Elevating adipose eosinophils in obese mice to physiologically normal levels does not rescue metabolic impairments.

Objective: Obesity is a metabolic disorder that has reached epidemic proportions worldwide and leads to increased risk for diabetes, cardiovascular disease, asthma, certain cancers, and various other diseases. Obesity and its comorbidities are associated with impaired adipose tissue (AT) function. In the last decade, eosinophils have been identified as regulators of proper AT function.

Fat-water MRI of a diet-induced obesity mouse model at 15.2T.

Quantitative fat-water MRI (FWMRI) methods provide valuable information about the distribution, volume, and composition of adipose tissue (AT). Ultra high field FWMRI of animal models may have the potential to provide insights into the progression of obesity and its comorbidities. Here, we present quantitative FWMRI with all known confounder corrections on a 15.

Loss of CCR5 results in glucose intolerance in diet-induced obese mice.

Macrophage and T cell infiltration into metabolic tissues contributes to obesity-associated inflammation and insulin resistance (IR). C-C chemokine receptor 5 (CCR5), expressed on macrophages and T cells, plays a critical role in the recruitment and activation of proinflammatory M1 and TH1 immune cells to tissues and is elevated in adipose tissue (AT) and liver of obese humans and mice. Thus, we hypothesized that deficiency of CCR5 would protect against diet-induced inflammation and IR.

Impact of macrophage inflammatory protein-1α deficiency on atherosclerotic lesion formation, hepatic steatosis, and adipose tissue expansion.

Macrophage inflammatory protein-1α (CCL3) plays a well-known role in infectious and viral diseases; however, its contribution to atherosclerotic lesion formation and lipid metabolism has not been determined. Low density lipoprotein receptor deficient (LDLR(-/-)) mice were transplanted with bone marrow from CCL3(-/-) or C57BL/6 wild type donors. After 6 and 12 weeks on western diet (WD), recipients of CCL3(-/-) marrow demonstrated lower plasma cholesterol and triglyceride concentrations compared to recipients of C57BL/6 marrow.

The role of macrophage leptin receptor in aortic root lesion formation.

Plasma leptin is often elevated in obese individuals, and previous studies have suggested leptin as a factor that links obesity and atherosclerosis. Because macrophages play a key role in atherogenesis and are responsive to leptin, we hypothesized that leptin increases aortic root lesion formation, in part, through macrophage leptin receptor (LepR). Three different bone marrow transplantation studies were conducted in which bone marrow, with or without LepR, was transplanted into lethally irradiated 1) LDL receptor-deficient (LDLR(-/-)) mice with moderate hyperleptinemia due to Western diet (WD) feeding, 2) LDLR(-/-) mice with WD feeding plus pharmacologically induced hyperleptinemia (daily injection of 125 microg leptin), or 3) obese, hyperleptinemic, LepR-deficient LDLR(-/-) (LepR(db/db);LDLR(-/-)) mice.

Macrophage-derived apolipoprotein E ameliorates dyslipidemia and atherosclerosis in obese apolipoprotein E-deficient mice.

Previous studies have demonstrated that macrophage-derived apolipoprotein E (apoE) reduces atherosclerotic lesion formation in lean apoE-deficient ((-/-)) mice. apoE has also been demonstrated to play a role in adipocyte differentiation and lipid accumulation. Because the prevalence of obesity has grown to epidemic proportions, we sought to determine whether macrophage-derived apoE could impact atherosclerotic lesion formation or adipose tissue expansion and inflammation in obese apoE(-/-) mice.

Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis.

The growing worldwide obesity epidemic is frequently linked to an increased risk of developing diseases such as diabetes, cardiovascular disease, and cancer. These diseases are associated with the infiltration of macrophages in white adipose tissue (WAT), the artery wall, and tumors, respectively; and these macrophages likely contribute to disease progression and pathogenesis. Abdominal WAT, adipose tissue surrounding the heart and artery wall, as well as carcinoma cells, secrete many factors that could induce macrophage infiltration.

Obesity causes very low density lipoprotein clearance defects in low-density lipoprotein receptor-deficient mice.

We have reported that obese leptin-deficient mice (ob/ob) lacking the low-density lipoprotein receptor (LDLR(-/-)) develop severe hyperlipidemia and spontaneous atherosclerosis. In the present study, we show that obese leptin receptor-deficient mice (db/db) lacking LDLR have a similar phenotype, even in the presence of elevated plasma leptin levels. We investigated the mechanism for the hyperlipidemia in obese LDLR(-/-) mice by comparing lipoprotein production and clearance rates in C57BL/6, ob/ob, LDLR(-/-) and ob/ob;LDLR(-/-) mice.

Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue.

Obesity, hyperlipidemia, and insulin resistance are cardinal features of the metabolic syndrome and individually increase the risk for developing diabetes and cardiovascular disease, a risk that is amplified when they are simultaneously present. It is becoming increasingly clear that macrophages can infiltrate white adipose tissue (WAT) in the obese state, and their presence is associated with pathophysiological consequences of obesity, such as inflammation and insulin resistance. To determine whether hyperlipidemia could potentiate macrophage infiltration into WAT in the presence of obesity, obesity-prone agouti yellow mice (A(y)/a) on a hyperlipidemia-prone LDL receptor (LDLR)-deficient (LDLR(-/-)) background were placed on chow or Western diet.

Effects of vitamin E on oxidative stress and atherosclerosis in an obese hyperlipidemic mouse model.

Vitamin E is a natural antioxidant that has been used in animal and human studies to determine its potential in reducing cardiovascular risk; however, a detailed study in an established obese model of atherosclerosis has yet to be performed. In our current study, we show that obesity and hyperlipidemia cause a synergistic, age-related increase in urinary isoprostane levels in mice deficient in both leptin and low-density lipoprotein receptor (ob/ob;LDLR-/-). Based upon this observation, we hypothesized that vitamin E supplementation would induce potent antiatherogenic effects in this model.

Plasma insulin levels predict atherosclerotic lesion burden in obese hyperlipidemic mice.

Despite a clear association between obesity, insulin resistance and atherosclerosis in humans, to date, no animal models have been described in which insulin resistance is associated with atherosclerotic lesion burden. Using two mouse models of obesity-induced hyperlipidemia:leptin deficient (ob/ob) mice on an apolipoprotein E deficient (apoE-/-) or low density lipoprotein receptor deficient (LDLR-/-) background, we sought to determine metabolic parameters most closely associated with atherosclerotic lesion burden. Total plasma cholesterol (TC) levels in ob/ob;apoE-/- mice and ob/ob;LDLR-/- mice were indistinguishable (682+/-48 versus 663+/-16, respectively).

Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I.

Obese mice without leptin (ob/ob) or the leptin receptor (db/db) have increased plasma HDL levels and accumulate a unique lipoprotein referred to as LDL/HDL1. To determine the role of apolipoprotein A-I (apoA-I) in the formation and accumulation of LDL/HDL1, both ob/ob and db/db mice were crossed onto an apoA-I-deficient (apoA-I(-/-)) background. Even though the obese apoA-I(-/-) mice had an expected dramatic decrease in HDL levels, the LDL/HDL1 particle persisted.