Contribution de l'activité sécrétoire de l'adipocyte au syndrome plurimétabolique
(2000)
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- Authors
- Supervisors
- Brichard, Sonia M.
- Abstract
- Obesity belongs to a cluster of metabolic abnormalities (insulin resistance, type 2 diabetes, hypertension, dyslipidemia and hypofibrinolysis) leading to an increased risk for cardiovascular disease. These related disorders are components of the metabolic syndrome. It has become clear from epidemiological studies that some increase in the adipose tissue mass antedates the development of other metabolic disorders. However, the cellular and molecular basis of this connection is still elusive <BR> Adipocytes synthesize and release a variety of peptides which may have regulatory properties. I have studied three of these peptides : leptin, PAI-1 and adiponectin. Leptin controls whole-body energy homeostasis while PAI-1 and adiponectin play a role in atherothrombosis, PAI-1 being a risk factor for and adiponectin a protective factor against cardiovascular disease. In obese subjects, plasma levels of leptin and PAI-1are increased while those of adiponectin are reduced. <BR> I have examined whether endocrine abnormalities associated with the Metabolic Syndrome could contribute to altered production of leptin, PAI-1 and adiponectin by adipose tissue and subsequently to altered plasma levels of these “adipopeptide”. <BR> To this end, I have investigated the hormonal regulation of genes encoding leptin, PAI-1 and adiponectin in explants of human adipose tissue. For leptin and PAI-1, I have also measured the secretion in the medium. <BR> Glucocorticoids stimulated the transcription of the ob gene, which encodes leptin. Interestingly, ob gene and leptin responses to glucocorticoids were more pronounced in omental adipose tissue from obese subjects as compared to lean ones. These results suggest that this hyperresponsiveness to glucocorticoids could contribute to the metabolic abnormalities associated with central obesity. If this hyperresponsiveness also turned out to be true in subcutaneous fat, hyperleptinemia in obesity would reflect not only a resistance to central receptors, but also a primary alteration of Adipocytes (i.e. abnormal steroid response). Insulin added to the medium for up to 48h had no stimulatory effect on leptin production and even inhibited the stimulation by dexaméthasone. This effect of insulin was not due to a lowering of intracellular cAMP levels, because the addition of (Bu)2-cAMP to the medium also decreased the accumulation of ob mARN and leptin. <BR> I also provided evidence for a reciprocal regulation of PAI-1 by dexaméthasone (positive effector) and cAMP/catecholamines (negative effectors) in explants of human adipose tissue. These changes were reproduced in isolated fat cells and involved mainly pretranslational mechanisms. Insulin was indirectly stimulatory on PAU-1 gene expression as it partly reversed the inhibitory effect of catecholamines. The stimulation by glucocorticoids and insulin, and the impaired inhibition by catecholamines could contribute to enhances PAI-1 production by adipose tissue and to high plasma levels of PAI-1 associated with central obesity, and thereby lay be a link between this disorder and cardiovascular disease. <BR> Finally, I studied the hormonal regulation of the apM1 gene, which encodes adiponectin. The expression of this gene was negatively regulated by glucocorticoids and cAMP and positively regulated by insulin and IGF1 in human adipose tissue. This regulation could again contribute to the variations of adiponectin plasma levels and explain the paradoxical decrease of an adipose-specific protein in insulin-resistant patients with obesity and/or the Metabolic Syndrome and the subsequent risk for cardiovascular disease. I also found that adipose tissue may regulate its own production of adiponectin by releasing a factor that destabilizes apM1 mARN. <BR> In conclusion, adipose tissue may play a key role in the pathogenesis of the Metabolic Syndrome through the production of a variety of regulatory peptides. These peptides may influence several organs/tissues, thereby promoting metabolic or maintain the Metabolic Syndrome by altering the production of some of these adipose peptides
- Affiliations
Citations
Halleux, C. (2000). Contribution de l’activité sécrétoire de l’adipocyte au syndrome plurimétabolique. https://hdl.handle.net/2078.5/111079