Angiopoietin-like Protein 2 Promotes Chronic Adipose Tissue Inflammation and Obesity-Related Systemic Insulin Resistance

Abstract

Recent studies of obesity have provided new insights into the mechanisms underlying insulin resistance and metabolic dysregulation. Numerous efforts have been made to identify key regulators of obesity-linked adipose tissue inflammation and insulin resistance. We found that angiopoietin-like protein 2 (Angptl2) was secreted by adipose tissue and that its circulating level was closely related to adiposity, systemic insulin resistance, and inflammation in both mice and humans. Angptl2 activated an inflammatory cascade in endothelial cells via integrin signaling and induced chemotaxis of monocytes/macrophages. Constitutive Angptl2 activation in vivo induced inflammation of the vasculature characterized by abundant attachment of leukocytes to the vessel walls and increased permeability. Angptl2 deletion ameliorated adipose tissue inflammation and systemic insulin resistance in diet-induced obese mice. Conversely, Angptl2 overexpression in adipose tissue caused local inflammation and systemic insulin resistance in nonobese mice. Thus, Angptl2 is a key adipocyte-derived inflammatory mediator that links obesity to systemic insulin resistance.

Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress

“…Since then, epidemiologic studies have confirmed the idea that chronic inflammation underlies many cancers (2). Recently, we reported that Angiopoietin-like protein 2 (Angptl2) acts as a chronic inflammatory mediator in several pathologic settings (3)(4)(5)(6), and demonstrated that increased Angptl2 expression in skin tissues promotes inflammation and accelerates carcinogenesis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model by increasing susceptibility to "preneoplastic change" and "malignant conversion" (7). In normal cells, initiating oncogenic mutation is considered essential to promote a "preneoplastic change," which, if unrepaired, is then followed by proliferation and acquisition of cellular survival capacity, allowing accumulation of additional mutations (8)(9)(10).…”

Postnatal exposure to voluntary exercise but not the antioxidant catechin protects the vasculature after a switch to an atherogenic environment in middle-age mice

“…In addition, we reported that 9 months of CAT magnified 50-folds the rise in COX2 expression associated with aging in the mouse aorta [26]. Angptl2, on the other hand, is associated with inflammation as its presence is increased in patients with rheumatoid arthritis and abdominal aortic aneurysm [47,69], while its deletion can lower pro-inflammatory cytokines in rodents [67,69]. Hence, our results suggest that early CAT treatment induces a pro-inflammatory environment upon the challenge of a WD: we propose that CAT limited the development of antioxidant defense mechanisms able to counteract the stress induced by the WD.…”

Nifedipine increases energy expenditure by increasing PGC-1α expression in skeletal muscle

“…Insulin and glucose tolerance tests (ITT and GTT, respectively) were performed as previously described. 18 For ITT, mice were administered 1.0 U kg À1 of human insulin by intraperitoneal injection. For GTT, mice were deprived of food for 16 h and were injected with glucose intraperitoneally at 1.25 g kg À1 .…”

“…Mouse adiposity was assessed by computed tomography scanning (LaTheta, Hitachi, Aloka Medical, Ltd, Tokyo, Japan) as previously described. 18 Blood pressure was monitored every 4 weeks using a tail-cuff monitor (BP Monitor for Mice & Rats Model MK-2000, Muromachi Co., Ltd, Tokyo, Japan). Oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), the respiratory exchange ratio (RER) and activity levels were determined (Light time; 13:00-17:00, Dark time; 1:00-5:00, air flow rate 0.50 l min À1 ) as previously described.…”

“…Oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), the respiratory exchange ratio (RER) and activity levels were determined (Light time; 13:00-17:00, Dark time; 1:00-5:00, air flow rate 0.50 l min À1 ) as previously described. 18 For exercise experiments, mice were allowed to adapt to an air-tight treadmill chamber (Model MK-680AT/02 M, Muromachi Co., Ltd) for 30 min (air flow rate 0.90 l min À1 ) at which point VO 2 and VCO 2 were stable; measurements were then continued for another 30 min while mice were in a sedentary state. Mice then exercised on a treadmill at a speed of 10 m min À1 , and VO 2 , VCO 2 and RER were measured for 30 min as previously described.…”