Does adiponectin play a role in pulmonary emphysema?

ADIPONECTIN IS ONE OF SEVERAL recently described, circulating, secretory products synthesized by adipose tissue and known collectively as “adipokines” and/or “adipocytokines” (7, 22). Adiponectin plays an important role in energy homeostasis, regulating both glucose and lipid metabolism (14, 26). Adiponectin exerts its metabolic effects by binding to two receptors: AdipoR1, which is ubiquitously expressed, and AdipoR2, which is found predominantly in the liver (11, 29). Transduction of the adiponectin signal by its receptors involves activation of AMP-activated protein kinase and the transcription factor peroxisome proliferator-activated receptor, which, overall, increases fatty acid oxidation and glucose uptake in skeletal muscle, while reducing glucose production in the liver (12–14). Although expression of adiponectin is normally stimulated by insulin, both adiponectin and its receptors are downregulated in obesity-linked insulin resistance, hyperinsulinemia, and type 2 diabetes (12, 13). Adiponectin is also an important anti-inflammatory molecule and has been implicated in the pathophysiology of obesity-related diseases (6, 12–15, 18, 19, 25, 26). Adiponectin is a collectin-like molecule that contains a collagen-like domain at the NH2 terminus and a globular, C1q-like domain at the COOH terminus, and shares structural characteristics with both the complement factor C1q and the TNF families of proteins (11, 26). Adiponectin forms trimers, hexamers, and higher-molecular-weight, multimeric complexes, which are found in the circulation of healthy individuals at relatively high concentrations (26). In humans, decreased circulating concentrations of adiponectin are associated with obesity, metabolic syndrome, insulin resistance, hyperinsulinemia, and type 2 diabetes, as well as with cardiovascular disease (12, 19, 26). In contrast, elevated serum levels of the proinflammatory adipocytokines, TNF, IL-6, C-reactive protein (CRP), and leptin are increased in these syndromes (12, 19, 26). It is currently thought that chronic, low-grade inflammation of adipose tissue, due to macrophage infiltration, causes release of these proinflammatory cytokines, which then inhibit the local production of adiponectin in the adipocyte (26). Macrophages are the major source of TNFproduction by adipose tissue, whereas both adipose tissue and macrophages contribute to circulating IL-6 levels (7, 15). Adiponectin, in turn, acts as an antiinflammatory molecule by modulating macrophage function through the inhibition of phagocytosis as well as by inhibiting TNFand IL-6 production (7, 15). Paradoxically, serum levels of adiponectin appear to increase in autoimmune diseases and/or in chronic inflammatory conditions that are unrelated to obesity, such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and Crohn’s disease. In these diseases, increased serum levels of adiponectin are correlated with increased serum levels of IL-6, CRP, TNF, and leptin (8). In this regard, adiponectin is thought to attenuate or modulate the effects of these proinflammatory adipocytokines (8). Serum levels of adiponectin are also increased in patients with chronic heart failure, end stage renal disease, and anorexia nervosa, all diseases associated with cachexia, or body wasting (1, 2). Likewise, long-term caloric restriction in adult mice increases circulating adiponectin and insulin sensitivity (26). One explanation for these differences is that increased serum adiponectin levels appear to be correlated with positive energy balance (obesity), whereas decreased serum adiponectin levels are correlated with negative energy balance (cachexia). Interestingly, calorie restriction in rodents and starvation in humans cause alveolar loss in the lung, whereas refeeding in rodents results in alveolar regeneration (16). Although pulmonary emphysema has been reported in patients with anorexia nervosa (5), no correlative studies on caloric restriction, alveolar loss, and serum adiponectin levels have been conducted in experimental animal models. While the role of adiponectin in energy metabolism and inflammation has been studied in a number of different human disorders, organ systems, tissues, and cells, little is known about its role in chronic lung disease. Chronic obstructive pulmonary disease (COPD) is a major, worldwide disease that results in progressive, irreversible airflow obstruction, or limitation. It is caused by chronic inflammation of the airways and the lung parenchyma in response to inhalation of environmental particles and gases, resulting in chronic bronchitis and pulmonary emphysema. In general, acute exacerbations of COPD (most often in response to bacterial infection) are associated with increased serum levels of CRP, IL-6, TNF, leptin, and adiponectin, as well as with increases in other factors associated with bacterial inflammation and infection (27). Recently, differences in body weight and serum adiponectin levels have been associated with the two major clinical phenotypes found in COPD. Pulmonary emphysema, which is characterized by destruction of the respiratory bronchioles, alveolar ducts, and mature alveoli, has been associated with cachexia, whereas chronic bronchitis, which results in disruption of the bronchial epithelium, smooth muscle hypertrophy, and fibrosis, has been associated with obesity. In a Japanese study of normal and underweight patients with emphysema, serum levels of adiponectin were elevated in both groups and were correlated with increased serum TNFand IL-6 levels, as well as with severity of lung disease (hyperinflation) (24). In contrast, while serum levels of TNF, IL-6, and leptin were significantly higher in a group of obese patients diagnosed with both COPD and metabolic syndrome, serum adiponectin levels were reduced and were associated with a less severe pulmonary phenotype compared with normal weight COPD patients (21). These studies suggest that adiAddress for reprint requests and other correspondence: S. E. Wert, Cincinnati Children’s Hospital Medical Center, Divisions of Neonatology and Pulmonary Biology, 3333 Burnet Ave., Cincinnati, OH 45229-3039 (e-mail: [email protected]). Am J Physiol Lung Cell Mol Physiol 294: L1032–L1034, 2008; doi:10.1152/ajplung.90273.2008.