| 1. |
- Hansson, Björn, et al.
(författare)
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Rosiglitazone drives cavin-2/SDPR expression in adipocytes in a CEBPα-dependent manner
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are abundant adipocyte surface domains involved in insulin signaling, membrane trafficking and lipid homeostasis. Transcriptional control mechanisms for caveolins and cavins, the building blocks of caveolae, are thus arguably important for adipocyte biology and studies in this area may give insight into insulin resistance and diabetes. Here we addressed the hypothesis that one of the less characterized caveolar components, cavin-2 (SDPR), is controlled by CCAAT/Enhancer Binding Protein (CEBPα) and Peroxisome Proliferator- Activated Receptor Gamma (PPARG). Using human mRNA expression data we found that SDPR correlated with PPARG in several tissues. This was also observed during differentiation of 3T3-L1 fibroblasts into adipocytes. Treatment of 3T3-L1-derived adipocytes with the PPARγ-activator Rosiglitazone increased SDPR and CEBPα expression at both the mRNA and protein levels. Silencing of CEBPα antagonized these effects. Further, adenoviral expression of PPARγ/CEBPα or Rosiglitazone-treatment increased SDPR expression in primary rat adipocytes. The myocardin family coactivator MKL1 was recently shown to regulate SDPR expression in human coronary artery smooth muscle cells. However, we found that actin depolymerization, known to inhibit MKL1 and MKL2, was without effect on SDPR mRNA levels in adipocytes, even though overexpression of MKL1 and MKL2 had the capacity to increase caveolins and cavins and to repress PPARγ/CEBPα. Altogether, this work demonstrates that CEBPα expression and PPARγ-activity promote SDPR transcription and further supports the emerging notion that PPARγ/CEBPα and MKL1/MKL2 are antagonistic in adipocytes.
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| 2. |
- Sernevi Säll, Johanna
(författare)
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Salt-inducible kinases in adipose tissue
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity, insulin resistance and type 2 diabetes (T2D) are metabolic diseases that increase rapidly in the modern society. The underlying mechanisms are complex and involve both environmental and genetic factors. Adipose tissue is an important organ for maintaining whole body energy homeostasis. In response to nutrient overload (as observed in obesity), adipocytes become hypertrophic and dysfunctional, which contribute to the development of systemic insulin resistance. AMP-activated protein kinase (AMPK) is described as a master regulator of whole body energy homeostasis. The salt-inducible kinases (SIKs) are related to AMPK. SIK2 displays abundant expression in adipose tissue and has been reported to be increased in adipose tissue in obese diabetic (db/db) mice, suggesting that SIK2 is potentially involved in the development of obesity and T2D. Taken together, this makes the SIKs, and SIK2 in particular, interesting to study in adipose tissue in the context of obesity and insulin resistance. This thesis has addressed the expression, regulation and biological role of SIKs, in particular SIK2, in adipose tissue. So far, studies on SIKs in adipose tissue have exclusively been performed in rodents. This thesis focuses on studying the role of SIKs in humans.We demonstrate that the transcriptional regulators CRTC2, CRTC3 and HDAC4 are direct downstream substrates of SIK2 in adipocytes. Moreover, we demonstrate that the expression of SIK2 and SIK3 is markedly downregulated in adipose tissue from obese or insulin-resistant individuals. Furthermore, the expression of SIK2 and SIK3 in adipose tissue is regulated in response to weight change and inflammation (TNF-α). SIKs are involved in promoting glucose uptake in adipocytes and the underlying mechanism(s) involves direct, and positive, effects on the insulin signalling pathway. We also identify a novel regulatory pathway of SIK2 in adipocytes through insulin-induced phosphorylation at Thr484. From a functional aspect, insulin stimulation appears to be important to increase SIK2 protein stability. Taken together, our data suggest that insulin resistance might be a causal factor underlying the downregulation of SIK2 in human adipose tissue. Given these findings, SIK2 might provide an attractive therapeutic target for the treatment of metabolic diseases in the future. Importantly, our findings on SIK2 expression in human obesity and insulin resistance are in contrast to what was previously identified in mice, and demonstrates that interspecies differences exist with regard to the regulation of SIK2 in metabolic disease. Furthermore, this emphasise the importance to study SIKs in human adipocytes.
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| 3. |
- Säll, Johanna, et al.
(författare)
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Salt-inducible kinase 2 and -3 are downregulated in adipose tissue from obese or insulin-resistant individuals : implications for insulin signalling and glucose uptake in human adipocytes
- 2017
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 60:2, s. 314-323
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Salt-inducible kinases (SIKs) are related to the metabolic regulator AMP-activated protein kinase (AMPK). SIK2 is abundant in adipose tissue. The aims of this study were to investigate the expression of SIKs in relation to human obesity and insulin resistance, and to evaluate whether changes in the expression of SIKs might play a causal role in the development of disturbed glucose uptake in human adipocytes.METHODS: SIK mRNA and protein was determined in human adipose tissue or adipocytes, and correlated to clinical variables. SIK2 and SIK3 expression and phosphorylation were analysed in adipocytes treated with TNF-α. Glucose uptake, GLUT protein levels and localisation, phosphorylation of protein kinase B (PKB/Akt) and the SIK substrate histone deacetylase 4 (HDAC4) were analysed after the SIKs had been silenced using small interfering RNA (siRNA) or inhibited using a pan-SIK-inhibitor (HG-9-91-01).RESULTS: We demonstrate that SIK2 and SIK3 mRNA are downregulated in adipose tissue from obese individuals and that the expression is regulated by weight change. SIK2 is also negatively associated with in vivo insulin resistance (HOMA-IR), independently of BMI and age. Moreover, SIK2 protein levels and specific kinase activity display a negative correlation to BMI in human adipocytes. Furthermore, SIK2 and SIK3 are downregulated by TNF-α in adipocytes. Silencing or inhibiting SIK1-3 in adipocytes results in reduced phosphorylation of HDAC4 and PKB/Akt, less GLUT4 at the plasma membrane, and lower basal and insulin-stimulated glucose uptake in adipocytes.CONCLUSION/INTERPRETATION: This is the first study to describe the expression and function of SIKs in human adipocytes. Our data suggest that SIKs might be protective in the development of obesity-induced insulin resistance, with implications for future treatment strategies.
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