The Role of Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance
Nance, Sierra
2023
Abstract
While epidemiologic studies show strong correlations between obesity and Type 2 Diabetes (DM), there is substantial variation in measures of metabolic disease in people with obesity. Two phenotypes that have been described are 1) metabolically unhealthy obesity (MUO) and 2) metabolically healthy obesity (MHO). Individuals with MHO often have more subcutaneous adipose tissue (SAT) than visceral adipose tissue (VAT), normal insulin resistance, and adiponectin levels comparable to their non-obese lean counterparts, protecting against metabolic diseases. The MUO phenotype is described as having more VAT than SAT and increased inflammation increasing the risk for obesity-associated DM. Adipose tissue macrophages (ATMs) are a primary mediator of inflammation in adipose tissue. In the obese state, inflammatory CD11c+ ATMs predominate, secreting pro-inflammatory cytokines that contribute to systemic insulin resistance. This dissertation aims to elucidate the role of ATMs in metabolic diseases and elucidate pathways that link obesity and DM by investigating two potential modulators of obesity-induced inflammation expressed in ATMs: macrophage scavenger receptor 1 (MSR1) and C-C motif chemokine ligand 18 (CCL18). Both genes were found to have higher expression in adipose tissue from obese DM individuals compared to non-DM individuals, but their potential contributions to insulin resistance are incompletely understood. In our first study, RNA sequencing of human adipose tissue (AT) from obese subjects demonstrated that MSR1 expression is macrophage-specific and is increased in VAT from obese individuals with DM compared to their obese, non-DM controls. Experiments in Msr1-/- and wild-type non-littermates suggested that Msr1-/- mice are protected from high-fat diet (HFD)-induced obesity. However, Msr1-/- mice were not protected from HFD-induced obesity, impaired glucose metabolism, or ATM accumulation when compared to Msr1+/- littermate controls suggesting that Msr1 is not required for obesity-associated inflammation and insulin resistance in mice. In our second study, single nuclear sequencing of obese human AT showed that CCL18 is expressed in the lipid-associated macrophage (LAM) ATM subset. To elucidate the role of CCL18 in AT, human mature adipocytes from obese subjects were treated with or without CCL18 and we observed that CCL18 suppresses immune pathway genes. Experiments in C57BL6 mice treated ± CCL18 revealed that CCL18 does not impair glucose tolerance or alter leukocyte content with short-term HFD. However, in a chronic model of HFD feeding for 6 weeks, CCL18 suppressed CD11c+ ATM accumulation in epididymal white adipose tissue (eWAT). The accumulation of CD11c+ ATMs was not related to changes in proliferation rates. CCL18 treatment of obese human AT or HUVECs did not alter angiogenesis. Overall, this work demonstrated that while Msr1 is not required for obesity-associated insulin resistance, CCL18 may have a protective role in obese adipose tissue by suppressing interleukin signaling and inflammatory ATM accumulation.Deep Blue DOI
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adipose tissue macrophage obesity insulin resistance
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