Jørn Vegard Sagen

• Pavithram, Aishwarya; Johansson, Bente Berg; Tjora, Erling; Svalastoga, Pernille; Mohamed, Khadra Aabdi & Koløen, Ingvild [Vis alle 17 forfattere av denne artikkelen] (2026). HNF1B-MODY in the Norwegian MODY Registry and the Norwegian Childhood Diabetes Registry: Clinical Insights and Prevalence Informed by Genetic and Functional Evaluation. International Journal of Molecular Sciences. ISSN 1661-6596. 27(11). doi: 10.3390/ijms27115067. Fulltekst i vitenarkiv
• Dhar, Indu; Svingen, Gard Frodahl Tveitevåg; Ulvik, Arve; Bjørnestad, Espen Øglænd; Sagen, Jørn Vegard & Nygård, Ottar Kjell (2025). Serum Vitamin A Is Associated with Variations in the Relationship between Plasma B6 Vitamers and Cardiovascular Disease Risk. Journal of Nutrition. ISSN 0022-3166. 156(1). doi: 10.1016/j.tjnut.2025.10.036. Fulltekst i vitenarkiv Vis sammendrag

  Background: Low concentrations of biologically active B6 vitamer, pyridoxal 5'-phosphate (PLP) are associated with an increased risk of cardiovascular disease (CVD). Vitamin A (Vit-A) promotes lipid homeostasis and the transport cholesterol. Vit-A may also stimulate the intracellular transport of PLP. Objectives: This study aimed to investigate whether Vit-A is associated with variations in the relationship of systemic B6-vitamers with incident acute myocardial infarctions (AMIs). Methods: A total of 4091 patients undergoing elective coronary angiography for suspected stable angina pectoris were studied. Associations of different plasma B6 vitamers, including PLP, pyridoxal (PL), 4-pyridoxic acid (PA), and PA/PL ratio with the risk of AMI according to median concentrations of Vit-A, were explored in Cox regression models. Results: Serum Vit-A demonstrated positive associations with PLP and PA/PL ratio at baseline (P < 0.001 for both). During a median follow-up of 7.5 y, 521 (12.7%) patients suffered an AMI. In age and sex-adjusted analyses, plasma PLP, PA, and PA/PL ratio showed an overall association with incident AMI {hazard ratio (HR) [95% confidence interval (CI)] per SD: 0.90 [0.82, 0.99; P = 0.02], 1.14 [1.05, 1.23; P < 0.001], and 1.28 [1.18, 1.39; P < 0.001], respectively}. However, low plasma PLP and high PA/PL ratio were associated with an increased risk of AMI primarily among patients with high compared with low Vit-A concentrations [HR (95% CI) per SD: 0.77 (0.68, 0.88; P < 0.001, P-interaction = 0.002) and 1.36 (1.23, 1.49; P < 0.001, P-interaction = 0.05), respectively]. The interactions persisted after multivariable adjustment (both P-interactions ≤ 0.04). Conclusions: The relationship between vitamin B6 indexes and AMI risk varied according to serum Vit-A concentrations. Additional research is needed to clarify the importance of Vit-A and B6 bioavailability in atherosclerotic CVD.

• Pavithram, Aishwarya; Zhang, Haichen; Maloney, Kristin A.; Ringdal, Monika; Kaci, Alba & Sagen, Jørn Vegard [Vis alle 12 forfattere av denne artikkelen] (2024). In Vitro Functional Analysis Can Aid Precision Diagnostics of HNF1B-MODY. Journal of Molecular Diagnostics. ISSN 1525-1578. 26(6), s. 530–541. doi: 10.1016/j.jmoldx.2024.03.006. Fulltekst i vitenarkiv Vis sammendrag

  Precision medicine relies on accurate and consistent classification of sequence variants. A correct diagnosis of hepatocyte nuclear factor (HNF) 1B maturity-onset diabetes of the young, caused by pathogenic variants in the HNF1B gene, is important for optimal disease management and prognosis, and it has implications for genetic counseling and follow-up of at-risk family members. We hypothesized that the functional characterization could provide valuable information to assist the interpretation of pathogenicity of HNF1B variants. Using different in vitro functional assays, variants identified among 313 individuals, suspected to have monogenic diabetes with or without kidney disease, were characterized. The data from the functional assays were subsequently conjugated with obtained clinical, biochemical, and in silico data. Two variants (p.A167P, p.H336Pfs∗22) showed severe loss of function due to impaired transactivation, reduced DNA binding (p.A167P), and mRNA instability (p.A167P). Although both these variant carriers were diagnosed with diabetes, the p.H336Pfs∗22 carrier also had congenital absence of a kidney, which is a characteristic trait for HNF1B maturity-onset diabetes of the young. Functional analysis of the p.A167P variant revealed damaging effects on HNF-1B protein function, which may warrant imaging of the kidneys and/or pancreas. In addition, the current study has generated important data, including evidence supporting the benign functional impact of five variants (p.D82N, p.T88A, p.N394D, p.V458G, and p.T544A), and piloting new approaches that will prove critical for the growth of HNF1B-diabetes diagnosis.

• Dasa, Marcus Småvik; Friborg, Oddgeir; Kristoffersen, Morten; Pettersen, Gunn; Sagen, Jørn Vegard & Torstveit, Monica Klungland [Vis alle 8 forfattere av denne artikkelen] (2024). Risk and prevalence of Relative Energy Deficiency in Sport (REDs) among professional female football players. European Journal of Sport Science (EJSS). ISSN 1746-1391. 24(7), s. 1032–1041. doi: 10.1002/ejsc.12129. Fulltekst i vitenarkiv Vis sammendrag

  A high prevalence of low energy availability (LEA) has been reported in female football players. This is of concern as problematic LEA may evolve into a syndromic pattern known as relative energy deficiency in sport (REDs). Given the difficulties in accurately assessing LEA, our study shifts emphasis to measurable indicators of REDs, serving as proxies for health detriments caused by LEA. The present cross-sectional study aimed to quantify the risk of REDs and to assess the prevalence of indicators indicative of the syndrome. 60 players (tiers 3 and 4) from three Norwegian football teams were analyzed as a single cohort but also stratified based on player position and menstrual status. The proportion of players at risk for REDs was 22%, that is, 17% with mild, 3% with moderate to high, and 2% with very high/extreme risk, respectively. The majority of the cohort (71%) presented with no primary indicators, while 20%, 7%, and 2% presented with one, two, and three primary indicators, respectively. Regarding secondary indicators, 57% had none, 33% had one, and 10% had two indicators. For associated indicators, 30% had none, 42% had one, 18% had two, 8% had three, and 2% had four indicators. Player position did not affect the prevalence of REDs indicators. Among noncontraceptive users (n = 27), secondary amenorrhea (AME) was reported by 30%. These findings indicate that health and performance teams should prioritize universal health promoting strategies rather than selective or indicative strategies. Particularly, focus on nutritional periodization to secure sufficient energy availability, mitigating the risk of problematic LEA and REDs should be addressed.

• Kaci, Alba; Solheim, Marie Holm; Silgjerd, Trine; Hjaltadottir, Jorunn; Hornnes, Lorentze Hope & Molnes, Janne [Vis alle 14 forfattere av denne artikkelen] (2024). Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects. Human Molecular Genetics. ISSN 0964-6906. 33(10), s. 894–904. doi: 10.1093/hmg/ddae027. Fulltekst i vitenarkiv Vis sammendrag

  Hepatocyte nuclear factor-4 alpha (HNF-4A) regulates genes with roles in glucose metabolism and β-cell development. Although pathogenic HNF4A variants are commonly associated with maturity-onset diabetes of the young (MODY1; HNF4A-MODY), rare phenotypes also include hyperinsulinemic hypoglycemia, renal Fanconi syndrome and liver disease. While the association of rare functionally damaging HNF1A variants with HNF1A-MODY and type 2 diabetes is well established owing to robust functional assays, the impact of HNF4A variants on HNF-4A transactivation in tissues including the liver and kidney is less known, due to lack of similar assays. Our aim was to investigate the functional effects of seven HNF4A variants, located in the HNF-4A DNA binding domain and associated with different clinical phenotypes, by various functional assays and cell lines (transactivation, DNA binding, protein expression, nuclear localization) and in silico protein structure analyses. Variants R85W, S87N and R89W demonstrated reduced DNA binding to the consensus HNF-4A binding elements in the HNF1A promoter (35, 13 and 9%, respectively) and the G6PC promoter (R85W ~10%). While reduced transactivation on the G6PC promoter in HepG2 cells was shown for S87N (33%), R89W (65%) and R136W (35%), increased transactivation by R85W and R85Q was confirmed using several combinations of target promoters and cell lines. R89W showed reduced nuclear levels. In silico analyses supported variant induced structural impact. Our study indicates that cell line specific functional investigations are important to better understand HNF4A-MODY genotype–phenotype correlations, as our data supports ACMG/AMP interpretations of loss-of-function variants and propose assay-specific HNF4A control variants for future functional investigations.

• Svalastoga, Pernille; Kaci, Alba; Molnes, Janne; Solheim, Marie Holm; Johansson, Bente Berg & Krogvold, Lars [Vis alle 16 forfattere av denne artikkelen] (2023). Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes. Diabetologia. ISSN 0012-186X. 66, s. 2226–2237. doi: 10.1007/s00125-023-06012-4. Fulltekst i vitenarkiv Vis sammendrag

  Aims/hypothesis Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers’ phenotype and treatment response to sulfonylurea. Results In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY.

• Dasa, Marcus Småvik; Friborg, Oddgeir; Kristoffersen, Morten; Pettersen, Gunn; Sagen, Jørn Vegard & Sundgot-Borgen, Jorunn [Vis alle 7 forfattere av denne artikkelen] (2023). Evaluating the Suitability of the Low Energy Availability in Females Questionnaire (LEAF-Q) for Female Football Players. Sports Medicine - Open. 9. doi: 10.1186/s40798-023-00605-4. Fulltekst i vitenarkiv Vis sammendrag

  Background The Low Energy Availability in Females Questionnaire (LEAF-Q) is a screening tool developed to detect endurance athletes and dancers at risk for development of persistent low energy availability (LEA) and the female athlete triad (Triad). This study investigated the applicability of the LEAF-Q in a cohort of sixty professional female football players. Methods The participants were classified as at risk (≥ 8) or not at risk (< 8) for persistent LEA and the Triad according to their LEAF-Q score, before being compared. Receiver operating curves were then conducted to examine the ability of the overall LEAF-Q and subcategories to correctly determine the presence of clinically defined markers of the Triad. Additionally, Youden’s index was calculated to determine the best fitting cut-off values. Results Thirty-two percent of participants were classified as at risk by the LEAF-Q. We found no statistically significant differences between the two groups for any markers associated with persistent LEA. Except for acceptable accuracy in determining menstrual status, all other LEAF-Q components exhibited poor accuracy and predictive values. Youden’s index scores imply that increasing the overall and injury cut-off values to ≥ 10 and ≥ 5 respectively, would yield increased performance. Conclusions Our findings do not support the use of the LEAF-Q for the purpose of detecting LEA and Triad conditions among female football players.

• Hjelmesæth, Jøran Sture; Lund, Randi Størdal; Sagen, Jørn Vegard & Valderhaug, Tone Gretland (2022). Vektreduserende medisiner – for hvem, hvordan, hvor lenge? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. doi: 10.4045/tidsskr.22.0115. Fulltekst i vitenarkiv Vis sammendrag

  Medikamentell behandling av fedme gjennomgår en faglig revolusjon, og det kan være vanskelig å følge med. To relativt nye medikamenter som demper sult og øker metthetsfølelsen, kan nå forskrives av alle leger.

• Madsen, Andre; Almås, Bjørg; Bruserud, Ingvild Særvold; Oehme, Ninnie Helen Bakken; Nielsen, Christopher Sivert & Roelants, Mathieu [Vis alle 13 forfattere av denne artikkelen] (2022). Reference Curves for Pediatric Endocrinology: Leveraging Biomarker Z-Scores for Clinical Classifications. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 107(7), s. 2004–2015. doi: 10.1210/clinem/dgac155. Fulltekst i vitenarkiv Vis sammendrag

  Context Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age. Objective We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI). Methods Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established “LMS” growth chart algorithm in R. Results Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (β = 0.5, P < 0.001) and leptin (β = 0.6, P < 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (β = −0.4, P < 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class. Conclusion Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.

• Rosenvinge, Jan H; Dasa, Marcus Småvik; Kristoffersen, Morten; Pettersen, Gunn; Sundgot-Borgen, Jorunn & Sagen, Jørn Vegard [Vis alle 7 forfattere av denne artikkelen] (2022). Study protocol: Prevalence of low energy availability and its relation to health and performance among female football players. BMJ Open sport & exercise medicine. 8, s. 1–5. doi: 10.1136/bmjsem-2021-001219. Fulltekst i vitenarkiv Vis sammendrag

  Enduring low energy availability (LEA) is associated with several potentially serious physiological and mental conditions. LEA has been found highly prevalent among female elite athletes within endurance sports, thus hampering athletes’ health and performance. The prevalence and the underpinning risk factors of LEA among female elite football players are less studied. One reason is that the existing self-report measures and technological devices to monitor energy intake and expenditure are inadequately adapted to capture the nature of the physical activity and energy expenditure among football players and are thus inaccurate. The present paper outlines a study protocol addressing the prevalence of LEA, the measurement of LEA and the correlations of LEA in terms of health and performance in female football players. Four studies will be conducted with the following aims (1) to evaluate the accuracy of global positioning systems (GPS)-based devices to monitor energy expenditure with indirect calorimetry as the gold standard, (2) to assess energy intake, quantify energy expenditure and investigate energy availability through self-report instruments, double labelled water (DLW) and GPS monitoring devices, (3) to determine the point prevalence of LEA using self-report instruments, DLW, dual-X-ray-absorptiometry (DXA) to quantify muscle and bone mass distribution and density, and a battery of hormonal analyses, and (4) to explore whether the prevalence of LEA varies across a full football season. Measures covering mental symptoms and psychological resources will be included, and a selection of biological measures derived from study 3. Measurements of DXA and DLW are resource-demanding and will be collected from one professional club (N~20 women). In contrast, the remaining data will be collected from four professional clubs (N~60 women) located in Bergen, the largest city within the Western region of Norway. Overall procedures and biobank storage procedures have been approved for data collection that will end in December 2024.

• Haugen, Christine; Lysne, Vegard; Haldorsen, Ingfrid S.; Tjora, Erling; Gudbrandsen, Oddrun Anita & Sagen, Jørn Vegard [Vis alle 8 forfattere av denne artikkelen] (2022). MRI adipose tissue segmentation and quantification in R (RAdipoSeg). Diabetology & Metabolic Syndrome. 14, s. 1–8. doi: 10.1186/s13098-022-00913-x. Fulltekst i vitenarkiv Vis sammendrag

  Background: Excess adipose tissue is associated with increased cardiovascular and metabolic risk, but the volume of visceral and subcutaneous adipose tissue poses different metabolic risks. MRI with fat suppression can be used to accurately quantify adipose depots. We have developed a new semi-automatic method, RAdipoSeg, for MRI adipose tissue segmentation and quantification in the free and open source statistical software R. Methods: MRI images were obtained from wild-type mice on high- or low-fat diet, and from 20 human subjects without clinical signs of metabolic dysfunction. For each mouse and human subject, respectively, 10 images were segmented with RAdipoSeg and with the commercially available software SliceOmatic. Jaccard difference, relative volume difference and Spearman’s rank correlation coefficients were calculated for each group. Agreement between the two methods were analysed with Bland–Altman plots. Results: RAdipoSeg performed similarly to the commercial software. The mean Jaccard differences were 10–29% and the relative volume differences were below ( ±) 20%. Spearman’s rank correlation coefficient gave p-values below 0.05 for both mouse and human images. The Bland–Altman plots indicated some systematic and proporitional bias, which can be countered by the flexible nature of the method. Conclusion: RAdipoSeg is a reliable and low cost method for fat segmentation in studies of mice and humans.

• Hanem, Liv Guro Engen; Salvesen, Øyvind; Madsen, Andre; Sagen, Jørn Vegard; Mellgren, Gunnar & Juliusson, Pétur Benedikt [Vis alle 9 forfattere av denne artikkelen] (2021). Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study. PLOS ONE. 16(9), s. 1–14. doi: 10.1371/journal.pone.0257186. Fulltekst i vitenarkiv Vis sammendrag

  Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

• Jersin, Regine Åsen; Tallapragada, Divya Sri Priyanka; Madsen, Andre; Skartveit, Linn; Fjære, Even & McCann, Adrian [Vis alle 29 forfattere av denne artikkelen] (2021). Role of the Neutral Amino Acid Transporter Slc7a10 in Adipocyte Lipid Storage, Obesity and Insulin Resistance. Diabetes. ISSN 0012-1797. 70(3), s. 680–695. doi: 10.2337/db20-0096. Fulltekst i vitenarkiv Vis sammendrag

  Elucidation of mechanisms that govern lipid storage, oxidative stress, and insulin resistance may lead to improved therapeutic options for type 2 diabetes and other obesity-related diseases. Here, we find that adipose expression of the small neutral amino acid transporter SLC7A10, also known as alanine-serine-cysteine transporter-1 (ASC-1), shows strong inverse correlates with visceral adiposity, insulin resistance, and adipocyte hypertrophy across multiple cohorts. Concordantly, loss of Slc7a10 function in zebrafish in vivo accelerates diet-induced body weight gain and adipocyte enlargement. Mechanistically, SLC7A10 inhibition in human and murine adipocytes decreases adipocyte serine uptake and total glutathione levels and promotes reactive oxygen species (ROS) generation. Conversely, SLC7A10 overexpression decreases ROS generation and increases mitochondrial respiratory capacity. RNA sequencing revealed consistent changes in gene expression between human adipocytes and zebrafish visceral adipose tissue following loss of SLC7A10, e.g., upregulation of SCD (lipid storage) and downregulation of CPT1A (lipid oxidation). Interestingly, ROS scavenger reduced lipid accumulation and attenuated the lipid-storing effect of SLC7A10 inhibition. These data uncover adipocyte SLC7A10 as a novel important regulator of adipocyte resilience to nutrient and oxidative stress, in part by enhancing glutathione levels and mitochondrial respiration, conducive to decreased ROS generation, lipid accumulation, adipocyte hypertrophy, insulin resistance, and type 2 diabetes.

• Romuld, Ingunn Bratland; Kalleklev, Tine-Lise; Molnes, Janne; Juliusson, Pétur Benedikt; Njølstad, Pål Rasmus & Sagen, Jørn Vegard (2021). Impact of overweight on glucose homeostasis in MODY2 and MODY3. Diabetic Medicine. ISSN 0742-3071. 38(10). doi: 10.1111/dme.14649. Fulltekst i vitenarkiv
• Dasa, Marcus Småvik; Kristoffersen, Morten; Ersvær, Elisabeth; Bovim, Lars Peder Vatshelle; Bjørkhaug, Lise & Moe-Nilssen, Rolf [Vis alle 8 forfattere av denne artikkelen] (2021). The Female Menstrual Cycles Effect on Strength and Power Parameters in High-Level Female Team Athletes. Frontiers in Physiology. 12. doi: 10.3389/fphys.2021.600668. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: The female menstrual cycle (MC) is characterized by hormonal fluctuations throughout its different phases. However, research regarding its effect on athletic performance in high level athletes is sparse. The aim of this study was to (i) investigate the female MCs effect on strength and power performance in highly trained female team athletes throughout the MC and (ii) examine whether eumenorrheic participants with natural hormonal fluctuations displayed enhanced performance in the follicular phase (FP) versus the luteal phase (LP), compared to controls using hormonal contraceptives. Materials and Methods: A total of 29 athletes (Age 21.2 ± 3.3 years; weight 65.6 ± 8.7 kg; height 170.2 ± 8.0 cm; and fat free mass 52.7 ± 7.1) completed the study after a 6-week testing period (8 eumenorrheic participants and 21 hormonal contraceptive controls). Participants were recruited from the team sports soccer, handball and volleyball. Testing protocol consisted of maximal voluntary isometric grip strength, 20-m sprint, countermovement jump and pneumatic leg-press. Based on self-reported use of hormonal contraceptives, participants were divided into non-hormonal contraceptive group and hormonal contraceptive group, the latter working as a control group. Differences in performance between the FP and LP were investigated. MC phase was confirmed by serum hormonal levels through venous blood samples in the non-hormonal contraceptive group. Results: There were no statistically significant changes for the two different phases of the MC, in terms of physical performance for the whole group. Further, there was no significant difference between groups during the MC for any of the outcome variables, maximal voluntary isometric grip strength F(3.29) = 0.362; 20-m sprint F(3.24) = 0.710; countermovement jump F(3.26) = 2.361; and leg-press F(3.26) = 1.746. Conclusion: In high level female team athletes, no difference in performance was observed based on hormonal contraceptive status. This suggests that the MC does not alter acute strength and power performance on a group level in high level team athletes.

• Bertelsen, Bjørn-Erik; Viste, Kristin; Helland, Thomas; Hagland, Magnus; Søiland, Håvard & Geisler, Jürgen [Vis alle 11 forfattere av denne artikkelen] (2021). Simultaneous Quantification of Aromatase Inhibitors and Estrogens in Postmenopausal Breast Cancer Patients. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 107(5), s. 1368–1374. doi: 10.1210/clinem/dgab923. Fulltekst i vitenarkiv Vis sammendrag

  Context Currently there are no assays that can simultaneously quantify serum levels of the third-generation aromatase inhibitors (AIs): letrozole, anastrozole, and exemestane, and the ultra-low levels of estrogens in postmenopausal breast cancer patients on AI treatment. Such measurements may be pivotal for the determination of optimal and individualized treatment regimens. We aimed at developing a liquid chromatography–tandem mass spectrometry (MS/MS) method for simultaneous assessment of letrozole, anastrozole, exemestane, and 17-hydroxyexemestane as well as subpicomolar levels of estradiol and estrone. Methods Internal standards, calibrators, serum samples, and quality controls were in fully automated steps transferred to a deep-well plate for a 2-step liquid-liquid extraction. The extracts were reconstituted and analytes were separated chromatographically using 2 serially coupled columns, then subject to MS/MS in electrospray ionization mode. The method was thoroughly validated and is traceable to 2 accredited estrogen methods. Results The measurement range for estrone and estradiol was 0.2 to 12 000 pmol/L and 0.8 to 13 000 pmol/L, and covered the expected therapeutic range for the AIs. All analytes had a precision of less than or equal to 13%, and accuracies within 100 ± 8%. As proof of concept, AI and estrogen levels were determined in serum samples from postmenopausal breast cancer patients under treatment. Conclusion We present here an assay suitable for the simultaneous measurement of serum levels of all third-generation AIs and ultra-low levels of estrogens, providing a powerful new tool to study drug efficacy and compliance. The method is highly valuable for postmenopausal patients whose pretreatment estradiol levels are below the threshold of detection for most routine assays, but still require suppression.

• Ueland, Grethe Åstrøm; Kellmann, Ralf; Jørstad, Melissa Davidsen; Viste, Kristin; Husebye, Eystein Sverre & Almås, Bjørg [Vis alle 11 forfattere av denne artikkelen] (2021). Bedtime Salivary Cortisol as a Screening Test for Cushing Syndrome in Children. Journal of the Endocrine Society (JES). 5(5), s. 1–8. doi: 10.1210/jendso/bvab033. Fulltekst i vitenarkiv Vis sammendrag

  Background:Diagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, de-pendent on correct urine collection. Late-night salivary cortisol is easier and is used as a screening test for CS in adults, but has not been validated for use in children. Objective:To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff values for bedtime and morning salivary cortisol and cortisone in children, and validate the results in children with and without CS. Methods:Bedtime and morning salivary samples were collected from 320 healthy chil-dren aged 4 to 16 years. Fifty-four patients from the children’s outpatient obesity clinic and 3 children with pituitary CS were used for validation. Steroid hormones were as-sayed by LC-MS/MS. Cutoff levels for bedtime salivary cortisol and cortisone were de-fined by the 97.5% percentile in healthy subjects. Results:Bedtime cutoff levels for cortisol and cortisone were 2.4 and 12.0 nmol/L, re-spectively. Applying these cutoff levels on the verification cohort, 1 child from the obesity clinic had bedtime salivary cortisol exceeding the defined cutoff level, but normal sal-ivary cortisone. All 3 children with pituitary CS had salivary cortisol and cortisone far above the defined bedtime cutoff levels. Healthy subjects showed a significant decrease in salivary cortisol from early morning to bedtime.

• Dicker, Dror; Bettini, Silvia; Farpour-Lambert, Nathalie; Frühbeck, Gema; Golan, Rachel & Goossens, Gijs [Vis alle 15 forfattere av denne artikkelen] (2020). Obesity and COVID-19: The two sides of the coin. Obesity Facts. ISSN 1662-4025. s. 1–9. doi: 10.1159/000510005. Fulltekst i vitenarkiv
• Dankel, Simon N; Grytten, Elise; Bjune, Jan-Inge; Nielsen, Hans Jørgen; Dietrich, Arne & Blüher, Matthias [Vis alle 8 forfattere av denne artikkelen] (2020). COL6A3 expression in adipose tissue cells is associated with levels of the homeobox transcription factor PRRX1. Scientific Reports. 10:20164, s. 1–11. doi: 10.1038/s41598-020-77406-2. Fulltekst i vitenarkiv Vis sammendrag

  Fibrillar collagen COL6α3 in adipose tissue has been associated with obesity, inflammation, insulin resistance and cancer. We here aimed to identify novel transcriptional regulators of COL6A3 expression. Based on a transcriptome dataset of adipose tissue, we identified strong correlations for 56 genes with COL6A3 mRNA, including targets of TGF-β/SMAD signaling. Among the identified candidates, the homeobox transcription factor PRRX1 showed a particularly striking co-expression with COL6A3, validated across several different cohorts, including patients with extreme obesity, insulin sensitive and resistant obesity (subcutaneous and omental), after profound fat loss (subcutaneous), and lean controls (subcutaneous). In human and mouse adipose cells, PRRX1 knockdown reduced COL6A3 mRNA and PRRX1 overexpression transactivated a reporter construct with the endogenous human COL6A3 promoter. Stable PRRX1 overexpression in 3T3-L1 cells induced Col6a3 mRNA threefold specifically after adipogenic induction, whereas TGF-β1 treatment upregulated Col6a3 mRNA also in the preadipocyte state. Interestingly, pro-inflammatory stimulus (i.e., TNF-α treatment) decreased PRRX1-mediated Col6a3 transactivation and mRNA expression, supporting a role for this mechanism in the regulation of adipose tissue inflammation. In conclusion, we identified the homeobox factor PRRX1 as a novel transcriptional regulator associated with COL6A3 expression, providing new insight into the regulatory mechanisms of altered adipose tissue function in obesity and insulin resistance.

• Madsen, Andre; Oehme, Ninnie; Roelants, Mathieu; Bruserud, Ingvild Særvold; Eide, Geir Egil & Viste, Kristin [Vis alle 12 forfattere av denne artikkelen] (2020). Testicular Ultrasound to Stratify Hormone References in a Cross-Sectional Norwegian Study of Male Puberty. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 105(6), s. 1888–1898. doi: 10.1210/clinem/dgz094. Fulltekst i vitenarkiv
• Frühbeck, Gema; Baker, Jennifer Lyn; Busetto, Luca; Dicker, Dror; Goossens, Gijs H. & Halford, Jason C.G. [Vis alle 18 forfattere av denne artikkelen] (2020). European Association for the Study of Obesity Position Statement on the Global COVID-19 Pandemic. Obesity Facts. ISSN 1662-4025. 13(2), s. 292–296. doi: 10.1159/000508082. Fulltekst i vitenarkiv
• Madsen, Andre; Bruserud, Ingvild Særvold; Bertelsen, Bjørn-Erik; Roelants, Mathieu; Oehme, Ninnie & Viste, Kristin [Vis alle 12 forfattere av denne artikkelen] (2020). Hormone references for ultrasound breast staging and endocrine profiling to detect female onset of puberty. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 105(12), s. e4886–e4895. doi: 10.1210/clinem/dgaa679. Fulltekst i vitenarkiv Vis sammendrag

  Context Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset. Objective To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche. Design Setting and Participants Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years. Main Outcome Measures Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range. Results References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P < 0.001). Ultrasound detection of nonpalpable glandular tissue in 14 out of 264 (5.3%) girls with clinically prepubertal presentation was associated with significantly higher median serum levels of E2 (12.5 vs 4.9 pmol/L; P < 0.05) and a distinct endocrine profile (arbitrary units; P < 0.001). Conclusions We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset.

• Bertelsen, Bjørn-Erik; Kellmann, Ralf; Viste, Kristin; Bjørnevik, Anne Turid; Eikesdal, Hans Petter & Lønning, Per Eystein [Vis alle 8 forfattere av denne artikkelen] (2020). An ultrasensitive routine LC-MS/MS method for estradiol and estrone in the clinically relevant sub-picomolar range. Journal of the Endocrine Society (JES). 4(6), s. 1–15. doi: 10.1210/jendso/bvaa047. Fulltekst i vitenarkiv Vis sammendrag

  Background Current analytical routine methods lack the sensitivity to monitor plasma estrogen levels in breast cancer patients treated with aromatase inhibitors. Such monitoring is warranted for premenopausal patients treated with an aromatase inhibitor and an LH-releasing hormone analogue in particular. Therefore, we aimed to develop a routine tandem mass spectroscopy combined with liquid chromatography (LC-MS/MS) method for estradiol (E2) and estrone (E1) for use in the sub-picomolar range. Method Calibrators, quality controls (QC), or serum samples were spiked with isotope-labeled internal standard and purified by liquid-liquid extraction. The reconstituted extracts were analyzed by LC-MS/MS in negative electrospray ionization mode. QCs at 6 levels made from pooled patient sera were used to validate the accuracy, sensitivity, and precision of the method. Results We achieved limits of quantification of 0.6 pmol/L (0.16 pg/mL) for E2 and 0.3 pmol/L (0.07 pg/mL) for E1. The coefficient of variation was below 9.0% at all QC levels for E2 (range, 1.7-153 pmol/L), and below 7.8% for E1 (range, 1.7-143 pmol/L). The method is traceable to the E2 reference standard BCR576. Reference ranges for E2 and E1 in healthy, postmenopausal women were obtained, for E2: 3.8 to 36 pmol/L, for E1: 22 to 122 pmol/L. We measured and confirmed ultra-low E2 and E1 concentrations in sera from patients on the aromatase inhibitors letrozole or exemestane. Conclusion This ultrasensitive LC-MS/MS method is suitable for routine assessment of serum E1 and E2 levels in breast cancer patients during estrogen suppression therapy. The method satisfies all requirements for measurement of E2 in the clinical setting as stated by the Endocrine Society in 2013. Precis We report an ultrasensitive LCMS/MS routine assay that measures pretreatment and suppressed levels of estradiol/estrone during aromatase inhibitor treatment of postmenopausal breast cancer patients.

• Dankel, Simon N; Røst, Therese Halvorsen; Kulyté, Agné; Fandalyuk, Zinayida; Skurk, Thomas & Hauner, Hans [Vis alle 10 forfattere av denne artikkelen] (2019). The Rho GTPase RND3 regulates adipocyte lipolysis. Metabolism: Clinical and Experimental. ISSN 0026-0495. 101:153999, s. 1–12. doi: 10.1016/j.metabol.2019.153999. Fulltekst i vitenarkiv Vis sammendrag

  Background: Adipose tissue plays a crucial role in diet- and obesity-related insulin resistance, with implications for several metabolic diseases. Identification of novel target genes and mechanisms that regulate adipocyte function could lead to improved treatment strategies. RND3 (RhoE/Rho8), a Rho-related GTP-binding protein that inhibits Rho kinase (ROCK) signaling, has been linked to diverse diseases such as apoptotic cardiomyopathy, heart failure, cancer and type 2 diabetes, in part by regulating cytoskeleton dynamics and insulin-mediated glucose uptake. Results: We here investigated the expression of RND3 in adipose tissue in human obesity, and discovered a role for RND3 in regulating adipocyte metabolism. In cross-sectional and prospective studies, we observed 5-fold increased adipocyte levels of RND3 mRNA in obesity, reduced levels after surgery-induced weight loss, and positive correlations of RND3 mRNA with adipocyte size and surrogate measures of insulin resistance (HOMA2-IR and circulating triglyceride/high-density lipoprotein cholesterol (TAG/HDL-C) ratio). By screening for RND3-dependent gene expression following siRNA-mediated RND3 knockdown in differentiating human adipocytes, we found downregulation of inflammatory genes and upregulation of genes related to adipocyte ipolysis and insulin signaling. Treatment of adipocytes with tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), hypoxia or cAMP analogs increased RND3 mRNA levels 1.5–2-fold. Functional assays in primary human adipocytes confirmed that RND3 knockdown reduces cAMP- and isoproterenol-induced lipolysis, which were mimicked by treating cells with ROCK inhibitor. This effect could partly be explained by reduced protein expression of adipose triglyceride lipase (ATGL) and phosphorylated hormone-sensitive lipase (HSL). Conclusion: We here uncovered a novel differential expression of adipose RND3 in obesity and insulin resistance, which may at least partly depend on a causal effect of RND3 on adipocyte lipolysis.

• Bjune, Jan-Inge; Dyer, Laurence; Røsland, Gro Vatne; Tronstad, Karl Johan; Njølstad, Pål Rasmus & Sagen, Jørn V. [Vis alle 8 forfattere av denne artikkelen] (2019). The homeobox factor Irx3 maintains adipogenic identity. Metabolism: Clinical and Experimental. ISSN 0026-0495. doi: 10.1016/j.metabol.2019.154014. Fulltekst i vitenarkiv
• Svärd, Jessica; Røst, Therese Halvorsen; Sommervoll, Camilla Elise Nergård; Haugen, Christine; Gudbrandsen, Oddrun Anita & Christensen, Anne Elisabeth Mellgren [Vis alle 11 forfattere av denne artikkelen] (2019). Absence of the proteoglycan decorin reduces glucose tolerance in overfed male mice. Scientific Reports. 9(1). doi: 10.1038/s41598-018-37501-x. Fulltekst i vitenarkiv Vis sammendrag

  Studies have implicated the extracellular matrix (ECM) of adipose tissue in insulin resistance. The proteoglycan decorin, a component of ECM, has been associated with glucose tolerance, but possible causal effects on metabolism remain to be explored. We here sought to determine metabolic consequences of loss of decorin in mice (DcnKO). DcnKO mice were fed a low-fat (LF) or high-fat (HF) diet for 10 weeks and body weight and food intake was recorded. An intraperitoneal glucose tolerance test was performed after eight weeks. Blood samples and adipose, liver and muscle tissues were collected at sacrifice. Global gene expression was measured in adipose tissue, and expression of decorin was also analyzed in human adipose samples. DcnKO mice showed increased feed efficiency during overfeeding and impaired glucose tolerance. Adipose leptin mRNA and circulating leptin levels were elevated in DcnKO mice, along with a downregulation of genes involved in ECM organization and triglyceride biosynthesis, and an upregulation of adipose genes involved in complement and coagulation cascades. Consistent with a protective metabolic role for decorin, in obese patients we found increased adipose decorin expression after profound fat loss, particularly in the stromal vascular fraction. Loss of decorin in mice caused impaired glucose tolerance in association with increased feed efficiency and altered gene expression in adipose tissue. Our data provide evidence that decorin is an important factor for maintaining glucose tolerance.

• Madsen, Andre; Oehme, Ninnie; Roelants, Mathieu; Bruserud, Ingvild Særvold; Eide, Geir Egil & Viste, Kristin [Vis alle 12 forfattere av denne artikkelen] (2019). Testicular ultrasound to stratify hormone references in a cross-sectional Norwegian study of male puberty. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. doi: 10.1210/clinem/dgz094. Fulltekst i vitenarkiv Vis sammendrag

  Context: Testicular growth represents the best clinical variable to evaluate male puberty, but current pediatric hormone references are based on chronological age and subjective assessments of discrete puberty development stages. Determination of testicular volume (TV) by ultrasound provides a novel approach to assess puberty progression and stratify hormone reference intervals. Objective: The objective of this article is to establish references for serum testosterone and key hormones of the male pituitary-gonadal signaling pathway in relation to TV determined by ultrasound. Design, Setting, and Participants: Blood samples from 414 healthy Norwegian boys between ages 6 and 16 years were included from the cross-sectional “Bergen Growth Study 2.” Participants underwent testicular ultrasound and clinical assessments, and serum samples were analyzed by liquid chromatography tandem–mass spectrometry and immunoassays. Main Outcome Measures: We present references for circulating levels of total testosterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin in relation to TV, chronological age, and Tanner pubic hair stages. Results: In pubertal boys, TV accounted for more variance in serum testosterone levels than chronological age (Spearman r = 0.753, P < .001 vs r = 0.692, P < .001, respectively). Continuous centile references demonstrate the association between TV and hormone levels during puberty. Hormone reference intervals were stratified by TV during the pubertal transition. Conclusions: Objective ultrasound assessments of TV and stratification of hormone references increase the diagnostic value of traditional references based on chronological age or subjective staging of male puberty.

• Helgeland, Øyvind; Vaudel, Marc; Juliusson, Petur Benedikt; Holmen, Oddgeir Lingaas; Juodakis, Julius & Bacelis, Jonas [Vis alle 17 forfattere av denne artikkelen] (2019). Genome-wide association study reveals dynamic role of genetic variation in infant and early childhood growth. Nature Communications. 10, s. 1–10. doi: 10.1038/s41467-019-12308-0. Fulltekst i vitenarkiv Vis sammendrag

  Infant and childhood growth are dynamic processes with large changes in BMI during development. By performing genome-wide association studies of BMI at 12 time points from birth to eight years (9286 children, 74,105 measurements) in the Norwegian Mother, Father, and Child Cohort Study, replicated in 5235 children, we identify a transient effect in the leptin receptor (LEPR) locus: no effect at birth, increasing effect in infancy, peaking at 6–12 months (rs2767486, P6m = 2.0 × 10−21, β6m = 0.16 sd-BMI), and little effect after age five. We identify a similar transient effect near the leptin gene (LEP), peaking at 1.5 years (rs10487505, P1.5y = 1.3 × 10−8, β1.5y = 0.079 sd-BMI). Both signals are protein quantitative trait loci for soluble-LEPR and LEP in plasma in adults independent from adult traits mapped to the respective genes, suggesting key roles of common variation in the leptin signaling pathway for healthy infant growth.

• Gudbrandsen, Oddrun Anita; Dankel, Simon N; Skumsnes, Lillian; Flølo, Tone Nygaard; Folkestad, Oddry H & Nielsen, Hans Jørgen [Vis alle 12 forfattere av denne artikkelen] (2019). Short-term effects of Vertical sleeve gastrectomy and Roux-en-Y gastric bypass on glucose homeostasis. Scientific Reports. 9:14817(1), s. 1–7. doi: 10.1038/s41598-019-51347-x. Fulltekst i vitenarkiv Vis sammendrag

  The objective of this study was to compare the biochemical changes related to glucose tolerance and lipid metabolism in non-diabetic patients shortly after vertical sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Non-diabetic women and men with morbid obesity were studied the day before and six days after SG (N = 15) or RYGB (N = 16). Patients completed an oral glucose tolerance test (OGTT; 75 g glucose) at both visits. SG and RYGB similarly improved fasting glucose homeostasis six days after surgery, with reduced glucose and insulin concentrations. The OGTT revealed differences between the two surgery groups that were not evident from the fasting serum concentrations. Postprandial (120 min) glucose and insulin concentrations were lower after RYGB but not after SG, whereas concentrations of glucagon-like peptide-1, peptide YY, glucagon and non-esterified fatty acids were elevated after both SG and RYGB. Fasting triacylglycerol concentration did not change after surgery, but concentrations of high density lipoprotein and low density lipoprotein cholesterols were reduced in both surgery groups, with no differences between the groups. To conclude, RYGB induced a more pronounced improvement in postprandial glucose homeostasis relative to SG, possibly due to improved insulin sensitivity rather than augmented insulin concentration.

• Stokke, Silje Agnethe; Myhr, Kjell-Morten; Holmøy, Trygve; Benth, Jurate Saltyte; Wergeland, Stig & Beiske, Antonie Giæver [Vis alle 11 forfattere av denne artikkelen] (2018). Serum levels of leptin and adiponectin are not associated with disease activity or treatment response in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 323, s. 73–77. doi: 10.1016/j.jneuroim.2018.07.011. Fulltekst i vitenarkiv
• Ueland, Grethe Åstrøm; Methlie, Paal; Øksnes, Marianne; Thordarson, Hrafnkell B; Sagen, Jørn V. & Kellmann, Ralf [Vis alle 13 forfattere av denne artikkelen] (2018). The short cosyntropin test revisited: new normal reference range using LC-MS/MS. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 103(4), s. 1696–1703. doi: 10.1210/jc.2017-02602. Fulltekst i vitenarkiv
• Ueland, Grethe Åstrøm; Methlie, Paal; Jøssang, Dag Eirik; Sagen, Jørn V.; Viste, Kristin & Thordarson, Hrafnkell B [Vis alle 11 forfattere av denne artikkelen] (2018). Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 103(12), s. 4553–4560. doi: 10.1210/jc.2018-01198. Fulltekst i vitenarkiv
• Bjune, Jan-Inge; Haugen, Christine; Gudbrandsen, Oddrun Anita; Nordbø, Ole Petter; Nielsen, Hans Jørgen & Våge, Villy [Vis alle 10 forfattere av denne artikkelen] (2018). IRX5 regulates adipocyte amyloid precursor protein and mitochondrial respiration in obesity. International Journal of Obesity. ISSN 0307-0565. doi: 10.1038/s41366-018-0275-y. Fulltekst i vitenarkiv
• Bozickovic, Olivera; Skartveit, Linn; Svendsen, Agnete; Helland, Thomas; Jonsdottir, Kristin & Flågeng, Marianne Hauglid [Vis alle 12 forfattere av denne artikkelen] (2018). A novel SRC-2-dependent regulation of epithelial-mesenchymal transition in breast cancer cells. Journal of Steroid Biochemistry and Molecular Biology. ISSN 0960-0760. 185, s. 57–70. doi: 10.1016/j.jsbmb.2018.07.011. Fulltekst i vitenarkiv
• Eldin, Mohammed Adhmed Abdel Ghafar Kareem; Frøysa, Håvard G; Karlsen, Odd Andre; Sagen, Jørn V.; Mellgren, Gunnar & Verhaegen, Steven [Vis alle 9 forfattere av denne artikkelen] (2018). LC-MS/MS based profiling and dynamic modelling of the steroidogenesis pathway in adrenocarcinoma H295R cells. Toxicology in Vitro. ISSN 0887-2333. 52, s. 332–341. doi: 10.1016/j.tiv.2018.07.002. Fulltekst i vitenarkiv
• Sagen, Jørn V.; Bjørkhaug, Lise; Haukanes, Bjørn Ivar; Grevle, Louise; Molnes, Janne & Nedrebø, Bjørn Gunnar [Vis alle 10 forfattere av denne artikkelen] (2017). The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes. Diabetes Research and Clinical Practice. ISSN 0168-8227. 133, s. 142–149. doi: 10.1016/j.diabres.2017.08.001. Fulltekst i vitenarkiv
• Veum, Vivian Lohmann; Laupsa-Borge, Johnny; Eng, Øyvin Andre Solberg; Rostrup, Espen; Larsen, Terje H & Nordrehaug, Jan Erik [Vis alle 11 forfattere av denne artikkelen] (2017). Visceral adiposity and metabolic syndrome after very high-fat and low-fat isocaloric diets: A randomized controlled trial. American Journal of Clinical Nutrition. ISSN 0002-9165. 105(1), s. 85–99. doi: 10.3945/ajcn.115.123463. Fulltekst i vitenarkiv
• Grytaas, Marianne Aardal; Strømsøy, Siri S.; Rørvik, Jarle; Arnes, Jarle; Heie, Anette & Arnesen, Thomas [Vis alle 16 forfattere av denne artikkelen] (2017). Clinical Characteristics and Long-Term Outcome of Primary Aldosteronism in a Norwegian Population. Hormone and Metabolic Research. ISSN 0018-5043. 49(11), s. 838–846. doi: 10.1055/s-0043-118909. Fulltekst i vitenarkiv
• Madsen, Andre Greger; Bjune, Jan Inge; Bjørkhaug, Lise; Mellgren, Gunnar & Sagen, Jørn V. (2016). The cAMP-dependent protein kinase downregulates glucose-6-phosphatase expression through RORα and SRC-2 coactivator transcriptional activity. Molecular and Cellular Endocrinology. ISSN 0303-7207. 419, s. 92–101. doi: 10.1016/j.mce.2015.10.003. Fulltekst i vitenarkiv
• Avila, Magali; Dyment, David A.; Sagen, Jørn V.; St-Onge, Judith; Moog, Ute & Chung, Brian Hon-Yin [Vis alle 45 forfattere av denne artikkelen] (2016). Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: Toward recommendation for molecular testing and management. Clinical Genetics. ISSN 0009-9163. 89(4), s. 501–506. doi: 10.1111/cge.12688. Fulltekst i vitenarkiv
• Stokke, Silje Agnethe; Methlie, Paal; Løvås, Kristian & Sagen, Jørn V. (2016). Nedsatt følsomhet for thyreoideahormon. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 136(7), s. 618–622. doi: 10.4045/tidsskr.15.0084. Fulltekst i vitenarkiv
• Stokke, Silje Agnethe; Myhr, Kjell-Morten; Holmøy, Trygve; Benth, Jurate Saltyte; Wergeland, Stig & Beiske, Antonie Giæver [Vis alle 17 forfattere av denne artikkelen] (2015). Body mass index influence interferon-beta treatment response in multiple sclerosis. Journal of Neuroimmunology. ISSN 0165-5728. 288, s. 92–97. doi: 10.1016/j.jneuroim.2015.09.008. Fulltekst i vitenarkiv
• Bozickovic, Olivera; Hoang, Tuyen; Fenne, Ingvild Sveinsgjerd; Helland, Thomas; Skartveit, Linn & Ouchida, Mamoru [Vis alle 8 forfattere av denne artikkelen] (2015). Cyclin C interacts with steroid receptor coactivator 2 and upregulates cell cycle genes in MCF-7 cells. BBA - Molecular Cell Research. ISSN 0167-4889. 1853(10), s. 2383–2391. doi: 10.1016/j.bbamcr.2015.05.016. Fulltekst i vitenarkiv
• Madsen, Andre Greger; Bozickovic, Olivera; Bjune, Jan Inge; Mellgren, Gunnar & Sagen, Jørn V. (2015). Metformin inhibits hepatocellular glucose, lipid and cholesterol biosynthetic pathways by transcriptionally suppressing steroid receptor coactivator 2 (SRC-2). Scientific Reports. 5:16430. doi: 10.1038/srep16430. Fulltekst i vitenarkiv Vis sammendrag

  The ability of the anti-diabetic drug metformin to inhibit anabolic processes including gluconeogenesis and lipogenesis is partly attributable to activation of the AMP-activated protein kinase (AMPK) pathway. The p160 steroid receptor coactivator 2 (SRC-2) is a key regulator of cellular metabolism and drives expression of the gluconeogenic enzyme glucose-6-phosphatase (G6Pc). Here, we uncovered a role for SRC-2 in the metabolic reprogramming imposed by metformin. In FaO cells, metformin dose-dependently reduced mRNA expression of SRC-2. Microarray analysis of metformin- treated cells revealed an overrepresentation of downregulated genes involved in biosynthesis of lipids and cholesterol. Several metformin-regulated genes including fatty acid synthase (FASN) were validated as transcriptional targets of SRC-2 with promoters characterized by sterol regulatory element (SRE) binding protein (SREBP) recognition sequences. Transactivation assays of the FASN promoter confirmed that SRC-2 is a coactivator of SREBP-1. By suppressing SRC-2 at the transcriptional level, metformin impeded recruitment of SRC-2 and RNA polymerase II to the G6Pc promoter and to SREs of mutual SRC-2/SREBP-1 target gene promoters. Hepatocellular fat accretion was reduced by metformin or knock-down of both SRC-2 and SREBP-1. Accordingly we propose that metformin inhibits glucose and lipid biosynthesis partly by downregulating SRC-2 gene expression.

• Dankel, Simon E Nitter; Svärd, Jessica; Matthä, Simone; Claussnitzer, Melina; Klöting, Nora & Glunk, Viktoria [Vis alle 16 forfattere av denne artikkelen] (2014). COL6A3 expression in adipocytes associates with insulin resistance and depends on PPARγ and adipocyte size. Obesity. ISSN 1930-7381. 22(8), s. 1807–1813. doi: 10.1002/oby.20758. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Degerud, Eirik Magnus Meek; Borkowski, Kamil; Fjære, Even; Midtbø, Lisa Kolden & Haugen, Christine [Vis alle 13 forfattere av denne artikkelen] (2014). Weight cycling promotes fat gain and altered clock gene expression in adipose tissue in C57BL/6J mice. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 306(2), s. E210–E224. doi: 10.1152/ajpendo.00188.2013. Fulltekst i vitenarkiv
• Negahdar, Maria; Aukrust, Ingvild; Molnes, Janne; Solheim, Marie Holm; Johansson, Bente Berg & Sagen, Jørn V. [Vis alle 12 forfattere av denne artikkelen] (2014). GCK-MODY diabetes as a protein misfolding disease: The mutation R275C promotes protein misfolding, self-association and cellular degradation. Molecular and Cellular Endocrinology. ISSN 0303-7207. 382(1), s. 55–65. doi: 10.1016/j.mce.2013.08.020. Fulltekst i vitenarkiv
• Hoang, Tuyen; Fenne, Ingvild Sveinsgjerd; Madsen, Andre Greger; Bozickovic, Olivera; Johannessen, Mona & Bergsvåg, Mari [Vis alle 11 forfattere av denne artikkelen] (2013). cAMP response element-binding protein interacts with and stimulates the proteasomal degradation of the nuclear receptor coactivator GRIP1. Endocrinology. ISSN 0013-7227. 154(4), s. 1513–1527. doi: 10.1210/en.2012-2049. Fulltekst i vitenarkiv
• Søvik, Oddmund; Irgens, Henrik Underthun; Molnes, Janne; Sagen, Jørn V.; Bjørkhaug, Lise & Ræder, Helge [Vis alle 8 forfattere av denne artikkelen] (2013). Monogenetic diabetes mellitus in Norway :. Norsk Epidemiologi. ISSN 0803-2491. 23(1), s. 55–60. doi: 10.5324/nje.v23i1.1603. Fulltekst i vitenarkiv
• Chudasama, Kishan Kumar; Winnay, Jonathan; Johansson, Stefan; Claudi, Tor; König, Rainer & Haldorsen, Ingfrid S. [Vis alle 13 forfattere av denne artikkelen] (2013). SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. American Journal of Human Genetics. ISSN 0002-9297. 93(1), s. 150–157. doi: 10.1016/j.ajhg.2013.05.023. Fulltekst i vitenarkiv
• Fenne, Ingvild Sveinsgjerd; Helland, Thomas; Flågeng, Marianne Hauglid; Dankel, Simon E Nitter; Mellgren, Gunnar & Sagen, Jørn V. (2013). Downregulation of steroid receptor coactivator-2 modulates estrogen-responsive genes and stimulates proliferation of MCF-7 breast cancer cells. PLOS ONE. 8(7). doi: 10.1371/journal.pone.0070096. Fulltekst i vitenarkiv
• York, Brian; Sagen, Jørn V.; Tsimelzon, Anna; Louet, Jean Francois; Chopra, Atul R. & Reineke, Erin L. [Vis alle 15 forfattere av denne artikkelen] (2013). Research resource: tissue- and pathway-specific metabolomic profiles of the steroid receptor coactivator (SRC) family. Molecular Endocrinology. ISSN 0888-8809. 27(2), s. 366–380. doi: 10.1210/me.2012-1324. Fulltekst i vitenarkiv
• Veum, Vivian Lohmann; Dankel, Simon E Nitter; Gjerde, Jennifer; Nielsen, Hans Jørgen; Solsvik, Margit Hildershavn & Haugen, Christine [Vis alle 13 forfattere av denne artikkelen] (2012). The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss. International Journal of Obesity. ISSN 0307-0565. 36(9), s. 1195–1202. doi: 10.1038/ijo.2011.240. Fulltekst i vitenarkiv
• York, Brian; Reineke, Erin L.; Sagen, Jørn V.; Nikolai, Bryan C.; Zhou, Suoling & Louet, Jean Francois [Vis alle 21 forfattere av denne artikkelen] (2012). Ablation of Steroid Receptor Coactivator-3 Resembles the Human CACT Metabolic Myopathy. Cell Metabolism. ISSN 1550-4131. 15(5), s. 752–763. doi: 10.1016/j.cmet.2012.03.020. Fulltekst i vitenarkiv
• Moi, Line Leonore Haugan; Flågeng, Marianne Hauglid; Dankel, Simon E Nitter; Hoang, Tuyen; Gjerde, Jennifer & Sagen, Jørn V. [Vis alle 8 forfattere av denne artikkelen] (2011). Steroid Receptor Coactivators and Endocrine Treatment in Breast Cancer, Nuclear Receptors. Nova Science Publishers. ISSN 9781612099804. s. 35–66. Fulltekst i vitenarkiv
• Sagen, Jørn V. (2011). Fysisk aktivitet. I Skafjeld, Anita & Graue, Marit (Red.), Diabetes : forebygging, oppfølging, behandling. Akribe Forlag. ISSN 9788279500742. s. 147–157. Fulltekst i vitenarkiv
• Sagen, Jørn V. (2011). Nuclear hormone receptors – a family of hormone dependent transcriptional regulators. Klinisk Biokemi i Norden. ISSN 1101-2013. 23(3), s. 30–35. Fulltekst i vitenarkiv
• Sagen, Jørn V. (2011). Sykdomslære. I Skafjeld, Anita & Graue, Marit (Red.), Diabetes : forebygging, oppfølging, behandling. Akribe Forlag. ISSN 9788279500742. s. 19–73. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Stavrum, Anne-Kristin; Stansberg, Christine; Holdhus, Rita & Hoang, Tuyen [Vis alle 12 forfattere av denne artikkelen] (2010). Switch from stress response to homeobox transcription factors in adipose tissue after profound fat loss. PLOS ONE. 5(6). doi: 10.1371/journal.pone.0011033. Fulltekst i vitenarkiv Vis sammendrag

  Background In obesity, impaired adipose tissue function may promote secondary disease through ectopic lipid accumulation and excess release of adipokines, resulting in systemic low-grade inflammation, insulin resistance and organ dysfunction. However, several of the genes regulating adipose tissue function in obesity are yet to be identified. Methodology/Principal Findings In order to identify novel candidate genes that may regulate adipose tissue function, we analyzed global gene expression in abdominal subcutaneous adipose tissue before and one year after bariatric surgery (biliopancreatic diversion with duodenal switch, BPD/DS) (n = 16). Adipose tissue from lean healthy individuals was also analyzed (n = 13). Two different microarray platforms (AB 1700 and Illumina) were used to measure the differential gene expression, and the results were further validated by qPCR. Surgery reduced BMI from 53.3 to 33.1 kg/m2. The majority of differentially expressed genes were down-regulated after profound fat loss, including transcription factors involved in stress response, inflammation, and immune cell function (e.g., FOS, JUN, ETS, C/EBPB, C/EBPD). Interestingly, a distinct set of genes was up-regulated after fat loss, including homeobox transcription factors (IRX3, IRX5, HOXA5, HOXA9, HOXB5, HOXC6, EMX2, PRRX1) and extracellular matrix structural proteins (COL1A1, COL1A2, COL3A1, COL5A1, COL6A3). Conclusions/Significance The data demonstrate a marked switch of transcription factors in adipose tissue after profound fat loss, providing new molecular insight into a dichotomy between stress response and metabolically favorable tissue development. Our findings implicate homeobox transcription factors as important regulators of adipose tissue function.

• York, Brian; Yu, Chundong; Sagen, Jørn V.; Liu, Zhaoliang; Nikolai, Bryan C. & Wu, Ray-Chang [Vis alle 9 forfattere av denne artikkelen] (2010). Reprogramming the posttranslational code of SRC-3 confers a switch in mammalian systems biology. Proceedings of the National Academy of Sciences of the United States of America (PNAS). ISSN 0027-8424. 107(24), s. 11122–11127. doi: 10.1073/pnas.1005262107. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Hoang, Tuyen; Flågeng, Marianne Hauglid; Sagen, Jørn V. & Mellgren, Gunnar (2010). cAMP-mediated regulation of HNF-4 alpha depends on the level of coactivator PGC-1 alpha. BBA - Molecular Cell Research. ISSN 0167-4889. 1803(9), s. 1013–1019. doi: 10.1016/j.bbamcr.2010.05.008. Fulltekst i vitenarkiv
• Søvik, Oddmund; Sagen, Jørn V. & Njølstad, Pål Rasmus (2008). MODY5 due to mutations in TCF2 (HNF-1ß): The clinical spectrum with special reference to urogenital malformations. I Epstein, Charles J.; Erickson, Robert P. & Wynshaw-Boris, Anthony (Red.), Inborn Errors of Development. Oxford University Press. ISSN 9780195306910. s. 1096–1102. Fulltekst i vitenarkiv
• Fenne, Ingvild Sveinsgjerd; Hoang, Tuyen; Hauglid, Marianne; Sagen, Jørn V.; Lien, Ernst Asbjørn & Mellgren, Gunnar (2008). Recruitment of coactivator glucocorticoid receptor interacting protein 1 to an estrogen receptor transcription complex is regulated by the 3',5'-cyclic adenosine 5'-monophosphate-dependent protein kinase. Endocrinology. ISSN 0013-7227. 149(9), s. 4336–4345. doi: 10.1210/en.2008-0037. Fulltekst i vitenarkiv
• Sagen, Jørn V.; Bjørkhaug, Lise; Molnes, Janne; Ræder, Helge; Grevle, Louise & Søvik, Oddmund [Vis alle 8 forfattere av denne artikkelen] (2008). Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatric Diabetes. ISSN 1399-543X. 9, s. 442–449. doi: 10.1111/j.1399-5448.2008.00399.x. Fulltekst i vitenarkiv
• Søvik, Oddmund; Tansek, Mojca Zerjav; Sagen, Jørn V. & Njølstad, Pål Rasmus (2007). Management of neonatal and infancy-onset diabetes mellitus. Endocrine Development. ISSN 1421-7082. 11, s. 94–105. Fulltekst i vitenarkiv

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• Løvås, Kristian; Skrede, Steinar & Sagen, Jørn Vegard (2024). Riktig bruk av laboratorieprøver. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(14). doi: 10.4045/tidsskr.24.0493. Fulltekst i vitenarkiv
• Dasa, Marcus Småvik; Rosenvinge, Jan Harald; Friborg, Oddgeir; Pettersen, Gunn; Torstveit, Monica Klungland & Kristoffersen, Morten [Vis alle 8 forfattere av denne artikkelen] (2023). PREVALENCE OF MARKERS ASSOCIATED WITH RED-S IN ELITE-LEVEL FEMALE FOOTBALL PLAYERS. Fulltekst i vitenarkiv
• Søiland, Håvard; Janssen, Emiel; Helland, Thomas; Eliassen, Finn Magnus; Hagland, Magnus & Nordgård, Oddmund [Vis alle 30 forfattere av denne artikkelen] (2022). Liquid biopsies and patient-reported outcome measures for integrative monitoring of patients with early-stage breast cancer: a study protocol for the longitudinal observational Prospective Breast Cancer Biobanking (PBCB) study. BMJ Open. 12(4). doi: 10.1136/bmjopen-2021-054404. Fulltekst i vitenarkiv
• Bjune, Jan-Inge; Laber, Samantha; Dyer, Laurence; Xu, Zhao; Claussnitzer, Melina & Njølstad, Pål Rasmus [Vis alle 11 forfattere av denne artikkelen] (2021). Epigenetic control of adipogenesis by Irx3. Fulltekst i vitenarkiv
• Nilsen, Mona Synnøve; Jersin, Regine Åsen; Madsen, Andre; McCann, Adrian; Svensson, Per-Arne & Ueland, Per Magne [Vis alle 9 forfattere av denne artikkelen] (2019). Adipocyte amino acid metabolism in obesity-related metabolic diseases. Fulltekst i vitenarkiv
• Nilsen, Mona Synnøve; Jersin, Regine Åsen; McCann, Adrian; Ulvik, Arve; Madsen, Andre & Svensson, Per-Arne [Vis alle 11 forfattere av denne artikkelen] (2019). Circulating 3-hydroxyisobutyrate (3-HIB) as a clinical marker of prediabetes and T2D in patients with obesity. Fulltekst i vitenarkiv
• Dankel, Simon N; Tallapragada, Divya Sri Priyanka; Armstrong, Nasa-Sinnott; Sagen, Jørn V.; Claussnitzer, Melina & Mellgren, Gunnar (2019). Integrative Genomics Links Homeobox Transcription Factors to Risk of Visceral Adiposity. Fulltekst i vitenarkiv
• Jersin, Regine; Madsen, Andre; Willems, Aron; Sagen, Jørn V.; Mellgren, Gunnar & Dankel, Simon N (2018). Impaired D-serine uptake in adipocytes promotes oxidative stress and visceral obesity. Fulltekst i vitenarkiv
• Nilsen, Mona Synnøve; Jersin, Regine Åsen; Madsen, Andre; McCann, Adrian; Svensson, Per-Arne & Ueland, Per Magne [Vis alle 9 forfattere av denne artikkelen] (2018). Amino acid metabolism in adipocytes. Fulltekst i vitenarkiv
• Bjune, Jan-Inge; Haugen, Christine; Gudbrandsen, Oddrun Anita; Nordbø, Ole Petter; Njølstad, Pål Rasmus & Sagen, Jørn V. [Vis alle 8 forfattere av denne artikkelen] (2018). Irx5 regulates body weight via amyloid precursor protein and mitochondrial respiration in adipocytes. Fulltekst i vitenarkiv
• Bjune, Jan-Inge; Haugen, Christine; Gudbrandsen, Oddrun Anita; Nordbø, Ole Petter; Njølstad, Pål Rasmus & Sagen, Jørn V. [Vis alle 8 forfattere av denne artikkelen] (2018). Irx5 regulates body weight via amyloid precursor protein (App) and mitochondrial respiration in adipocytes. Fulltekst i vitenarkiv
• Bjune, Jan-Inge; Madsen, Andre; Bjørkhaug, Lise; Mellgren, Gunnar & Sagen, Jørn V. (2016). PKA downregulates glucose-6phosphatase Expression through RORα and SRC2. Fulltekst i vitenarkiv
• Madsen, Andre; Bozickovic, Olivera; Bjune, Jan-Inge; Mellgren, Gunnar & Sagen, Jørn V. (2016). Repression of liver SRC-2 by metformin inhibits glucose, lipid and cholesterol biosynthesis. Fulltekst i vitenarkiv
• Haugen, Christine; Dankel, Simon N; Kim, K. Han; Solsvik, Margit; Sagen, Jørn V. & Gudbrandsen, Oddrun Anita [Vis alle 8 forfattere av denne artikkelen] (2014). Role of homeobox transcription factors IRX3 and IRX5 in mitochondrial development and activity in adipose tissue. Fulltekst i vitenarkiv Vis sammendrag

  The homeobox transcription factors Iroquois homeobox protein 3 (IRX3) and 5 (IRX5) are located close to the Fat mass and obesity-associated protein (FTO) in the mouse and human genomes, and have been shown to be associated with obesity in several studies. In one of these studies, we found that the expression levels of several homeobox transcription factors, including IRX3 and IRX5, were reduced in subcutaneous fat in human obesity. In another study, we measured an elevated expression of Pgc1α and Ucp1 in epididymal white adipose tissue (eWAT) from Irx5 deficient mice. In adipose tissue, PGC1α and UPC1 are known markers for browning, the process where white adipose tissue (WAT) gain an increasing amount of brown-like adipocytes, known as brite or beige adipocytes. The browning is characterised by increased number and activity of mitochondria that facilitate energy expenditure. Our data suggest that IRX3 and IRX5 have a role in the development of adipose tissue, partially through the activity of mitochondria, and that they may influence the development of obesity and weakened metabolic health. We are now investigating in more detail the role IRX3 and IRX5 have on mitochondria in adipose tissue. We will present how overexpression or knock-down of Irx3 and Irx5 in cell lines affect mitochondrion number and function. This work is supported by KG Jebsen Center for Diabetes Research, and is funded by the Western Norway Regional Health Authority and Bergen Medical Research Foundation, University of Bergen

• Flågeng, Marianne Hauglid; Bozickovic, Olivera; Skartveit, Linn; Sagen, Jørn V. & Mellgren, Gunnar (2014). Steroid receptor coactivators during short-term estrogen deprivation. Fulltekst i vitenarkiv
• Veum, Vivian Lohmann; Laupsa-Borge, Johnny; Eng, Øyvin Solberg; Rostrup, Espen; Larsen, Terje H & Nordrehaug, Jan Erik [Vis alle 10 forfattere av denne artikkelen] (2014). A moderate energy-restricted very-high-fat diet reduces fat mass and improves metabolic health in abdominally obese middle-aged men. Fulltekst i vitenarkiv
• Haugen, Christine; Dankel, Simon E Nitter; Kim, K. Han; Solsvik, Margit; Sagen, Jørn V. & Gudbrandsen, Oddrun Anita [Vis alle 8 forfattere av denne artikkelen] (2013). Deficiency of Irx5 is associated with decreased fat mass in male CD1 mice. Fulltekst i vitenarkiv
• Haugen, Christine; Dankel, Simon E Nitter; Kim, K. Han; Solsvik, Margit; Sagen, Jørn V. & Gudbrandsen, Oddrun Anita [Vis alle 8 forfattere av denne artikkelen] (2013). Role of homeobox transcription factor IRX5 in obesity and metabolic health. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Degerud, Eirik Magnus Meek; Fjære, Even; Haugen, Christine; Sagen, Jørn V. & Mellgren, Gunnar [Vis alle 7 forfattere av denne artikkelen] (2012). Weight cycling affects adipose tissue genes involved in circadian rhythm and lipid metabolism. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: A common challenge with dieting is eventual fat regain after fat loss. Repeated over time, this weight cycling (“yo-yo” dieting) may increase total fat gain and potentially also risk of disease. Studies are needed to elucidate molecular mechanisms in adipose tissue that underlie increased fat regain after weight cycling. Methods: We subjected young C57BL/6 mice to weight cycling (WC, n=11) or chronic overfeeding (CO, n=11), and compared global gene expression in adipose tissues by Illumina microarrays. Because mouse 3T3-L1 preadipocytes require four days to differentiate in vitro to mature adipocytes, WC mice were given four days of energy restriction between four 10-day periods of fat gain. White adipose tissues (epididymal and inguinal WAT) were collected after a final 3 week overfeeding period. Results: The weight cycled mice gained significantly more weight than mice that were chronically overfed (12.14 compared to 9.92 grams, p=0.028), even though total energy intake was identical. Many of the most down-regulated genes in both epididymal and inguinal WAT after WC were involved in circadian rhythm regulation (Dbp, Per1-3, Tef), which have been shown to modulate lipid metabolism and adaptation to substrate delivery related to feeding. Several of the differentially expressed genes showed an increased expression during in vitro differentiation of 3T3-L1 fibroblasts to mature adipocytes. Conclusion: Our study has identified genes that may contribute to increased feed efficiency for fat storage after weight cycling.

• Degerud, Eirik Magnus Meek; Dankel, Simon E Nitter; Fjære, Even; Haugen, Christine; Sagen, Jørn V. & Mellgren, Gunnar [Vis alle 7 forfattere av denne artikkelen] (2012). CDKN1A associates with fat regain after weight cycling in mice. Fulltekst i vitenarkiv Vis sammendrag

  Weight cycling involves repeated failures to maintain weight loss, potentially leading to net fat gain. The molecular mechanisms underlying fat regain after weight cycling are unknown. We wanted to identify new gene candidates that may modulate weight cycling. Young C57BL/6 mice were subjected to chronic overfeeding (CO, n=11) or weight cycling (WC, n=11). WC mice were overfed for six 10-day periods, interrupted by five 4-day periods of energy restriction. Despite identical energy intake, the WC mice had a greater weight gain than the CO (WC=12.14, CO=9.92 grams, p=0.028). Global gene expression was compared in inguinal and epididymal white adipose tissue (WAT) by Significance Analysis of Microarrays (SAM), after a final 3-week period of weight gain. One of the genes with the most changed expression after weight cycling, confirmed by qPCR, was Cdkn1a (p21) (fold change=1.58, p=0.002). To assess the human relevance, we mined human microarray data of fractionated adipose tissue from extremely obese patients undergoing bariatric surgery, sampled before (BMI 53) and one year after (BMI 33) surgery-induced weight loss. CDKN1A variant 1 was significantly down-regulated in the adipose tissue after weight loss (fold change=10.07). We then differentiated primary human preadipocytes in vitro and measured CDKN1A mRNA expression with qPCR. CDKN1A variant 1 was significantly up-regulated during differentiation (day 12 vs. day 2 fold change=4.3, p-value=0.004). CDKN1A expression associated with fat re-gain after weight cycling in mice, and with extreme obesity and adipocyte differentiation in humans. The findings suggest that increased CDKN1A expression may facilitate weight gain after repeated dieting.

• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Christoforou, Andrea; Haugen, Christine; Røst, Therese Halvorsen & Gudbrandsen, Oddrun Anita [Vis alle 14 forfattere av denne artikkelen] (2012). Integrative genomics links homeobox transcription factors to intra-abdominal obesity. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Excessive intra-abdominal fat storage increases risk of disease. We have combined global gene expression data on human adipose tissue with data on gene variants (single-nucleotide polymorphisms, SNPs) that associate with waist-hip ratio (WHR) or body-mass index (BMI). Methods/Results: By microarray analysis, we first identified genes with a differential expression between omental and subcutaneous adipose tissue in extreme obesity. Next we identified which of these genes also showed a change in expression after profound fat loss in subcutaneous fat, revealing 67 candidate genes that may modulate intra-abdominal fat storage. Interestingly, several of these genes encoded developmental homeobox transcription factors. To see whether the 67 genes may increase susceptibility for intra-abdominal obesity, we interrogated data from the large European GIANT meta-analyses of genome-wide association studies (GWAS) (n=123,865 for BMI and n=77,167 for WHR adjusted for BMI). The gene set as a whole associated with WHRadjBMI (p=0.08) but not with BMI (p=0.98) (conservative MAGENTA Mann-Whitney test). Furthermore, by in vitro experiments in 3T3-L1 cells, we found that some of the identified homeobox transcription factors modulated peroxisome proliferator-activated receptor (PPAR) expression and/or activity. Conclusion: We have identified homeobox transcription factors that may contribute to intra-abdominal obesity and related disease risk.

• Dankel, Simon E Nitter; Degerud, Eirik Magnus Meek; Fjære, Even; Haugen, Christine; Sagen, Jørn V. & Mellgren, Gunnar [Vis alle 7 forfattere av denne artikkelen] (2012). Candidate genes for fat regain after weight cycling in mice. Fulltekst i vitenarkiv Vis sammendrag

  Many individuals wishing to lose fat follow weight loss programs intermittently, only to experience short-term success and an eventual fat regain. Repeated over time, this weight cycling (“yo-yo” dieting) may increase total fat gain and potentially also risk of disease. More studies are needed to elucidate the molecular mechanisms in adipose tissue that underlie increased fat regain after weight cycling. We subjected young C57BL/6 mice to weight cycling (WC, n=11) or chronic overfeeding (CO, n=11), and compared global gene expression in adipose tissues by Illumina microarrays. We hypothesized that weight cycling promotes fat gain by increasing adipocyte differentiation (adipogenesis) and/or lipogenesis. Because mouse 3T3-L1 preadipocytes require four days to differentiate in vitro to mature adipocytes, WC mice were given four days of energy restriction between four 10-day periods of fat gain. White adipose tissues (epididymal and inguinal WAT) as well as brown adipose tissue (inguinal BAT) were collected after a final 3 week refeeding period. The weight cycled mice gained significantly more weight than mice that were chronically overfed (12.14 compared to 9.92 grams, p=0.028), corresponding with increased feed efficiency. Rank product analysis of the microarray data showed 67 differentially expressed genes in eWAT, 165 in iWAT and 379 in iBAT (q-value<0.05). A combined rank product meta-analysis of eWAT and iWAT revealed the strongest over-representation of genes in the PANTHER gene ontology category Lipid metabolic process (p=2.85E-11). In iBAT, the top category was Muscle contraction (p=7.42E-28), followed by Lipid metabolic process (p=6.43E-20). We then differentiated 3T3-L1 cells and primary human preadipocytes in vitro and performed qPCR for selected candidate genes. Several of the genes were significantly induced during differentiation, suggesting involvement in the mechanism of fat regain after weight cycling.

• Veum, Vivian Lohmann; Dankel, Simon E Nitter; Gjerde, Jennifer; Nielsen, Hans Jørgen; Solsvik, Margit Hildershavn & Haugen, Christine [Vis alle 13 forfattere av denne artikkelen] (2011). The nuclear receptors NURR77, NURR1 and NOR1 in obesity and during fat loss. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Gudbrandsen, Oddrun Anita; Veum, Vivian Lohmann; Våge, Villy & Steen, Vidar Martin [Vis alle 8 forfattere av denne artikkelen] (2011). Prediction of obesity candidate genes by multiple gene expression analyses of adipose tissue. Fulltekst i vitenarkiv
• Hoang, Tuyen; Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Veum, Vivian Lohmann; Våge, Villy & Steen, Vidar Martin [Vis alle 8 forfattere av denne artikkelen] (2010). Gene Expression Profile of Nuclear Receptors and Coregulators in Adipose Tissues in Morbid Obesity and after Profound Fat Loss. Endocrine reviews. ISSN 0163-769X. 31(3). Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Stavrum, Anne-Kristin; Stansberg, Christine; Holdhus, Rita & Hoang, Tuyen [Vis alle 12 forfattere av denne artikkelen] (2010). From stress response to developmental processes in abdominal subcutaneous adipose tissue after bariatric surgery. Endocrine journal. ISSN 0918-8959. 57, s. S429–S429. Fulltekst i vitenarkiv
• Hoang, Tuyen; Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Veum, Vivian Lohmann; Våge, Villy & Steen, Vidar M [Vis alle 8 forfattere av denne artikkelen] (2010). Gene Expression Profile of Nuclear Receptors and Coregulators in Adipose Tissues in Morbid Obesity and after Profound Fat Loss. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Stavrum, Anne-Kristin; Stansberg, Christine; Holdhus, Rita & Hoang, Tuyen [Vis alle 12 forfattere av denne artikkelen] (2010). From stress response to developmental processes in abdominal subcutaneous adipose tissue after bariatric surgery. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Fadnes, Dag Jone Stokke; Gudbrandsen, Oddrun Anita; Veum, Vivian Lohmann; Våge, Villy & Steen, Vidar Martin [Vis alle 8 forfattere av denne artikkelen] (2010). Low Omental Expression of Fat Loss-Associated Homeobox Transcription Factors in Morbid Obesity. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Hoang, Tuyen; Sagen, Jørn V. & Mellgren, Gunnar (2008). cAMP/PKA Exerts Differential Effects on GRIP1- and PGC-1α-Mediated HNF-4α Transcriptional Activity in HepG2 and COS-1 Cells. Fulltekst i vitenarkiv
• Dankel, Simon E Nitter; Hoang, Tuyen; Sagen, Jørn V. & Mellgren, Gunnar (2008). cAMP Regulates Nuclear Receptor Coactivator GRIP1–Mediated Coactivation of HNF-4alpha in HepG2 Cells. Fulltekst i vitenarkiv
• Mellgren, Gunnar; Hoang, Tuyen; Sagen, Jørn V. & Dankel, Simon E Nitter (2007). Regulation of HNF-4alpha transcriptional activity by the coactivators GRIP1 and PGC-1alpha. Fulltekst i vitenarkiv
• Sagen, Jørn V. (2007). Overvekt og Diabetes. Fulltekst i vitenarkiv
• Sagen, Jørn V. (2007). Nyheter innen MODY-forskningen. Fulltekst i vitenarkiv
• Madsen, Andre Greger & Sagen, Jørn V. (2015). Function and regulation of Steroid Receptor Coactivator 2. Transcriptional regulation of cellular metabolism. Universitetet i Bergen. ISSN 9788230834176. Fulltekst i vitenarkiv Vis sammendrag

  Nuclear hormone receptors (NRs) associate with coregulators to enable complex programs of gene expression. The p160 steroid receptor coactivator 2 (SRC- 2/GRIP1) regulates metabolism and cellular processes in a tissue-specific manner by enhancing transcription of hormone regulated target genes. The transcriptional regulation and metabolic programming imposed by SRC-2 and its partner NRs has implications for several pathological processes. Although SRC-2 is known to facilitate lipogenesis and survival of prostate cancer cells, its role in breast cancer remains unclear. Hepatic ablation of SRC-2 impairs expression of key lipogenic and gluconeogenic enzymes, causing fasting hypoglycemia in mice. Previously, it has been shown that the cAMP/PKA pathway regulates the protein level of SRC-2. This thesis aimed to further investigate the functions of SRC-2 and characterize whether upstream regulation of SRC-2 affects its ability to promote expression of metabolic target genes. Paper I elucidates a mechanism by which cellular SRC-2 protein is subject to inhibitory upstream regulation by the cAMP/PKA pathway. Here, we showed that the cAMP response element-binding protein (CREB) has a key role in this mechanism by interacting with and stimulating proteasomal degradation of SRC-2. We demonstrated that the CREB basic leucine zipper (bZIP) domain and two functionally independent protein domains of SRC-2 (amino acids 347-758 and 1121-1462) are required to trigger degradation of SRC-2. Furthermore, overexpression of CREB inhibited the ability of SRC-2 to modulate expression of estrogen receptor alpha (ERα) target genes. These findings suggest that the previously established inhibitory effect of PKA on SRC-2 is executed via a direct interaction between CREB and SRC-2. Paper II reports that SRC-2 has a crucial function in regulating hepatocellular gluconeogenesis. Transcription of gluconeogenic enzymes including the rate-limiting glucose 6-phosphatase (G6Pase) is enabled by fasting hormone signaling via the cAMP/PKA pathway. Previously, it was demonstrated that SRC-2 liver knock-out mice exhibit fasting hypoglycemia due to reduced G6Pase expression. We validated that SRC-2 coactivates the RAR-related orphan receptor alpha (RORα) at the proximal G6Pase promoter in HepG2 cells. In line with the findings from the first paper, we observed that SRC-2 protein was subject to degradation in presence of the PKA catalytic subunit (PKA-Cα). Overexpression of PKA-Cα also reduced recruitment of SRC-2 and RNA polymerase II to the G6Pase promoter and rendered SRC-2 unable to coactivate RORα. Furthermore, we found that the presence of SRC- 2, via its association with RORα, is required for the transactivational effect of the master gluconeogenic regulator PPARG coactivator 1-alpha (PGC-1α) on the G6Pase promoter. These results suggest that PKA-mediated degradation of SRC-2 may represent an indirect feedback mechanism by which gluconeogenesis is suppressed throughout long-term starvation. Paper III elucidates a novel mechanism by which the anti-diabetic drug metformin reprograms hepatocellular metabolism via SRC-2. Tissue from SRC-2 liver knockout mouse model is characterized by impaired expression of lipogenic and gluconeogenic enzymes. Here, we showed that treatment of cells with metformin is accompanied by transcriptional repression of specifically SRC-2. Microarray analysis of FaO hepatoma cells treated with metformin revealed an overrepresentation of downregulated SRC-2 target genes involved in lipid and cholesterol biosynthesis. Promoter analyses confirmed that these genes were also transcriptional targets of the lipogenic sterol regulatory element (SRE) binding protein 1 (SREBP-1). Transactivation assays demonstrated that SRC-2 is a coactivator of SREBP-1, but not SREBP-2, on the fatty acid synthase (FASN) promoter. By repressing SRC-2 expression, metformin impeded recruitment of SRC-2 and RNA polymerase II to the G6Pc promoter and to SREs of SRC-2/SREBP-1 target gene promoters. Furthermore, metformin or knock-down of SRC-2 and SREBP-1 reduced hepatocellular fat accretion. Accordingly we propose that metformin transcriptionally suppresses hepatic gluconeogenesis and lipogenesis partly by inhibiting expression of SRC-2.

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