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      Human adipocytes secrete mineralocorticoid-releasing factors

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          Abstract

          Obesity has become an epidemic problem in western societies, contributing to metabolic diseases, hypertension, and cardiovascular disease. Overweight and obesity are frequently associated with increased plasma levels of aldosterone. Recent evidence suggests that human fat is a highly active endocrine tissue. Therefore, we tested the hypothesis that adipocyte secretory products directly stimulate adrenocortical aldosterone secretion. Secretory products from isolated human adipocytes strongly stimulated steroidogenesis in human adrenocortical cells (NCI-H295R) with a predominant effect on mineralocorticoid secretion. Aldosterone secretion increased 7-fold during 24 h of incubation. This stimulation was comparable to maximal stimulation of these cells with forskolin (2 x 10(-5) M). On the molecular level, there was a 10-fold increase in the expression of steroid acute regulatory peptide mRNA. This effect was independent of adipose angiotensin II as revealed by the stimulatory effect of fat cell-conditioned medium even in the presence of the angiotensin type 1 receptor antagonist, valsartan. None of the recently defined adipocytokines accounted for the effect. Mineralocorticoid-stimulating activity was heat sensitive and could be blunted by heating fat cell-conditioned medium to 99 degrees C. Centrifugal filtration based on molecular mass revealed at least two releasing factors: a heat sensitive fraction (molecular mass >50 kDa) representing 60% of total activity, and an inactive fraction (molecular mass <50 kDa). However, the recovery rate increased to 92% when combining these two fractions, indicating the interaction of at least two factors. In conclusion, human adipocytes secrete potent mineralocorticoid-releasing factors, suggesting a direct link between obesity and hypertension.

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          Most cited references46

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          Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ.

          The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.
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            Control of energy homeostasis and insulin action by adipocyte hormones: leptin, acylation stimulating protein, and adiponectin.

            P Havel (2002)
            Adipose tissue performs complex metabolic and endocrine functions. This review will focus on the recent literature on the biology and actions of three adipocyte hormones involved in the control of energy homeostasis and insulin action, leptin, acylation-stimulating protein, and adiponectin, and mechanisms regulating their production. Results from studies of individuals with absolute leptin deficiency (or receptor defects), and more recently partial leptin deficiency, reveal leptin's critical role in the normal regulation of appetite and body adiposity in humans. The primary biological role of leptin appears to be adaptation to low energy intake rather than a brake on overconsumption and obesity. Leptin production is mainly regulated by insulin-induced changes of adipocyte metabolism. Consumption of fat and fructose, which do not initiate insulin secretion, results in lower circulating leptin levels, a consequence which may lead to overeating and weight gain in individuals or populations consuming diets high in energy derived from these macronutrients. Acylation-stimulating protein acts as a paracrine signal to increase the efficiency of triacylglycerol synthesis in adipocytes, an action that results in more rapid postprandial lipid clearance. Genetic knockout of acylation-stimulating protein leads to reduced body fat, obesity resistance and improved insulin sensitivity in mice. The primary regulator of acylation-stimulating protein production appears to be circulating dietary lipid packaged as chylomicrons. Adiponectin increases insulin sensitivity, perhaps by increasing tissue fat oxidation resulting in reduced circulating fatty acid levels and reduced intramyocellular or liver triglyceride content. Adiponectin and leptin together normalize insulin action in severely insulin-resistant animals that have very low levels of adiponectin and leptin due to lipoatrophy. Leptin also improves insulin resistance and reduces hyperlipidemia in lipoatrophic humans. Adiponectin production is stimulated by agonists of peroxisome proliferator-activated receptor-gamma; an action may contribute to the insulin-sensitizing effects of this class of compounds. The production of all three hormones is influenced by nutritional status. These adipocyte hormones, the pathways controlling their production, and their receptors represent promising targets for managing obesity, hyperlipidemia, and insulin resistance.
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              Dietary sodium intake and subsequent risk of cardiovascular disease in overweight adults.

              Dietary sodium is positively associated with blood pressure, and ecological and animal studies both have suggested that high dietary sodium intake increases stroke mortality. To examine the risk of cardiovascular disease associated with dietary sodium intake in overweight and nonoverweight persons. Prospective cohort study. The first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, conducted in 1982-1984, 1986, 1987, and 1992. Of those aged 25 to 74 years when the survey was conducted in 1971 -1975 (14407 participants), a total of 2688 overweight and 6797 nonoverweight persons were included in the analysis. Dietary sodium and energy intake were estimated at baseline using a single 24-hour dietary recall method. Incidence and mortality data for cardiovascular disease were obtained from medical records and death certificates. For overweight and nonoverweight persons, over an average of 19 years of follow-up, the total number of documented cases were as follows: 680 stroke events (210 fatal), 1727 coronary heart disease events (614 fatal), 895 cardiovascular disease deaths, and 2486 deaths from all causes. Among overweight persons with an average energy intake of 7452 kJ, a 100 mmol higher sodium intake was associated with a 32% increase (relative risk [RR], 1.32; 95% confidence interval [CI], 1.07-1.64; P = .01) in stroke incidence, 89% increase (RR, 1.89; 95% CI, 1.31-2.74; P<.001) in stroke mortality, 44% increase (RR, 1.44; 95% CI, 1.14-1.81; P = .002) in coronary heart disease mortality, 61% increase (RR, 1.61; 95% CI, 1.32-1.96; P<.001) in cardiovascular disease mortality, and 39% increase (RR, 1.39; 95% CI, 1.23-1.58; P<.001) in mortality from all causes. Dietary sodium intake was not significantly associated with cardiovascular disease risk in nonoverweight persons. Our analysis indicates that high sodium intake is strongly and independently associated with an increased risk of cardiovascular disease and all-cause mortality in overweight persons.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                May 01 2011
                November 25 2003
                November 12 2003
                November 25 2003
                : 100
                : 24
                : 14211-14216
                Article
                10.1073/pnas.2336140100
                283571
                14614137
                1d1e5f95-af71-4f9d-a93b-47e292bef226
                © 2003
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