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- van Harmelen, Vanessa
(författare)
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Metabolic and endocrine function of human adipose tissue with focus on regional differences
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The major function of human adipose tissue is to store excess ingested energy and to release free fatty acids after hydrolysis of triglycerides (lipolysis), to meet the energy demands of other organs. Adipose tissue also has a secretory function. It secretes several proteins, such as acylation stimulating protein (ASP), plasminogen activator inhibitor-1 (PAI-1), tumour necrosis factor-cc (TNF-alpha) and leptin, that in an auto-, para-, or endocrine fashion might regulate energy metabolism and/or growth of adipose tissue, although the exact mechanisms are unclear. The in vitro effects of two adipose tissue secretory proteins, TNF- alpha and ASP respectively, on human adipose metabolism were studied. It was shown that TNF-alpha inhibited insulin-stimulated glucose transport in adipose tissue specimens in culture and that adipose tissue TNF-alpha secretion correlated negatively with insulin-stimulated glucose transport in isolated adipocytes. ASP was found to inhibit both basal and noradrenaline-induced FFA release, by inhibiting lipolysis and stimulating FFA re-esterification. The intracellular signalling pathway of ASP leading to these effects was shown to include phosphodiesterase(PDE). The pathway preceding PDE is not known yet, but it was shown that it may not include protein kinase C or phosphatidyl inositol 3-kinase. Thus, adipose TNF-alpha and ASP seem to be important autocrine factors that inhibit and stimulate triglyceride storage in the adipocyte, respectively. Another feature of adipose tissue is that it is heterogeneous with respect to metabolic capacity. The triglyceride-turnover is higher in the visceral as compared to the subcutaneous adipose depot. It was found that noradrenaline stimulated lipolysis to the same extent in human isolated mesenteric and omental adipocytes, but that the lipolytic response in both these visceral fat cell types was significantly higher as compared to in the abdominal subcutaneous adipocytes. These observations were shown to be mainly due to an enhanced beta3- and decreased alpha2-adrenoceptor function in the visceral adipocytes. No difference was found in noradrenaline-induced lipolysis between in vitro differentiated omental and subcutaneous preadipocytes. This suggests that extrinsic rather than intrinsic factors are responsible for the regional differences in lipolysis seen in adipocytes. Adipose tissue metabolic heterogeneity might induce regional differences in the endocrine function of adipose tissue. It was shown that leptin mRNA expression and secretion rate were significantly higher in subcutaneous as compared to omental adipose tissue specimens and differentiated preadipocytes. Since the adipose tissue is the major leptin- producing organ in the body, these results suggest that the subcutaneous adipose tissue depot is the body's most important source of leptin. The findings on the preadipocytes suggest that regional differences in adipocyte leptin production may have an intrinsic basis. PAI-1 mRNA expression and secretion rate were shown to be higher in subcutaneous than in omental adipose specimens from obese subjects. Thus, the subcutaneous adipose depot might be an important source of PAM in obesity. No difference in TNF-alpha secretion was found between omental and subcutaneous adipose specimens, which is in agreement with the results on preadipocytes that did not show a regional difference in TNF-alpha secretion and mRNA expression. Taken together, human adipose tissue is heterogeneous in both its metabolic and endocrine function.
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| 2. |
- van Harmelen, Vanessa, et al.
(författare)
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The vascular peptide endothelin-1 links fat accumulation with alterations of visceral adipocyte lipolysis
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 57:2, s. 378-386
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTAT-Visceral obesity increases risk of insulin resistance and type 2 diabetes. This may partly be due to a region-specific resistance to insulin's antilipolytic effect in visceral adipocytes. We investigated whether adipose tissue releases the vascular peptide endothelin-1 (ET-1) and whether ET-1 could account for regional differences in lipolysis. RESEARCH DESIGN AND METHODS-One group consisted of eleven obese and eleven nonobese subjects in whom ET-1 levels were compared between abdominal subcutaneous and arterialized blood samples. A second group included subjects undergoing anti-obesity surgery. Abdominal subcutaneous and visceral adipose tissues were obtained to study the effect of ET-1 on differentiated adipocytes regarding lipolysis and gene and protein expression. RESULTS-Adipose tissue had a marked net release of ET-1 in vivo, which was 2.5-fold increased in obesity. In adipocytes treated with ET-1, the antilipolytic effect of insulin was attenuated in Visceral but not in subcutaneous adipocytes, which could not be explained by effects of ET-1 on adipocyte differentiation. ET-1 decreased the expression of insulin receptor, insulin receptor substrate-1 and phosphodiesterase-3B and increased the expression of endothelin receptor-B (ETBR) in visceral but not in subcutaneous adipocytes. These effects were mediated via ETBR with signals through protein kinase C and calmodulin pathways. The effect of ET-1 could be mimicked by knockdown of IRS-1. CONCLUSIONS-ET-1 is released front human adipose tissue and links fat accumulation to insulin resistance. It selectively counteracts insulin inhibition of visceral adipocyte lipolysis via ETBR signaling pathways, which affect multiple steps in insulin signaling.
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