Short-term Caloric Restriction Attenuates Obesity-induced Proinflammatory Response in Male Rhesus Macaques

White adipose tissue (WAT) hypertrophy is an essential hallmark of obesity and is associated with activation of resident immune cells. While the benefits of caloric restriction (CR) on healthspan are generally accepted; its effects on WAT physiology are not well understood. We have 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 shows that WSD induced adipocyte hypertrophy and inhibited beta-adrenergic-simulated lipolysis. CR reversed adipocyte hypertrophy; but WAT remained insensitive to beta-adrenergic agonist stimulation. Whole-genome transcriptional analysis revealed that beta3-adrenergic receptor and de novo lipogenesis genes were downregulated by WSD and remained downregulated after CR. In contrast; WSD-induced proinflammatory gene expression was effectively reversed by CR. Furthermore; peripheral blood monocytes isolated during the CR period exhibited a significant reduction in the production of proinflammatory cytokines compared to those obtained after WSD. Collectively; this study demonstrates that short-term CR eliminates an obesity-induced proinflammatory response in WAT and peripheral monocytes. The sustained downregulation of the beta-adrenergic and de novo lipogenesis genes may explain why obese patients regain weight soon after the termination of dietary intervention.