Interleukin-6 Regulates Human Adipose Tissue Lipid Metabolism and Leptin Production<i>in Vitro</i>

Trujillo, María E.; Sullivan, Sean; Harten, Ingrid A.; Schneider, Stephen H.; Greenberg, Andrew S.; Fried, Susan K.

doi:10.1210/jc.2004-0603

Cited by 225 publications

(150 citation statements)

References 40 publications

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“…It is largely a result of the observations that circulating TNFa levels are unchanged or undetectable (52,53) , as well as elevated (54,55) , in patients with cancer cachexia. IL-6 has been shown to moderately increase lipolysis in human adipose tissue in vitro (56) . Treatment with CNTO-328, a monoclonal antibody to IL-6, is able to reverse tumour-induced cachexia in nude mice (57) .…”

Section: Cytokinesmentioning

confidence: 99%

New insights into adipose tissue atrophy in cancer cachexia

Chen

Trayhurn

2009

Proc. Nutr. Soc.

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Profound loss of adipose and other tissues is a hallmark of cancer cachexia, a debilitating condition associated with increased morbidity and mortality. Fat loss cannot be attributable to reduced appetite alone as it precedes the onset of anorexia and is much more severe in experimental models of cachexia than in food restriction. Morphological examination has shown marked remodelling of adipose tissue in cancer cachexia. It is characterised by the tissue containing shrunken adipocytes with a major reduction in cell size and increased fibrosis in the tissue matrix. The ultrastructure of ‘slimmed’ adipocytes has revealed severe delipidation and modifications in cell membrane conformation. Although the molecular mechanisms remain to be established, evidence suggests that altered adipocyte metabolism may lead to adipose atrophy in cancer cachexia. Increased lipolysis appears to be a key factor underlying fat loss, while inhibition of adipocyte development and lipid deposition may also contribute. Both tumour and host-derived factors are implicated in adipose atrophy. Zinc-α2-glycoprotein (ZAG), which is overexpressed by certain malignant tumours, has been identified as a novel adipokine. ZAG transcripts and protein expression in adipose tissue are up regulated in cancer cachexia but reduced with adipose tissue expansion in obesity. Studies in vitro demonstrate that recombinant ZAG stimulates lipolysis. ZAG may therefore act locally, as well as systemically, to promote lipid mobilisation in cancer cachexia. Further elucidation of ZAG function in adipose tissue may lead to novel targets for preventing adipose atrophy in malignancy.

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Section: Cytokinesmentioning

confidence: 99%

New insights into adipose tissue atrophy in cancer cachexia

Chen

Trayhurn

2009

Proc. Nutr. Soc.

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“…In human adipose tissue, TNF␣ increases leptin mRNA only when added together with dexamethasone, and the mechanism involves an activation of p38 MAPK (80). Interleukin-6, another inflammatory cytokine, also increases leptin production when added in the presence of dexamethasone, but the mechanism is not yet established (81). Thus the increase in local cortisol and inflammatory cytokines in adipose tissue may contribute to higher leptin mRNA levels in obesity and contribute to higher leptin levels observed after endotoxin administration (19).…”

Section: Chronic Changes In Nutritional Status Regulate Leptin At Thementioning

confidence: 99%

Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion

Lee¹,

Fried²

2009

American Journal of Physiology-Endocrinology and Metabolism

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112

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Lee M-J, Fried SK. Integration of hormonal and nutrient signals that regulate leptin synthesis and secretion. Am J Physiol Endocrinol Metab 296: E1230 -E1238, 2009. First published March 24, 2009 doi:10.1152/ajpendo.90927.2008.-This review summarizes recent advances in our understanding of the pre-and posttranscriptional mechanisms that regulate leptin production and secretion in adipocytes. Basal leptin production is proportional to the status of energy stores, i.e., fat cell size, and this is mainly regulated by alterations in leptin mRNA levels. Leptin mRNA levels are regulated by hormones, including glucocorticoids and catecholamines, but little is known about the transcriptional mechanisms involved. Leptin synthesis and secretion is also acutely modulated in response to hormones such as insulin and the availability of metabolic fuels. Acute variations in leptin production over a time course of minutes to hours are mediated at the levels of both translation and secretion. Increases in amino acids and insulin after a meal activate the mammalian target of rapamycin (mTOR) pathway, leading to an increase in specific rates of leptin biosynthesis. Cross-talk among mTOR, PKA, and AMPactivated protein kinase pathways appears to integrate hormonal and nutrient signals that regulate leptin mRNA translation, at least in part through mechanisms involving its 5Ј-and 3Ј-untranslated regions. In addition, the rate of leptin secretion from preformed stores in response to hormonal cues is also regulated. Insulin stimulates, and adrenergic agonists inhibit, leptin secretion, and this likely contributes to variations in the magnitude of nutrition-related leptin excursions and oscillations. Overall, the study of leptin production has contributed to a deepening understanding of leptin biology and, more broadly, to our understanding of the cellular and molecular mechanisms by which the adipocyte integrates hormonal and nutrient signals to regulate adipokine production. adipose tissue; adrenergic; feeding; insulin; obesity LEPTIN IS A 16-KDA PROTEIN encoded by the obese (lep) gene that is expressed and secreted mainly by adipocytes. When energy stores are low, a fall in leptin decreases thermogenesis, promotes fatty acid (FA) over glucose oxidation, and decreases the activity of the hypothalamic pituitary adrenal and gonadal axes (1). Leptin also modulates the activities of the hematopoietic (5) and immune (52) systems, as well as angiogenesis (7).

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“…108 Either in relation to HIV-1 infection itself or to HAART, the increase in TNFa and other cytokines in adipose tissue may play a major role in the sustained increase in lipolysis. TNFa, like other cytokines such as interleukin-6, 109 activates lipolysis in adipocytes 110 and has been directly implicated in the increased release of fatty acids from adipose tissue in HALS patients. 111 Moreover, co-culture of adipocytes and macrophages indicates that FFAs released by adipose cells activate TNFa release by macrophages, thus indicating a positive cross-talk between adipocytes and macrophages involving mainly FFA and TNFa release, respectively.…”

Section: The Paradox Of the Common Inflammation Status In Adipose Tismentioning

confidence: 99%