Insulin Resistance and Obesity in a Mouse Model of Systemic Lupus Erythematosus

Abstract

Abstract-Accumulating data indicate that metabolic syndrome is an inflammatory condition. Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with nephritis and cardiovascular disease. Evidence suggests that individuals with SLE are at risk for developing insulin resistance; however, this has not been directly examined. Using an established mouse strain with SLE (NZBWF1), we examined whether SLE is associated with increased body weight and fat deposition. Mean arterial pressure was significantly increased (140Ϯ4 versus 114Ϯ2 mm Hg; nՆ5) in SLE mice by 36 weeks of age compared with control mice (NZW/LacJ). Body weight in SLE mice was higher at each age compared with controls by 12%, 22%, and 34% (nϾ30). Visceral adipose tissue weight was increased in SLE by 44%, 74%, and 117% at 8, 20, and 36 weeks, respectively (nՆ12 etabolic syndrome can be characterized by a group of metabolic risk factors that includes central obesity, insulin resistance, dyslipidemia, increased blood pressure, and endothelial dysfunction. 1 Individuals with metabolic syndrome are at a markedly increased risk for developing hypertension and renal disease. Recent evidence indicates that inflammatory cytokines are elevated in patients with metabolic syndrome, 2-4 thus suggesting a role for chronic inflammation as an underlying mechanism for progression of this disease.Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that predominantly affects women during their reproductive years. The presence of autoantibodies (typically antinuclear antibodies) is used diagnostically, and although SLE can influence many organ systems, the skin, joints, and kidneys are typically affected. Like metabolic syndrome, a large percentage of individuals with SLE are hypertensive. Evidence suggests that individuals with SLE are also at increased risk for developing insulin resistance 5 and changes in body mass composition 6 ; however, this has not been adequately examined.The purpose of the present study was to test whether the progression of SLE is associated with changes in body composition, insulin sensitivity, and other characteristics of the metabolic syndrome. To examine this, we used a genetic mouse model of SLE (NZBWF1) that exhibits many features of human SLE, including a complex genetic origin, a bias for the female sex, immune complex glomerulonephritis, and the presence of antinuclear antibodies. We reported recently that these mice have hypertension and impaired endothelialdependent relaxation. 7 The results of the present study show that NZBWF1 mice also have several other characteristics of the metabolic syndrome that may contribute to the hypertension, including central obesity, insulin resistance, and hyperleptinemia. These data show that the NZBWF1 strain may be an important model to study the effects of obesity and insulin resistance on SLE-associated hypertension. Methods AnimalsFemale NZBWF1 (SLE) and NZW/LacJ (control) obtained from Jackson Laboratories (Bar Harbor, ME) were maintained on a 12-hour light/d...

Rosiglitazone decreases blood pressure and renal injury in a female mouse model of systemic lupus erythematosus

“…This age was selected because NZBWF1 mice typically begin to develop signs of proteinuria after this time. Consistent with our previous study (46), food intake was not different between SLE and control mice. The targeted dose of rosiglitazone was 5 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 .…”

“…At the end of the experimental protocol, glucose was measured in blood (100 -200 l) obtained by retro-orbital puncture using the Accu-Chek Advantage glucometer (Roche), as previously described (46). Remaining blood samples were centrifuged, and plasma samples were used to measure insulin as previously described (46) and triglycerides using a commercially available kit (Pointe Scientific, Canton, MI). Data are expressed as follows: glucose (mg/dl), insulin (ng/ml), and triglycerides (mg/dl).…”

“…Mean arterial pressure (MAP) was recorded using indwelling carotid artery catheters in conscious mice at the end of the 4-wk treatment period, as previously described in our laboratory (46). Data are presented as the mean pressure measured over two consecutive days.…”

Mouse models of the metabolic syndrome

“…These mice have age-onset obesity, increased visceral adiposity, increased plasma leptin concentrations, altered glucose tolerance and hypertension, suggesting that they are also a model of MetS with hypertension (Ryan et al, 2006). Interestingly, treatment of the NZBWF1 mice with a thiazolidinedione (TZD) reduced blood pressure, however it did not alter insulin sensitivity (Venegas-Pont et al, 2009).…”

Leptin resistance contributes to obesity and hypertension in mouse models of Bardet-Biedl syndrome

“…Hyperleptinemia is usually considered to reflect a state of leptin resistance, which often predicts a loss of metabolic responsiveness to leptin (33). However, emerging evidence indicates that obesity can develop independently from defects in leptin action (36,37). For instance, mice null for neuromedin U are obese and hyperleptinemic, but have a preserved metabolic response to the exogenous administration of leptin (37).…”