| 1. |
- Dickson, Elna, et al.
(author)
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Altered Adipocyte Cell Size Distribution Prior to Weight Loss in the R6/2 Model of Huntington's Disease
- 2023
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In: Journal of Huntington's disease. - 1879-6397. ; 12:3, s. 253-266
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Journal article (peer-reviewed)abstract
- BACKGROUND: Metabolic alterations contribute to disease onset and prognosis of Huntington's disease (HD). Weight loss in the R6/2 mouse model of HD is a consistent feature, with onset in mid-to-late stage of disease.OBJECTIVE: In the present study, we aimed to investigate molecular and functional changes in white adipose tissue (WAT) that occur at weight loss in R6/2 mice. We further elaborated on the effect of leptin-deficiency and early obesity in R6/2 mice.METHODS: We performed analyses at 12 weeks of age; a time point that coincides with the start of weight loss in our R6/2 mouse colony. Gonadal (visceral) and inguinal (subcutaneous) WAT depot weights were monitored, as well as adipocyte size distribution. Response to isoprenaline-stimulated glycerol release and insulin-stimulated glucose uptake in adipocytes from gonadal WAT was assessed.RESULTS: In R6/2 mice, WAT depot weights were comparable to wildtype (WT) mice, and the response to insulin and isoprenaline in gonadal adipocytes was unaltered. Leptin-deficient R6/2 mice exhibited distinct changes compared to leptin-deficient WT mice. At 12 weeks, female leptin-deficient R6/2 mice had reduced body weight accompanied by an increased proportion of smaller adipocytes, while in contrast; male mice displayed a shift towards larger adipocyte sizes without a significant body weight reduction at this timepoint.CONCLUSIONS: We here show that there are early sex-specific changes in adipocyte cell size distribution in WAT of R6/2 mice and leptin-deficient R6/2 mice.
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| 2. |
- Fryklund, Claes
(author)
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Adipocyte size and function in the epididymal and inguinal fat depots
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Nearly 60% of the worlds adult population is projected to be overweight or obese by 2030. The prevalence of obesity- related diseases, such as type 2 diabetes (T2D), has increased markedly in the past decades. The adipose tissue plays an important role in disease progression of T2D. Adipocyte insulin sensitivity, adipose tissue’s ability to expand, and accumulation of subcutaneous rather than visceral fat, are all important factors for adipose tissue function and systemic metabolic health.This thesis aims to broaden the understanding of adipose tissue function, focusing on the importance of adipocyte cell-size and differences between visceral and subcutaneous adipocytes. This knowledge may in the future contribute to novel treatments that focus on improving function of specific fat depots.Our first project (Paper I) examines the importance of EHD2, a caveolae-associated protein, and its influence on different fat depots by using knockout (Ehd2-/-) mice. Ehd2-/- mice display impaired expansion of epididymal fat, most likely caused by weakened hyperplastic growth, while the inguinal adipocytes exhibit impaired lipolytic response. The results indicate that EHD2 is required for healthy fat expansion since both impaired lipolysis and reduced hyperplastic growth are associated with dysfunctional adipose tissue.In Paper II, we examine the effect of the anti-diabetic drug, rosiglitazone, on hypertrophic adipocytes, and suggest a new mechanism of action for improving insulin-sensitivity in adipocytes. We propose that remodeling of the extracellular matrix (ECM), results in reduced stress-induced intracellular signaling, reduced filamentous (F)-actin and improved insulin-stimulated glucose uptake. The improvement in glucose uptake from rosiglitazone-treated mice are greater in epididymal adipocytes compared to inguinal, which is also reflected in larger changes in ECM expression, intracellular stress signaling and level of F-actin.The last project (Paper III) examines the plasticity of adipose tissue, focusing on cell-size and actin dynamics during weight gain and weight loss. We examine differences between the inguinal and epididymal depots using temporal resolution and correlate the findings to changes in systemic insulin sensitivity. Our data suggest that there are fat depot-specific differences in cell-size plasticity during weight gain, but not during weight loss. Epididymal adipocytes expand in size early during weight gain (after 4 weeks) while inguinal adipocytes expand at a later timepoint (after 12 weeks). During weight loss, both fat depots display intact plasticity, regarding cell-size, weight, and level of F- actin, for short interventions (4 and 8 weeks) but not following prolonged overfeeding (12 weeks).The inguinal depot, in comparison to the epididymal depot, displays stronger correlation between insulin sensitivity and number of hypertrophic adipocytes, suggesting that hypertrophic inguinal adipocytes may contribute to the progression of insulin resistance in mice.
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| 3. |
- Fryklund, Claes, et al.
(author)
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Adipocyte traits limiting cellular insulin responsiveness and glucose transport
- 2023
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In: American Journal of Physiology - Endocrinology and Metabolism. - 1522-1555. ; 325:6, s. 682-687
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Journal article (peer-reviewed)abstract
- Adipocyte dysfunction is a hallmark of systemic insulin resistance. Insulin-responsive glucose transporter 4 (GLUT4) is downregulated in the insulin resistant state, and cellular insulin responsiveness varies depending on fat-depot origin and degree of adipose expansion. Here, we have resolved factors limiting cellular insulin responsiveness, by examining adipocyte function and traits related to glucose transport at the cellular level. Subcutaneous (inguinal) and visceral (epididymal) adipocytes were isolated from C57BL/6J mice fed either chow or high-fat diet. Cell-size was determined using coulter counter method, glucose uptake and cytosolic volume were assessed using glucose-tracer assays. Total and GLUT4 protein content expression were determined by western blot. We found that basal glucose uptake per cell was preserved independent of diet or fat depot origin. Insulin-stimulated glucose uptake per cell was sustained in visceral adipocytes but decreased with adipose expansion in subcutaneous adipocytes. In parallel, the cytosolic space and total protein increased proportionally to total cellular volumetric expansion in visceral, but not subcutaneous, adipocytes, while GLUT4 content decreased exclusively in expanding subcutaneous adipocytes. Together, these data support the existence of distinct phenotypic adipocyte traits that could limit cellular insulin responsiveness. Potentially, these characteristics account for fat depot-specific differences related to glucose transport capacity.
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| 4. |
- Holt, Vance, et al.
(author)
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Acute cytokine treatment stimulates glucose uptake and glycolysis in human keratinocytes
- 2023
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In: Cytokine. - : Elsevier BV. - 1043-4666. ; 161
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Journal article (peer-reviewed)abstract
- During inflammation, cellular glucose uptake and glycolysis are upregulated to meet an increased energy demand. For example, keratinocyte glycolysis is essential for progression of psoriasis. Therefore, understanding the regulation of glucose metabolism in keratinocytes is of importance. Here, we show that the pro-inflammatory cytokines IFNγ and TNF together rapidly induce glucose uptake, glycolysis, and glycolytic capacity in cultured keratinocytes. Furthermore, we found that acute IFNγ and TNF stimulation induces glucose transporter 4 (GLUT4) translocation to the plasma membrane and engages AMPK-dependent intracellular signaling. Together, these findings suggest acute cytokine-induced glucose metabolism in keratinocytes could contribute to inflammation in psoriatic disease, and that GLUT4 is involved in these processes.
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| 5. |
- Neuhaus, Mathis, et al.
(author)
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EHD2 regulates plasma membrane integrity and downstream insulin receptor signalling events
- 2023
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In: Molecular Biology of the Cell. - 1939-4586. ; 34:12
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Journal article (peer-reviewed)abstract
- Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein 2 (EHD2) as one of the most highly upregulated genes at the early stage of adipose tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signalling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signalling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.
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| 6. |
- Säll, Johanna, et al.
(author)
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Salt-inducible kinases are required for glucose uptake and insulin signaling in human adipocytes
- 2023
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In: Obesity. - 1930-739X. ; 31:10, s. 2515-2529
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Salt-inducible kinase 2 (SIK2) is abundantly expressed in adipocytes and downregulated in adipose tissue from individuals with obesity or insulin resistance. The main aims of this work were to investigate the involvement of SIKs in the regulation of glucose uptake in primary mature human adipocytes and to identify mechanisms underlying this regulation.METHODS: Primary mature adipocytes were isolated from human, rat, or mouse adipose tissue and treated with pan-SIK inhibitors. Adipocytes isolated from wild type, ob/ob, and SIK2 knockout mice were also used. Glucose uptake was examined by glucose tracer assay. The insulin signaling pathway was monitored by Western blotting, co-immunoprecipitation, and total internal reflection fluorescence microscopy.RESULTS: This study demonstrates that SIK2 is downregulated in obese ob/ob mice and that SIK activity is required for intact glucose uptake in primary human and mouse adipocytes. The underlying mechanism involves direct effects on the insulin signaling pathway, likely at the level of phosphatidylinositol (3,4,5)-trisphosphate (PIP3) generation or breakdown. Moreover, lack of SIK2 alone is sufficient to attenuate glucose uptake in mouse adipocytes.CONCLUSIONS: SIK2 is required for insulin action in human adipocytes, and the mechanism includes direct effects on the insulin signaling pathway.
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