Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue.

/pdf/adipose-tissue-as-an-endocrine-organ-18h86uxhhc.pdf

Adipose Tissue as an Endocrine Organ

The complement system is an evolutionary old and crucial component of innate immunity key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph and interstitial fluids that mediates the opsonization and lytic killing of bacteria, fungi and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity – indicating that complement’s function is likely broader than initially anticipated - the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond ‘classic’ immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature – mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement’s emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather ‘predictable’ but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.

/pdf/keeping-it-all-going-complement-meets-metabolism-zth049hzu4.pdf

Keeping It All Going—Complement Meets Metabolism

Excess body weight is associated not only with an increased risk of type 2 diabetes and cardiovascular disease (CVD)butalsowithvarioustypesofmalignancies.Adiponectin,themostabundantproteinsecretedbyadipose tissue, exhibits insulin-sensitizing, antiinflammatory, antiatherogenic, proapoptotic, and antiproliferative properties.Circulatingadiponectinlevels,whicharedeterminedpredominantlybygeneticfactors,diet,physical activity, and abdominal adiposity, are decreased in patients with diabetes, CVD, and several obesity-associated cancers. Also, adiponectin levels are inversely associated with the risk of developing diabetes, CVD, and several malignancies later in life. Many cancer cell lines express adiponectin receptors, and adiponectin in vitro limits cell proliferation and induces apoptosis. Recent in vitro studies demonstrate the antiangiogenic and tumor growth-limiting properties of adiponectin. Studies in both animals and humans have investigated adiponectin and adiponectin receptor regulation and expression in several cancers. Current evidence supports a role of adiponectin as a novel risk factor and potential diagnostic and prognostic biomarker in cancer. In addition, either adiponectin per se or medications that increase adiponectin levels or up-regulate signaling pathways downstream of adiponectin may prove to be useful anticancer agents. This review presents the role of adiponectin in carcinogenesis and cancer progression and examines the pathophysiological mechanisms that underlie the association between adiponectin and malignancy in the context of a dysfunctional adipose tissue in obesity. Understanding of these mechanisms may be important for the development of preventive and therapeutic strategies against obesity-associated malignancies. (Endocrine Reviews 33: 547–594, 2012)

/pdf/the-role-of-adiponectin-in-cancer-a-review-of-current-515zsm5kwc.pdf

The Role of Adiponectin in Cancer: A Review of Current Evidence

Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK), and increased peroxisome proliferator-activated receptor alpha (PPARα) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. © 2017 American Physiological Society. Compr Physiol 8:1031-1063, 2018.

Adiponectin Regulation and Function

Diabetes, oxidative stress and therapeutic strategies

○ Lack of donors has led to a worldwide increase in commercial kidney transplantation programs where recipients acquire kidneys either from executed prisoners or live non-related donors. ○ Commercial transplantation is prohibited by legislation in Australia. ○ Our centres have had 16 patients who have travelled overseas to receive a commercial kidney transplant; five have subsequently died. ○ As has been found previously, patients who received commercial transplants were more likely to develop infections such as HIV, hepatitis B virus, cytomegalovirus and fungal infections. ○ Previous reports have found that patient and graft survival were comparable to local results, whereas we found that patient and graft survival were worse than transplantation within Australia. ○ Patients considering the option of overseas commercial donation should be advised that heightened risks to life and graft survival exist.

/pdf/outcome-of-overseas-commercial-kidney-transplantation-an-2tdbyn9qe7.pdf

Outcome of overseas commercial kidney transplantation: an Australian perspective.

Adiponectin binds C1q and activates the classical pathway of complement.

Human adiponectin binds to bacterial lipopolysaccharide.

The collagenous region of adiponectin is glycosylated in vitro with glucosylgalactosyl moieties on four conserved lysines. We investigated the glycosylation of human adiponectin in vivo. Sugar vicinyl hydroxides on adiponectin were oxidized with 10 or 1 mM metaperiodate, and the result analyzed by two-dimensional electrophoresis and immunoblotting. Only 10 mM metaperiodate caused significant changes in electrophoretic mobility and an altered susceptibility to proteinase K digestion. Such treatment also increased the susceptibility of hexamers and high molecular weight (HMW) isoforms to dissociation by SDS. By contrast, untreated low molecular weight (LMW) isoforms were readily dissociated by low concentrations of SDS. Reduced HMW isoforms were able to partially reassemble following the removal of dithiothreitol, and this process was unaffected by metaperiodate. The presence of sialic acid was detected by Maackia amurensis Lectin II blotting, and by oxidation with 1 mM metaperiodate, followed by detection with Emerald Green 300 fluorescent dye. Quantitation of sugars on affinity-purified adiponectin from nine human plasmas showed that dimers of HMW isoforms contained a 1.3-fold greater amount of total sugar than LMW isoforms. However, both contained similar amounts of sialic acid. We conclude that glucosylgalactosyl residues contribute to the conformation of HMW human plasma adiponectin. In addition, the HMW isoform contains greater amounts of glucosylgalactosyl residues than the LMW isoform, and these sugars are important in determining its stability in vivo.

/pdf/glycosylation-of-human-adiponectin-affects-its-conformation-1o0zpce2gq.pdf

Glycosylation of human adiponectin affects its conformation and stability

SUMMARY

The multifactorial glycoprotein, adiponectin has demonstrable insulin-sensitizing, anti-atherogenic and anti-inflammatory properties. However, despite the prevalence of both insulin-resistance and vascular disease in patients with end-stage kidney disease, levels of adiponectin are high. Adiponectin circulates in different sizes (the high-molecular-weight (HMW) isoform is thought to be the most insulin-sensitizing type) and binds to two receptors, adiponectin receptors (AdipoR) 1 and 2. The adiponectin/receptor system appears to be upregulated in end-stage kidney disease possibly as an appropriate counter-regulatory response to the uraemic milieu. In contrast, adiponectin and its HMW isoform, AdipoR mRNA expression on peripheral blood mononuclear cells decrease after kidney transplantation, likely secondary to immunosuppression and/or an improvement in glomerular filtration rate and the uraemic environment. Adiponectin has also been detected in the urine of patients with proteinuric kidney disease. The presence of AdipoR on an immortal cell line of proximal tubular epithelial cells (HK-2) and an increased amount of intact HMW isoform in the urine of patients with various forms of proteinuria lead us to speculate about the potential role of urinary adiponectin. This review will also discuss the structure and function of adiponectin and its potential relevance to patients with kidney disease and the different factors that may influence the metabolism of this protein in kidney failure.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1440-1797.2008.01018.x

Review article: Adiponectin: its role in kidney disease.

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