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- Murdolo, Giuseppe, 1966, et al.
(författare)
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Acute hyperinsulinemia differentially regulates interstitial and circulating adiponectin oligomeric pattern in lean and insulin-resistant, obese individuals
- 2009
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Ingår i: J Clin Endocrinol Metab. - 1945-7197. ; 94:11, s. 4508-16
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Hyperinsulinemia emerges as a negative modulator of the circulating high-molecular-weight adiponectin multimers. OBJECTIVES: Here we asked whether, in vivo, acute hyperinsulinemia regulates adiponectin formation and oligomeric complex distribution at the transcriptional or posttranslational level. DESIGN: Nine lean and nine uncomplicated obese males were studied in the postabsorptive state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Subcutaneous abdominal adipose tissue biopsies and interstitial and serum samples were taken at baseline and after the hyperinsulinemia. Adiponectin complexes were characterized by nonheating/nonreducing SDS-PAGE. RESULTS: At baseline, serum and interstitial total adiponectin levels were lower (P < 0.01) in obese than in lean subjects primarily due to a reduction of the high-molecular-weight isoforms. After hyperinsulinemia, serum and interstitial total adiponectin was reduced in both groups. The degree of adiponectin reduction was more prominent in interstitial fluid than in serum. Lean individuals showed an equal suppression of the high-, low-, and middle-molecular-weight adiponectin complexes both in serum and in situ (P < 0.01 vs. basal). In obese subjects, despite the lower interstitial adiponectin subfractions, insulin challenge reduced significantly the circulating middle-molecular-weight forms only. At the mRNA level, adiponectin and its receptors 1 and 2, as well as the abundance of the endoplasmic reticulum chaperone proteins ERp44 and Epsilonro1-Lalpha were similar within the groups, before and after the clamp. CONCLUSIONS: In human obesity, the impaired adiponectin oligomeric pattern in the circulation is mimicked at the tissue level, and hyperinsulinemia may differentially affect the compartmental distribution of the adiponectin complexes.
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| 2. |
- Murdolo, Giuseppe, 1966, et al.
(författare)
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In situ profiling of adipokines in subcutaneous microdialysates from lean and obese individuals
- 2008
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Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 295:5, s. E1095-E1105
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue (AT) had emerged as an endocrine organ and a key regulator of the metabolically triggered inflammation. The aims of this study were 1) to investigate the usefulness of a multiplexed bioassay in characterizing a panel of adipokines in subcutaneous (sc) microdialysate samples and 2) to determine whether lean and obese individuals differ in their interstitial adipokines levels following microdialysis (MD) probe insertion. Ultrafiltrating MD membranes were inserted in opposite sites of the sc abdominal AT of six lean (L) and six obese (OB) males at the beginning (M1) and during the last 120 min (M2) of the study. Interstitial and serum concentrations of adipokines were quantified using the Luminex technique and ELISA at 60-min intervals for 5 h. In comparison with L subjects, OB subjects exhibited elevated interstitial leptin ( P < 0.001), IL-8 ( P < 0.05), and IL-18 levels ( P = 0.05), as well as higher serum concentrations of leptin ( P < 0.0001), IL-6 ( P < 0.0001), tumor necrosis factor-α ( P < 0.001), IL-8 ( P = 0.01) and interferon-γ-inducible protein 10 ( P < 0.05). In samples from the M1 membranes, leptin decreased and IL-1α, IL-18, and RANTES (regulated on activation, normal T-cell expressed and secreted) remained relatively stable, whereas IL-6, IL-8, and monocyte chemoattractant protein-1 significantly increased after the first hour ( P < 0.0001 vs. baseline). Notably, either the magnitude of increase from the initial values or the time pattern of all the adipokines in M1 and M2 dialysates were similar between the groups. In conclusion, the current work provides valuable information on the optimal time frame to collect in situ AT microdialysate samples. Further studies are needed, however, to unravel the intricate interplay of cytokines in AT interstitial fluid.
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| 3. |
- Murdolo, Giuseppe, 1966, et al.
(författare)
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Insulin differentially modulates the peripheral endocannabinoid system in human subcutaneous abdominal adipose tissue from lean and obese individuals.
- 2007
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Ingår i: Journal of endocrinological investigation. - 1720-8386. ; 30:8, s. RC17-21
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Tidskriftsartikel (refereegranskat)abstract
- Human obesity has been associated with a dysregulation of the peripheral and adipose tissue (AT) endocannabinoid system (ES). The aim of this study was to elucidate the acute in vivo effects of insulin on gene expression of the cannabinoid type 1 (CB-1) and type 2 (CB-2) receptors, as well as of the fatty acid amide hydrolase (FAAH) in the sc abdominal adipose tissue (SCAAT). Nine lean (L) and 9 obese (OB), but otherwise healthy males were studied in the fasting state and during a euglycemic hyperinsulinemic clamp (40 mU/m2 * min(-1)). SCAAT biopsies were obtained at baseline and after 270 min of i.v. maintained hyperinsulinemia. The basal SCAAT gene expression pattern revealed an upregulation of the FAAH in the OB (p=0.03 vs L), whereas similar CB-1 and CB-2 mRNA levels were seen. Following hyperinsulinemia, the FAAH mRNA levels significantly increased approximately 2-fold in the L (p=0.01 vs baseline) but not in the OB. In contrast, insulin failed to significantly change both the adipose CB-1 and CB-2 gene expression. Finally, the FAAH gene expression positively correlated with the fasting serum insulin concentration (r 0.66; p=0.01), whereas an inverse association with the whole-body glucose disposal (r -0.58; p<0.05) was seen. Taken together, these first time observations demonstrate that the ES-related genes in the SCAAT differentially respond to hyperinsulinemia in lean/insulin-sensitive and in obese/insulin-resistant individuals. We suggest that insulin may play a key role in the obesity-linked dysregulation of the adipose ES at the gene level.
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| 4. |
- Murdolo, Giuseppe, 1966, et al.
(författare)
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Monocyte chemoattractant protein-1 in subcutaneous abdominal adipose tissue: characterization of interstitial concentration and regulation of gene expression by insulin
- 2007
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Ingår i: J Clin Endocrinol Metab. - : The Endocrine Society. - 0021-972X. ; 92:7, s. 2688-95
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: The chemokine monocyte chemoattractant protein-1 (MCP-1) is implicated in obesity-associated chronic inflammation, insulin resistance, and atherosclerosis. OBJECTIVES: The objectives of this study were to: 1) characterize the interstitial levels and the gene expression of MCP-1 in the sc abdominal adipose tissue (SCAAT), 2) elucidate the response of MCP-1 to acute hyperinsulinemia, and 3) determine the relationship between MCP-1 and arterial stiffness. DESIGN: Nine lean (L) and nine uncomplicated obese (OB) males were studied in the fasting state and during a euglycemic-hyperinsulinemic clamp combined with the microdialysis technique. Interstitial and serum MCP-1 (iMCP-1 and sMCP-1, respectively) levels, pulse wave analysis, and SCAAT biopsies were characterized at baseline and after hyperinsulinemia. RESULTS: OB showed elevated sMCP-1 (P < 0.01) but similar iMCP-1 levels as compared with L. Basal iMCP-1 concentrations were considerably higher than sMCP-1 (P < 0.0001), and a gradient between iMCP-1 and sMCP-1 levels was maintained throughout the hyperinsulinemia. At baseline, SCAAT gene expression profile revealed a "co-upregulation" of MCP-1, MCP-2, macrophage inflammatory protein-1alpha, and CD68 in OB, and whole-body glucose disposal inversely correlated with the MCP-1 gene expression. After hyperinsulinemia, MCP-1 and MCP-2 mRNA levels significantly increased in L, but not in OB. Finally, sMCP-1 excess in the OB positively correlated with the stiffer vasculature. CONCLUSIONS: These observations demonstrate similar interstitial concentrations and a differential gene response to hyperinsulinemia of MCP-1 in the SCAAT from L and OB individuals. In human obesity, we suggest the SCAAT MCP-1 gene overexpression as a biomarker of an "inflamed" adipose organ and impaired glucose metabolism.
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| 5. |
- Murdolo, Giuseppe, 1966, et al.
(författare)
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The dysregulated adipose tissue: a connecting link between insulin resistance, type 2 diabetes mellitus and atherosclerosis
- 2006
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Ingår i: Nutr Metab Cardiovasc Dis. - 0939-4753. ; 16 Suppl 1, s. S35-8
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Tidskriftsartikel (refereegranskat)abstract
- An emerging paradigm supports the view that adipose tissue (AT) dysregulation might play a crucial role in the pathogenesis of insulin-resistance and atherosclerosis. The net result of such a dysregulation is a state of low-grade, chronic, systemic inflammation that, in turn, links both the metabolic and the vascular pathologies. Overwhelming evidence shows that high circulating levels of markers of chronic inflammation predict the development of T2DM and atherosclerotic manifestations. Therefore, atherosclerotic cardiovascular disease and T2DM seem to arise from a "common soil", and chronic inflammation is a candidate. In this scenario, the dysfunctional AT provide a common hallmark for these apparently divergent disorders. An important question then is whether dysregulated and inflamed AT can be converted to healthy fat and, consequently, the development or the progression of metabolic and vascular impairment can be prevented or reversed by the modulation of the inflammatory profile. The beneficial effects of weight loss on obesity-related complications are clearly associated with the modification of the inflammatory profile in the AT. Furthermore, the thiazolidinediones (TZDs) possess both anti-inflammatory and anti-atherogenic properties. Intriguingly, in contrast to the paradoxical weight gain, TZDs influence favorably the pattern of adipokines. In conclusion, accepting the paradigm of AT dysfunction, the use of TZDs will represent an additional therapeutic approach that, in association with lifestyle interventions, would improve inflammation, ameliorate insulin sensitivity, and alleviate the related risk of atherosclerosis.
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