A Paracrine Loop Between Adipocytes and Macrophages Aggravates Inflammatory Changes

Abstract

Objective-Weight gain is associated with infiltration of fat by macrophages, suggesting that they are an important source of inflammation in obese adipose tissue. Here we developed an in vitro coculture system composed of adipocytes and macrophages and examined the molecular mechanism whereby these cells communicate. Methods and Results-Coculture of differentiated 3T3-L1 adipocytes and macrophage cell line RAW264 results in the marked upregulation of proinflammatory cytokines, such as tumor necrosis factor ␣ (TNF-␣), and the downregulation of the antiinflammatory cytokine adiponectin. Such inflammatory changes are induced by the coculture without direct contact, suggesting the role of soluble factors. A neutralizing antibody to TNF-␣, which occurs mostly in macrophages, inhibits the inflammatory changes in 3T3-L1, suggesting that TNF-␣ is a major macrophage-derived mediator of inflammation in adipocytes. Conversely, free fatty acids (FFAs) may be important adipocyte-derived mediators of inflammation in macrophages, because the production of TNF-␣ in RAW264 is markedly increased by palmitate, a major FFA released from 3T3-L1. The inflammatory changes in the coculture are augmented by use of either hypertrophied 3T3-L1 or adipose stromal vascular fraction obtained from obese ob/ob mice. Key Words: macrophage Ⅲ adipocyte Ⅲ fatty acids Ⅲ TNF-␣ Ⅲ obesity T he metabolic syndrome is a constellation of visceral fat obesity, impaired glucose metabolism, atherogenic dyslipidemia, and blood pressure elevation, which all independently increase a risk of atherosclerotic diseases, such as ischemic heart disease and cerebral stroke. 1,2 The molecular basis for the clustering of such independent risks of atherosclerosis has not fully been elucidated, with visceral fat obesity considered most important. 3,4 Systemic insulin resistance has been implicated as one possible factor that links visceral fat obesity and the adverse metabolic consequences. 4,5 Evidence has accumulated indicating that obesity is associated with a state of chronic, low-grade inflammation, suggesting that inflammation may be a potential mechanism whereby obesity leads to insulin resistance. 5,6 Indeed, obesity and insulin resistance are strongly associated with systemic markers of inflammation, and, clinically, inflammation has been recognized as a major predictor of atherosclerotic disease. [5][6][7] Conclusions-We See coverThe adipose tissue is an important endocrine organ that secretes many biologically active substances, such as leptin, adiponectin, tumor necrosis factor ␣ (TNF-␣), and monocyte chemoattractant protein 1 (MCP-1), which are collectively termed adipocytokines. 4,8 -10 Dysregulated production of proinflammatory and antiinflammatory adipocytokines seen in visceral fat obesity is associated with the metabolic syndrome, 4,6 suggesting that inflammatory changes within the adipose tissue may critically contribute to the development of many aspects of the metabolic syndrome and results in diabetes and atherosclerosis. For example, it has bee...

Neel revisited: the adipocyte, seasonality and type 2 diabetes

“…Recent studies support the view that a 'paracrine loop' exists between the adipocyte and macrophages to enhance inflammatory responses. This seems to be driven from the macrophage by TNF-α and from the adipocyte by increased NEFA [16]. TNF-α also enhances the production of PAI-1 from the adipocyte and other cell lines [17].…”

Increased Epicardial, Pericardial, and Subcutaneous Adipose Tissue Is Associated with the Presence and Severity of Coronary Artery Calcium

“…In fact, EAT and PAT are associated with multiple markers of inflammation, vascular dysfunction, and oxidative stress, including C-reactive protein, fibrinogen, intracellular adhesion molecule-1, interleukin-6, MCP-1, P-selectin, tumor necrosis factor receptor-2, and urinary isoprostanes, vascular endothelial growth factor, and plasminogen activator inhibitor-1 (23)(24)(25). Increased levels of the chemokine MCP-1 in visceral adipose tissue attract more monocytes and macrophages, inducing a self-sustaining inflammatory cycle (26,27).…”

Lipodystrophy in HIV 1-infected patients: lessons for obesity research

“…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. 112 As recently reviewed, excess lipolysis and increased levels of circulating FFAs are commonly observed in obesity. 113 This abnormality is considered to be the cause of at least some of the metabolic defects (dyslipidemia, insulin resistance) associated with obesity, and high FFA levels are involved in multiple metabolic alterations, from impaired insulin action in muscle to lipotoxicity in pancreatic b-cells.…”