| 1. |
- Ahmed, Fozia, et al.
(författare)
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Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : ENDOCRINE SOC. - 0021-972X .- 1945-7197. ; 107:5, s. E1879-E1889
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Tidskriftsartikel (refereegranskat)abstract
- Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.
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| 2. |
- Ahmed, Fozia, et al.
(författare)
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The effects of bisphenol A and bisphenol S on adipokine expression and glucose metabolism in human adipose tissue
- 2020
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 445
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Tidskriftsartikel (refereegranskat)abstract
- PurposeThe environmental endocrine disruptors, bisphenol A (BPA) and bisphenol S (BPS) are associated with the development of type 2 diabetes. We aim to study the effects of BPA or BPS exposure on adipokine expression in human adipose tissue and on adipocyte glucose uptake.MethodsHuman subcutaneous adipose tissue was treated for 24 or 72 h with environmentally-relevant and supraphysiological concentrations of BPA or BPS (1–104 nM). Following exposure, gene expression of proinflammatory cytokines, adipokines, and estrogen receptors was measured in adipose tissue. Glucose uptake and the insulin signalling pathway were analyzed in isolated adipocytes following adipose tissue culture with BPA for 24 h.ResultsAdipose tissue treated with BPA for 24 h had reduced expression of the proinflammatory genes (IL6, IL1B, TNFA) and adipokines (ADIPOQ, FABP4). BPA and BPS had no effect on the expression of other proinflammatory genes (IL33), adipokines (LEP), or receptors (ESR1, ESR2) after 72-h exposure. Adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h had reduced insulin-stimulated glucose uptake, without altered gene and protein levels of key insulin signalling pathway markers.ConclusionsWe found that human adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h, but not BPS, reduced expression of proinflammatory genes and adipokines. Furthermore, BPA reduced glucose uptake in adipocytes independently of insulin signalling. Such mechanisms can contribute to the development of insulin resistance associated with BPA exposure.
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| 3. |
- Dipta, P., et al.
(författare)
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Macrophage-derived secretome is sufficient to confer olanzapine-mediated insulin resistance in human adipocytes
- 2021
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Ingår i: Comprehensive Psychoneuroendocrinology. - : Elsevier BV. - 2666-4976. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Olanzapine and Aripiprazole are widely used second-generation antipsychotic drugs. Olanzapine, more than Aripiprazole, leads to considerable metabolic side effects including obesity and diabetes. While the underlying mechanisms are not fully understood, these side effects are likely associated with mild inflammation in the metabolic organs. An in vitro model that accurately recapitulates the metabolic impact of olanzapine and aripiprazole should be useful to elucidate the underlying mechanisms. Methods: We established co-cultures of matured adipocytes derived from the human SGBS cell line and the THP-1 human monocytic cell-derived or primary macrophages to explore the effects of both drugs on the response to insulin. Results: Olanzapine, but not aripiprazole induced insulin resistance in SGBS adipocytes only when co-cultured with THP-1 or primary macrophages, polarized either into M0, M1 or M2. Noteworthy, M2 macrophages induced olanzapine-dependent insulin resistance in the absence of induction of pro-inflammatory cytokines. Insulin resistance by olanzapine was stronger than induced by high concentration of pro-inflammatory cytokines even in combinations, suggesting the contribution of factors other than the classical inflammatory cytokines to promote insulin resistance in adipocytes by olanzapine. Conclusion: Macrophage/adipocyte co-cultures recapitulate the features of olanzapine-induced insulin resistance and implicate the existence of yet unknown factors in mediating this effect.
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| 4. |
- Ferreira, Vitor, et al.
(författare)
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Modulation of hypothalamic AMPK phosphorylation by olanzapine controls energy balance and body weight
- 2022
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Ingår i: Metabolism. - : Elsevier. - 0026-0495 .- 1532-8600. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- Background: Second-generation antipsychotics (SGAs) are a mainstay therapy for schizophrenia. SGA-treated patients present higher risk for weight gain, dyslipidemia and hyperglycemia. Herein, we evaluated the effects of olanzapine (OLA), widely prescribed SGA, in mice focusing on changes in body weight and energy balance. We further explored OLA effects in protein tyrosine phosphatase-1B deficient (PTP1B-KO) mice, a preclinical model of leptin hypersensitivity protected against obesity. Methods: Wild-type (WT) and PTP1B-KO mice were fed an OLA-supplemented diet (5 mg/kg/day, 7 months) or treated with OLA via intraperitoneal (i.p.) injection or by oral gavage (10 mg/kg/day, 8 weeks). Readouts of the crosstalk between hypothalamus and brown or subcutaneous white adipose tissue (BAT and iWAT, respectively) were assessed. The effects of intrahypothalamic administration of OLA with adenoviruses expressing constitutive active AMPK alpha 1 in mice were also analyzed. Results: Both WT and PTP1B-KO mice receiving OLA-supplemented diet presented hyperphagia, but weight gain was enhanced only in WT mice. Unexpectedly, all mice receiving OLA via i.p. lost weight without changes in food intake, but with increased energy expenditure (EE). In these mice, reduced hypothalamic AMPK phosphorylation concurred with elevations in UCP-1 and temperature in BAT. These effects were also found by intrahypothalamic OLA injection and were abolished by constitutive activation of AMPK in the hypothalamus. Additionally, OLA i. p. treatment was associated with enhanced Tyrosine Hydroxylase (TH)-positive innervation and less sympathetic neuron-associated macrophages in iWAT. Both central and i.p. OLA injections increased UCP-1 and TH in iWAT, an effect also prevented by hypothalamic AMPK activation. By contrast, in mice fed an OLA-supplemented diet, BAT thermogenesis was only enhanced in those lacking PTP1B. Our results shed light for the first time that a threshold of OLA levels reaching the hypothalamus is required to activate the hypothalamus BAT/iWAT axis and, therefore, avoid weight gain. Conclusion: Our results have unraveled an unexpected metabolic rewiring controlled by hypothalamic AMPK that avoids weight gain in male mice treated i.p. with OLA by activating BAT thermogenesis and iWAT browning and a potential benefit of PTP1B inhibition against OLA-induced weight gain upon oral treatment.
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| 5. |
- Jui, Bipasha Nandi, et al.
(författare)
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Evaluation of RNA Isolation Methods in Human Adipose Tissue
- 2022
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Ingår i: Laboratory medicine. - : Oxford University Press. - 0007-5027 .- 1943-7730. ; 53:5, s. E129-E133
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Research has shown that RNA extraction from adipose tissue (AT) is challenging because of high lipid content and low RNA quantity. We compared a traditional RNA extraction with a column-based method in human AT to evaluate RNA quantity and quality. Materials and Methods: Human subcutaneous AT (n = 9) was collected through needle biopsy, and RNA was extracted using the phenolchloroform traditional method and the RNeasy Lipid Tissue Mini Kit column-based method. The RNA quantity, quality, integrity, and expression of key AT genes were assessed. Results: We found that the RNA quantity and integrity were reduced by 40% and 15-20%, respectively, using the column-based method compared to the traditional method, but the findings were not statistically significant. The column-based method showed a higher 260/280 ratio (similar to 2.0) compared to the traditional method (similar to 1.8) (P <.05), suggesting lower amounts of contaminants. The expression of AT genes was comparable between methods. Conclusion: The traditional extraction method provides adequate RNA yield and integrity compared to the column-based method, which is an advantage when AT specimens are small.
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| 6. |
- Pereira, Maria J, 1981-, et al.
(författare)
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Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes
- 2020
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Ingår i: Molecular and Cellular Endocrinology. - : ELSEVIER IRELAND LTD. - 0303-7207 .- 1872-8057. ; 503
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Tidskriftsartikel (refereegranskat)abstract
- We aim to investigate the expression of the glucagon receptor (GCGR) in human adipose tissue, and the impact of glucagon in glucose uptake and lipolysis in human adipocytes. GCGR gene expression in human subcutaneous and visceral adipose tissue was demonstrated, albeit at low levels and with an inter-individual variation. Furthermore, GCGR expression was not significantly different between subjects with T2D and matched controls, and we found no significant association with BMI. Glucagon only at a supra-physiological concentration (10-100 nM) significantly increased basal and insulin-stimulated glucose uptake by up to 1.5-fold. Also, glucagon (0.01 and 1 nM) dose-dependently increased basal and isoproterenol-stimulated lipolysis up to 3.7- and 1.7-fold, respectively, compared to control. In addition, glucagon did not change insulin sensitivity to stimulate glucose uptake or inhibit lipolysis. In conclusion, we show that the GCGR gene is expressed at low levels in human adipose tissue, and glucagon at high concentrations can increase both glucose uptake and lipolysis in human adipocytes. Taken together, our data suggest that glucagon at physiological levels has minor direct effects on the regulation of adipocyte metabolism, but does not antagonize the insulin effect to stimulate glucose uptake and inhibit lipolysis in human adipocytes.
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| 7. |
- Sarsenbayeva, Assel
(författare)
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Adverse drug effects on glucose and lipid metabolism: is human adipose tissue of importance?
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many pharmacological agents that are widely prescribed in clinical practice have adverse metabolic effects, such as hyperglycaemia, insulin resistance, and diabetes. Among such drugs are antipsychotics, prescribed for treatment of schizophrenia; statins, which inhibit cholesterol synthesis and prevent cardiovascular events; finally, potent anti-inflammatory agents, glucocorticoids. This thesis is focused on investigating the direct effects of second-generation antipsychotics (SGAs), statins, and glucocorticoids on human adipose tissue metabolism and inflammation, particularly in the light of macrophage-adipocyte cross talk.In Paper I, the direct effects of SGAs on adipose tissue glucose and lipid metabolism were studied. SGAs had a mild effect on adipocyte glucose uptake and lipolysis at therapeutic concentrations. At supra-therapeutic concentrations, the drugs demonstrated anti-inflammatory potential, reducing the expression of pro-inflammatory genes in the adipose tissue.In Paper II, the anti-inflammatory potential of SGAs and dexamethasone was further explored. The effects of the drugs on macrophage phenotype and communication with adipocytes were addressed. SGAs at supra-therapeutic concentrations exerted mild anti-inflammatory effects on macrophages, while dexamethasone acted as a potent anti-inflammatory agent and promoted alternatively activated M2 macrophage phenotype. Macrophages, in turn, induced marked upregulation of pro-inflammatory genes in adipocytes, which was partially reversed by dexamethasone, while SGAs had no effects on macrophage-adipocyte communication.In Paper III, we examined the association of statin therapy on systemic insulin resistance and direct effects statins on human adipose tissue and pancreatic islets functions. We also studied association of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the enzyme involved in cholesterol synthesis, and genetic inhibition of HMGCR seen with certain polymorphisms with adipose tissue and plasma metabolome. Our study demonstrated minor direct effects of statins on human adipose tissue metabolism and insulin secretion in pancreatic islets. We observed that HMGCR expression was associated with a number of metabolic and mitochondrial pathways in the adipose tissue, while LDL-lowering HMGCR polymorphism was negatively associated with plasma phosphatidylcholines and sphingomyelins. In Paper IV we studied the effects of glucocorticoids on adipose tissue fibrosis, particularly in terms of macrophage-preadipocyte communication. Together with inflammation, adipose tissue fibrosis impairs adipocyte metabolism and functions. We observed that glucocorticoids at high concentrations have pro-fibrotic effects in adipose tissue. Macrophage-preadipocyte co-culture data showed that macrophages stimulate phenotypic switch of preadipocytes to pro-fibrotic myofibroblasts, and this effect was exacerbated by dexamethasone. Our findings suggest that pro-fibrotic effects of excess glucocorticoids on adipose tissue are at least partially mediated via their effects on macrophage-preadipocyte communication.We conclude that SGAs and statins have a mild direct effect on adipose tissue metabolism and their diabetogenic effects could to be induced via other organs, such as brain, liver or muscle. By contrast, glucocorticoids, directly impair adipose tissue metabolism and exacerbates adipose tissue fibrosis, which could be one of the contributing factors to their metabolic adverse effects.
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| 8. |
- Sarsenbayeva, Assel, et al.
(författare)
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Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism
- 2019
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Ingår i: Psychoneuroendocrinology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0306-4530 .- 1873-3360. ; 110
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Metabolic syndrome is prevalent in up to 50% of schizophrenia patients, which reduces their quality of life and their compliance with the treatment. It is unclear whether metabolic adverse effects of these agents are due to their direct effect on insulin-sensitive tissues or are secondary to increased adiposity. The study aimed to investigate the direct effects of the second-generation antipsychotics olanzapine and aripiprazole on human subcutaneous adipose tissue and isolated adipocyte metabolism.Methods: Abdominal subcutaneous adipose tissue needle biopsies were taken from 72 healthy subjects (49 F/23 M; age: 19-78 yr; BMI: 20.0-35.6 kg/m(2)). Isolated adipocytes or adipose tissue were respectively pre-incubated short- (30 min) and long-term (24 h, 72 h) with or without olanzapine (0.004 mu M - 20 mu M) and aripiprazole (0.002 mu M - 100 mu M). Pre-incubated adipose tissue was then snap-frozen for mRNA expression analysis of adipokines genes and genes involved in inflammation, adipogenesis, and mitochondrial function. Isolated adipocytes were used to measure basal and insulin-stimulated glucose uptake and lipolysis.Results: Acute treatment with a therapeutic concentration of olanzapine decreases basal lipolysis in isolated adipocytes; this effect was not observed after long-term incubation with the drug. Supra-therapeutic concentration of aripiprazole reduced basal and insulin-stimulated glucose uptake after short- and long-term preincubation. Both drugs at supra-therapeutic concentrations downregulated the expression of the pro-inflammatory cytokines IL6 and IL1B genes after 72 h incubation. Similarly, supra-therapeutic concentrations of both drugs and therapeutic concentration of olanzapine, reduced the expression of PPARGC1A, PDK4, and CPT1B genes involved in the regulation of mitochondria] functions. Neither of the antipsychotics affected the expression of the main adipokines LEP and ADIPOQ, genes involved in the regulation of lipid metabolism, LPL and FASN, nor the master adipogenesis regulator, PPARG.Conclusion: Therapheutic concentrations of olanzapine and aripiprazole have a moderate direct effect on adipocyte lipid and glucose metabolism, respectively. At supra-therapeutic concentrations, both of the antipsychotics seem to act as anti-inflammatory agents and mildly suppressed genes involved in the regulation of mitochondrial functions, which could potentially contribute to metabolic adverse effects. Alternatively, second-generation antipsychotics could induce metabolic side effects via acting on other insulin-sensitive tissues and central nervous system.
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| 9. |
- Sarsenbayeva, Assel, et al.
(författare)
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Excess glucocorticoid exposure contributes to adipose tissue fibrosis which involves macrophage interaction with adipose precursor cells
- 2022
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Ingår i: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839. ; 198
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Tidskriftsartikel (refereegranskat)abstract
- Chronic exposure to elevated glucocorticoid levels, as seen in patients with Cushing’s syndrome, can induce adipose tissue fibrosis. Macrophages play a pivotal role in adipose tissue remodelling. We used the synthetic glucocorticoid analogue dexamethasone to address glucocorticoid effects on adipose tissue fibrosis, in particular involving macrophage to preadipocyte communication. We analysed the direct effects of dexamethasone at a supra-physiological level, 0.3 µM, on gene expression of pro-fibrotic markers in human subcutaneous adipose tissue. The effects of dexamethasone on the differentiation of human SGBS preadipocytes were assessed in the presence or absence of THP1-macrophages or macrophage-conditioned medium. We measured the expression of different pro-fibrotic factors, including α-smooth muscle actin gene (ACTA2) and protein (α-SMA). Dexamethasone increased the expression of pro-fibrotic genes, e.g. CTGF, COL6A3, FN1, in adipose tissue. Macrophages abolished preadipocyte differentiation and increased the expression of the ACTA2 gene and α-SMA protein in preadipocytes after differentiation. Exposure to dexamethasone during differentiation reduced adipogenesis in preadipocytes, and elevated the expression of pro-fibrotic genes. Moreover, dexamethasone added together with macrophages further increased ACTA2 and α-SMA expression in preadipocytes, making them more myofibroblast-like. Cells differentiated in the presence of conditioned media from macrophages pretreated with or without dexamethasone had a higher expression of profibrotic genes compared to control cells. Our data suggest that macrophages promote adipose tissue fibrosis by directly interfering with preadipocyte differentiation and stimulating gene expression of pro-fibrotic factors. Excess glucocorticoid exposure also has pro-fibrotic effect on adipose tissue, but this requires the presence of macrophages.
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| 10. |
- Sarsenbayeva, Assel, et al.
(författare)
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Human macrophages stimulate expression of inflammatory mediators in adipocytes; effects of second-generation antipsychotics and glucocorticoids on cellular cross-talk
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier. - 0306-4530 .- 1873-3360. ; 125
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Adipose tissue inflammation and distorted macrophage-adipocyte communication are positively associated with metabolic disturbances. Some pharmacological agents, such as second-generation antipsychotics (SGAs) and synthetic glucocorticoid (GC) dexamethasone, tend to induce adverse metabolic side effects and the underlying mechanisms are not fully understood. Our work aimed to study whether SGAs and dexamethasone affect macrophage phenotype and macrophage-adipocyte communication on gene expression level. We selected the model involving THP-1-derived macrophages, polarized into M0, M1, and M2 phenotypes, and primary human mature subcutaneous adipocytes.Methods: Abdominal subcutaneous adipose tissue needle biopsies were obtained from 6 healthy subjects (4F/2M; age: 22-64 yr; BMI: 21.7-27.6 kg/m2) followed by isolation of mature adipocytes. THP-1-human monocytic cell line was used for the study. THP-1 monocytes were differentiated and polarized into M0 (naive), M1 (classically activated), and M2 (alternatively activated) macrophages. During and after polarization the macrophages were treated for 24 h without (control) or with therapeutic and supra-therapeutic concentrations of olanzapine (0.2 mu M and 2.0 mu M), aripiprazole (1.0 mu M and 10 mu M) and its active metabolite dehydroaripiprazole (0.4 mu M and 4.0 mu M). Isolated mature human adipocytes were co-incubated with THP-1-derived polarized macrophages pretreated with SGAs after their polarization. Adipocytes and macrophages were collected before and after co culture for mRNA expression analysis of genes involved in inflammation.Results: Co-incubation of mature human adipocytes with human macrophages, regardless of polarization, resulted in a marked induction of pro-inflammatory cytokines in adipocytes, including IL1B,IL6, TNFA, and IL10. Remarkably, it did not affect the expression of adipokines and genes involved in the regulation of energy, lipid, and glucose metabolism in adipocytes. Dexamethasone markedly reduced gene expression of pro-inflammatory cytokines in macrophages and prevented macrophage-induced inflammatory response in adipocytes. In contrast, SGAs did not affect macrophage-adipocyte communication and had a minute anti-inflammatory effect in macrophages at supra-therapeutic concentrations. Interestingly, the adipocytes co-incubated with M1 macrophages pre-treated with dexamethasone and SGAs particularly the supra-therapeutic concentration of olanzapine, reduced expression of LPL, LIPE, AKT1, and SLC2A4, suggesting that the expression of metabolic genes in adipocytes was dependent on the presence of pro-inflammatory M1 macrophages.Conclusion: Together, these data suggest that macrophages induce expression of pro-inflammatory genes in human subcutaneous adipocytes without affecting the expression of adipokines or genes involved in energy regulation. Furthermore, our findings demonstrated that SGAs and dexamethasone had a mild effect on macrophage-adipocyte communication in M1 macrophage phenotype.
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