benrick@gu.se or anna.benrick@his.se

This research was funded by the Swedish Research Council (2013-07107, 2020-02485, 2020-01463), the NovoNordisk Foundation (NNF19OC0056601), the Swedish Diabetes Foundation (DIA2019-419), the Diabetes Research and Wellness Foundation, Magnus Bergvall Foundation (2018-02891), Åke Wiberg Foundation (M17-0113), Adlerbertska Foundation (E 2017/26), Hjalmar Svensson Foundation (HJSV2017070), and The Royal Society of Arts and Sciences in Gothenburg (2019-330).

Available from: 2022-05-12 Created: 2022-05-12 Last updated: 2022-07-13Bibliographically approved
Wu, Y., Chanclón, B., Micallef, P., Stener-Victorin, E., Wernstedt Asterholm, I. & Benrick, A. (2021). Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice. The FASEB Journal, 35(4), Article ID e21299.
Open this publication in new window or tab >>Maternal adiponectin prevents visceral adiposity and adipocyte hypertrophy in prenatal androgenized female mice
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2021 (English)In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 35, no 4, article id e21299Article in journal (Refereed) Published
Abstract [en]

Hyperandrogenism is the main characteristic of polycystic ovary syndrome, which affects placental function and fetal growth, and leads to reproductive and metabolic dysfunction in female offspring. Adiponectin acts on the placenta and may exert endocrine effects on the developing fetus. This study aims to investigate if maternal and/or fetal adiponectin can prevent metabolic and reproductive dysfunction in prenatal androgenized (PNA) female offspring. Adiponectin transgenic (APNtg) and wild-type dams received dihydrotestosterone/vehicle injections between gestational days 16.5-18.5 to induce PNA offspring, which were followed for 4 months. Offspring from APNtg dams were smaller than offspring from wild-type dams, independent of genotype. Insulin sensitivity was higher in wild-type mice from APNtg dams compared to wild-types from wild-type dams, and insulin sensitivity correlated with fat mass and adipocyte size. PNA increased visceral fat% and adipocyte size in wild-type offspring from wild-type dams, while wild-type and APNtg offspring from APNtg dams were protected against this effect. APNtg mice had smaller adipocytes than wild-types and this morphology was associated with an increased expression of genes regulating adipogenesis (Ppard, Pparg, Cebpa, and Cebpb) and metabolism (Chrebp and Lpl). Anogenital distance was increased in all PNA-exposed wild-type offspring, but there was no increase in PNA APNtg offspring, suggesting that adiponectin overexpression protects against this effect. In conclusion, elevated adiponectin levels in utero improve insulin sensitivity, reduce body weight and fat mass gain in the adult offspring and protect against PNA-induced visceral adiposity. In conclusion, these data suggest that PNA offspring benefit from prenatal adiponectin supplementation. 

Place, publisher, year, edition, pages
John Wiley & Sons, 2021
Keywords
adiponectin, adiposity, imprinting, PCOS, PNA
National Category
Endocrinology and Diabetes
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19580 (URN)10.1096/fj.202002212R (DOI)000635216100077 ()33715227 (PubMedID)2-s2.0-85102916113 (Scopus ID)
Funder
Swedish Research Council, 2017-00792, 2018-02435, 2013-7107 and 2020-02435Diabetesfonden, DIA2019-419Magnus Bergvall Foundation, 2017-02069
Note

CC BY-NC-ND 4.0

© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Available from: 2021-04-01 Created: 2021-04-01 Last updated: 2021-08-16Bibliographically approved
Risal, S., Manti, M., Lu, H., Fornes, R., Larsson, H., Benrick, A., . . . Stener-Victorin, E. (2021). Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders. Translational Psychiatry, 11(1), Article ID 45.
Open this publication in new window or tab >>Prenatal androgen exposure causes a sexually dimorphic transgenerational increase in offspring susceptibility to anxiety disorders
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2021 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 11, no 1, article id 45Article in journal (Refereed) Published
Abstract [en]

If and how obesity and elevated androgens in women with polycystic ovary syndrome (PCOS) affect their offspring’s psychiatric health is unclear. Using data from Swedish population health registers, we showed that daughters of mothers with PCOS have a 78% increased risk of being diagnosed with anxiety disorders. We next generated a PCOS-like mouse (F0) model induced by androgen exposure during late gestation, with or without diet-induced maternal obesity, and showed that the first generation (F1) female offspring develop anxiety-like behavior, which is transgenerationally transmitted through the female germline into the third generation of female offspring (F3) in the androgenized lineage. In contrast, following the male germline, F3 male offspring (mF3) displayed anxiety-like behavior in the androgenized and the obese lineages. Using a targeted approach to search for molecular targets within the amygdala, we identified five differentially expressed genes involved in anxiety-like behavior in F3 females in the androgenized lineage and eight genes in the obese lineage. In mF3 male offspring, three genes were dysregulated in the obese lineage but none in the androgenized lineage. Finally, we performed in vitro fertilization (IVF) using a PCOS mouse model of continuous androgen exposure. We showed that the IVF generated F1 and F2 offspring in the female germline did not develop anxiety-like behavior, while the F2 male offspring (mF2) in the male germline did. Our findings provide evidence that elevated maternal androgens in PCOS and maternal obesity may underlie the risk of a transgenerational transmission of anxiety disorders in children of women with PCOS.

Place, publisher, year, edition, pages
Springer, 2021
National Category
Obstetrics, Gynecology and Reproductive Medicine Endocrinology and Diabetes Physiology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19435 (URN)10.1038/s41398-020-01183-9 (DOI)000609920200004 ()33441551 (PubMedID)2-s2.0-85099339971 (Scopus ID)
Note

CC BY 4.0

Correspondence: Elisabet Stener-Victorin (elisabet.stener-victorin@ki.se)

Available from: 2021-01-28 Created: 2021-01-28 Last updated: 2024-01-17Bibliographically approved
Davegårdh, C., Säll, J., Benrick, A., Broholm, C., Volkov, P., Perfilyev, A., . . . Ling, C. (2021). VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics. Nature Communications, 12(1), Article ID 2431.
Open this publication in new window or tab >>VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigenetics
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2021 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 12, no 1, article id 2431Article in journal (Refereed) Published
Abstract [en]

Insulin resistance and lower muscle quality (strength divided by mass) are hallmarks of type 2 diabetes (T2D). Here, we explore whether alterations in muscle stem cells (myoblasts) from individuals with T2D contribute to these phenotypes. We identify VPS39 as an important regulator of myoblast differentiation and muscle glucose uptake, and VPS39 is downregulated in myoblasts and myotubes from individuals with T2D. We discover a pathway connecting VPS39-deficiency in human myoblasts to impaired autophagy, abnormal epigenetic reprogramming, dysregulation of myogenic regulators, and perturbed differentiation. VPS39 knockdown in human myoblasts has profound effects on autophagic flux, insulin signaling, epigenetic enzymes, DNA methylation and expression of myogenic regulators, and gene sets related to the cell cycle, muscle structure and apoptosis. These data mimic what is observed in myoblasts from individuals with T2D. Furthermore, the muscle of Vps39+/− mice display reduced glucose uptake and altered expression of genes regulating autophagy, epigenetic programming, and myogenesis. Overall, VPS39-deficiency contributes to impaired muscle differentiation and reduced glucose uptake. VPS39 thereby offers a therapeutic target for T2D. 

Place, publisher, year, edition, pages
Springer Nature, 2021
National Category
Endocrinology and Diabetes
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-19684 (URN)10.1038/s41467-021-22068-5 (DOI)000656463600015 ()33893273 (PubMedID)2-s2.0-85104824362 (Scopus ID)
Funder
Swedish Research CouncilEuropean Commission
Note

CC BY 4.0

© 2021, The Author(s).

Correspondence and requests for materials should be addressed to C.L.

Available from: 2021-05-06 Created: 2021-05-06 Last updated: 2023-03-28Bibliographically approved
Stener-Victorin, E., Padmanabhan, V., Walters, K. A., Campbell, R. E., Benrick, A., Giacobini, P., . . . Abbott, D. H. (2020). Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome. Endocrine reviews, 41(4), Article ID bnaa010.
Open this publication in new window or tab >>Animal Models to Understand the Etiology and Pathophysiology of Polycystic Ovary Syndrome
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2020 (English)In: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 41, no 4, article id bnaa010Article, review/survey (Refereed) Published
Abstract [en]

More than 1 out of 10 women worldwide are diagnosed with polycystic ovary syndrome (PCOS), the leading cause of female reproductive and metabolic dysfunction. Despite its high prevalence, PCOS and its accompanying morbidities are likely underdiagnosed, averaging > 2 years and 3 physicians before women are diagnosed. Although it has been intensively researched, the underlying cause(s) of PCOS have yet to be defined. In order to understand PCOS pathophysiology, its developmental origins, and how to predict and prevent PCOS onset, there is an urgent need for safe and effective markers and treatments. In this review, we detail which animal models are more suitable for contributing to our understanding of the etiology and pathophysiology of PCOS. We summarize and highlight advantages and limitations of hormonal or genetic manipulation of animal models, as well as of naturally occurring PCOS-like females. 

Place, publisher, year, edition, pages
Oxford University Press, 2020
Keywords
adipogenic constraint-induced lipotoxicity, androgen excess, developmental programming, genetic manipulation, naturally hyperandrogenic female monkeys, therapeutic prevention
National Category
Obstetrics, Gynecology and Reproductive Medicine Physiology
Research subject
Translational Medicine TRIM
Identifiers
urn:nbn:se:his:diva-18551 (URN)10.1210/endrev/bnaa010 (DOI)000545338200003 ()32310267 (PubMedID)2-s2.0-85086282447 (Scopus ID)
Available from: 2020-06-22 Created: 2020-06-22 Last updated: 2020-08-27Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-4616-6789

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