Abstract
White adipose tissue (WAT) hypertrophy is an essential hallmark of obesity and is associated with the activation of resident immune cells. While the benefits of caloric restriction (CR) on health span are generally accepted, its effects on WAT physiology are not well understood. We previously demonstrated that short-term CR reverses obesity in male rhesus macaques exposed to a high-fat Western-style diet (WSD). Here, we analyzed subcutaneous WAT biopsies collected from this cohort of animals before and after WSD and following CR. This analysis showed that WSD induced adipocyte hypertrophy and inhibited β-adrenergic-simulated lipolysis. CR reversed adipocyte hypertrophy, but WAT remained insensitive to β-adrenergic agonist stimulation. Whole-genome transcriptional analysis revealed that β3-adrenergic receptor and de novo lipogenesis genes were downregulated by WSD and remained downregulated after CR. In contrast, WSD-induced pro-inflammatory gene expression was effectively reversed by CR. Furthermore, peripheral blood monocytes isolated during the CR period exhibited a significant reduction in the production of pro-inflammatory cytokines compared to those obtained after WSD. Collectively, this study demonstrates that short-term CR eliminates an obesity-induced pro-inflammatory response in WAT and peripheral monocytes.
Highlights
Consumption of a high-fat/calorie-dense Western-style diet (WSD) and physical inactivity are the main risk factors contributing to obesity characterized by a chronic low-grade pro-inflammatory state and insulin resistance [1]
WSD-Induced Adipocyte Hypertrophy but not β-Adrenergic Resistance is Reversed by caloric restriction (CR)
We demonstrated that adult male rhesus macaques exposed to six months of WSD exhibited a significant increase in fat mass
Summary
Consumption of a high-fat/calorie-dense Western-style diet (WSD) and physical inactivity are the main risk factors contributing to obesity characterized by a chronic low-grade pro-inflammatory state and insulin resistance [1]. CR decreases the risk of cardiovascular and metabolic diseases [5,6,7,8,9] and reduces obesity in older adults [10]. CR has been shown to decrease body weight and adiposity in postmenopausal women [11,12,13]. A significant fraction of these women regained weight soon after the termination of dietary intervention [14]. We have shown that long-term CR initiated during early adulthood delayed T-cell senescence [15,16]. CR initiated during early adulthood preserved circulating naïve CD8 and CD4 T-cells, maintained T-cell receptor diversity, and reduced T-cell production of pro-inflammatory cytokines
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