Abstract
Inflammation and endoplasmic reticulum (ER) stress are hallmarks of metabolic syndrome. While these metabolic derangements have been well-investigated in white adipose tissue, their existence and etiology in brown adipose tissue (BAT) are poorly understood. Here, we aimed to investigate ER homeostasis and the inflammatory status and of BAT lacking uncoupling protein-1 (UCP1), a protein required for BAT thermogenesis. H&E staining illustrated lipid accumulation and crown-like structures surrounding adipocytes in BAT of UCP1-/- mice housed at room temperature compared to control mice. Further, immunohistological evaluation of F4/80 and gene expression studies demonstrated BAT macrophage infiltration and robust elevation of pro-inflammatory markers in UCP1-/- BAT. ER stress was also present in BAT of UCP1-/- mice, as evidenced by elevated gene expression and post-translational modifications of unfolded protein response components. After four weeks of thermoneutral housing, UCP1-/- mice did not exhibit elevated BAT inflammation and ER stress gene expression compared to WT mice, but depot expansion persisted. Collectively, we demonstrate that the effects of UCP1 deficiency in BAT are not restricted to mitochondrial uncoupling. We conclude that brown adipose tissue of UCP1-/- mice exhibits pro-inflammatory immune cell infiltration and perturbations in ER homeostasis and that this phenotype is driven by cold exposure rather than lipid accumulation.
Highlights
Inflammation and endoplasmic reticulum (ER) stress are implicated in numerous metabolic disorders, including obesity, Type I diabetes, and Type II diabetes [1, 2]
Mice lacking uncoupling protein-1 (UCP1) exhibited brown adipose tissue expansion compared to wildtype littermate controls (Fig 1C), and histological evaluation illustrated that UCP1-/- brown adipocytes contained larger lipid droplets compared to WT brown adipocytes (Fig 1D)
In addition to increased LD size, H&E staining revealed crownlike structures around UCP1-/- brown adipocytes, and we used F4/80 immunohistochemistry to confirm that the cells encapsulating UCP1-/- adipocytes were macrophages (Fig 1E)
Summary
Inflammation and endoplasmic reticulum (ER) stress are implicated in numerous metabolic disorders, including obesity, Type I diabetes, and Type II diabetes [1, 2]. WAT adipose tissue in obesity is characterized by chronic, low-grade inflammation, and the immune cell population is estimated to shift from 10% to 50% during obesification of WAT of mice [3] as proinflammatory macrophages and immune cells infiltrate the depot [2]. ER stress activates the unfolded protein response (UPR), a tripartite molecular system that aims to suspend broader protein synthesis and promote protein folding via protein chaperones. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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