Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages

Abstract

Obesity-related changes in adipose tissue leukocytes, in particular adipose tissue macrophages (ATMs) and dendritic cells (ATDCs), are implicated in metabolic inflammation, insulin resistance, and altered regulation of adipocyte function. We evaluated stromal cell and white adipose tissue (WAT) expansion dynamics with high fat diet (HFD) feeding for 3-56 days, quantifying ATMs, ATDCs, endothelial cells (ECs), and preadipocytes (PAs) in visceral epididymal WAT and subcutaneous inguinal WAT. To better understand mechanisms of the early response to obesity, we evaluated ATM proliferation and lipid accumulation. ATMs, ATDCs, and ECs increased with rapid WAT expansion, with ATMs derived primarily from a CCR2-independent resident population. WAT expansion stimulated proliferation in resident ATMs and ECs, but not CD11c ATMs or ATDCs. ATM proliferation was unperturbed in Csf2- and Rag1-deficient mice with WAT expansion. Additionally, ATM apoptosis decreased with WAT expansion, and proliferation and apoptosis reverted to baseline with weight loss. Adipocytes reached maximal hypertrophy at 28 days of HFD, coinciding with a plateau in resident ATM accumulation and the appearance of lipid-laden CD11c ATMs in visceral epididymal WAT. ATM increases were proportional to tissue expansion and adipocyte hypertrophy, supporting adipocyte-mediated regulation of resident ATMs. The appearance of lipid-laden CD11c ATMs at peak adipocyte size supports a role in responding to ectopic lipid accumulation within adipose tissue. In contrast, ATDCs increase independently of proliferation and may be derived from circulating precursors. These changes precede and establish the setting in which large-scale adipose tissue infiltration of CD11c ATMs, inflammation, and adipose tissue dysfunction contributes to insulin resistance.

Contributions of innate type 2 inflammation to adipose function

“…MAC-1, F4/80, CD68) in WAT [23]. Mechanisms by which macrophages accumulate in WAT in the chronic setting of obesity include recruitment, retention [35] proliferation [36,37], and reduced apoptotic turnover [38,39] pro-inflammatory signaling in WAT has been shown to be an adaptive response that enables proper storage of excess energy [40]. This vast literature is nicely covered in a recent review written by Engleman and colleagues [41].…”

Adipose tissue's rapid response team

“…Virtually all studies that led the macrophage recruitment hypothesis used obesity‐prone male C57BL/6 mice fed a very high fat diet (HFD; usually 60% fat calories) for a prolonged period, at least 3 months, to induce obesity. However, analysis of the established obese state cannot reflect the dynamics of its development and hence its etiology, as Muir et al . have accomplished in this issue of the journal.…”

“…Muir et al . performed careful time course experiments and show that during the initial stages of overnutrition, within 3 days of exposure to an obesifying HFD and prior to any increase in body weight, body fat depots have already expanded (∼2×) by adipocyte hypertrophy and there is a twofold increase in the number of ATMs as well adipose tissue dendritic cells (ATDC) per depot in both epididymal adipose tissue (eWAT) and inguinal subcutaneous (iWAT).…”

“…Knowledge of how chronic nutrient excess or deficiency, or other environmental challenges, diverts this adaptive remodeling and repair process into a pathological one are clearly needed. Muir et al provide critical groundwork for needed advancements in our understanding of metabolic inflammation in obesity.…”

Metabolic regulation of NK cells in blood cancers: Lipid-rich environment in blood cancers is associated with metabolic and functional changes of NK cells

“…In addition, mitochondrial dysfunction caused by excessive FA levels leads to increased lipid droplet levels by promoting FA synthesis over catabolism (Boren andBrindle, 2012) (Di Meo et al, 2017;Hirabara et al, 2010;Kwon et al, 2014). Immune cells, such as macrophages, also display intracellular lipid accumulation in response to high fat feeding (Muir et al, 2018). Similarly, effector T cells increase neutral lipid levels in response to FA treatments (O'Sullivan et al, 2014).…”