Dietary blueberry attenuates whole-body insulin resistance in high fat-fed mice by reducing adipocyte death and its inflammatory sequelae

Abstract

Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMPhi). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMPhi (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMPhi gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-kappaB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology.

Figures

FIGURE 1

Body weight of mice fed the LFD, HFD, or HFD+B for 8 wk. Values are means ± SEM, n = 8. Means at wk 8 without a common letter differ, P < 0.05.

FIGURE 2

ITT in mice fed the LFD, HFD, or HFD+B for 8 wk. Data represent the clearance of blood glucose in response to an insulin bolus in food-deprived mice. Glucose values at 30, 45, 60, and 90 min after intraperitoneal insulin injection were expressed for each mouse as a proportion of the value at baseline (100%). Values are means ± SEM, n = 8. ITT [AUC] for lines without a common letter differ, P < 0.05.

FIGURE 3

Frequency of dead adipocytes in mice fed the LFD (A), HFD (B), or HFD+B (C) for 8 wk. Representative hematoxylin- and eosin-stained histological sections of eAT from mice are shown. Dead adipocytes are indicated by CLS of ATMΦ surrounding remnant lipid droplets (arrows). Scale bar = 200 μm.