Adiponectin in inflammatory and immune-mediated diseases

Highlights

• Adiponectin is elevated in inflammatory and immune-mediated diseases.

• Positive association between adiponectin and inflammation in inflammatory diseases.

• Adipose tissue physiology influences adiponectin levels in inflammatory diseases.

• Many conflicting factors contribute to regulation of adiponectin levels.

• Strain-dependent phenotypes of adiponectin KO mice.

Abstract

Circulating levels of adiponectin (APN) are reduced in obesity and associated comorbidities, with inflammation playing an important role in downregulating APN production. In contrast to obesity and metabolic disease, elevated systemic and local levels of APN are present in patients with inflammatory and immune-mediated diseases, including autoimmune and pulmonary conditions, heart and kidney failure, viral hepatitis, organ transplantation and perhaps critical illness. A positive association between inflammation and APN is usually reported in inflammatory/immune pathologies, in contrast with the negative correlation typical of metabolic disease. This review discusses the role of APN in modulation of inflammation and immunity and the potential mechanisms leading to increased levels of APN in inflammatory/immune diseases, including modification of adipose tissue physiology; relative contribution of different tissues and adipose depots; hormonal, pharmacological, nutritional and life style factors; the potential contribution of the microbiota as well as the role of altered APN clearance and release from T-cadherin-associated tissue reservoirs. Potential reasons for some of the apparently contradictory findings on the role of APN as a modulator of immunity and inflammation are also discussed, including a comparison of types of recombinant APN used for in vitro studies and strain-dependent differences in the phenotype of APN KO mice.

Introduction

The adipokine adiponectin (APN) has been extensively studied for its involvement in obesity and associated morbidities, particularly cardiovascular disease (CVD), the metabolic syndrome and Type 2 diabetes. A massive amount of data accumulated over the past 20 years strongly supports the notion of reduced production of APN from adipocytes in the above-mentioned conditions. Inflammation is the common thread generally invoked to explain suppressed production of APN in obesity and its co-morbidities, with strong evidence supporting these claims. Briefly, expansion of adipose tissue in obesity, with or without additional contributions from CVD and/or insulin resistance, leads to development of chronic inflammation, which in turn contributes to inhibition of APN. Excellent and numerous reviews discussing the regulation of production and role of APN in the context of metabolic disease have been published (see for example [1], [2], [3], [4]). On the other hand, a less extensive – although growing – body of evidence points to paradoxical upregulation of APN in several types of inflammatory and immune-mediated conditions [5], [6], [7], [8], [9], [10], [11], [12]. Here, after an introduction about APN and its effects on modulation of inflammatory and immune responses, I discuss evidence on the association between APN and inflammatory/immune diseases and potential factors contributing to this association.

Adipocytes are the most important source of APN, but other cell types – including skeletal and cardiac myocytes, airway epithelial cells and lymphocytes – can also produce this adipokine [3], [13], [14], [15], [16]. Although extra-adipocyte sources of APN may be important modulators of the local microenvironment, they are unlikely to significantly contribute to the circulating pool of APN under physiological conditions. Activation of the transcription factors PPARα and γ and FOXO1 is critical in regulating production of APN in adipocytes [17]. The complex structure of APN, its receptors ADIPOR1, ADIPOR2 and T-cadherin, the signaling pathways activated by APN as well as its effects on metabolism have been described in detail in several excellent reviews [1], [2], [3], [4]. A plethora of beneficial effects of APN have been reported in metabolic disease, as reviewed in [1], [2], [3], [4], even though the occasional conflicting result has also been reported [18], [19].