Fatty Acid and NOD1-mediated Macrophage Polarization: Implications for Metabolic Inflammation and Insulin Resistance
Year: 2017
Type: dissertation
Abstract: Insulin resistance is a major contributor to the pathogenesis of obesity-linked type 2 diabetes (T2D). Over the last 15 years, T2D has become increasingly recognized as a chronic inflammatory disease, with immune cells, most notably macrophages, representing an important link between lipid intake and insulin resistance. During high fat diets (HFD), macrophages infiltrate tissues that regulate glucose metabolism, including adipose tissue, liver, and skeletal muscle. Concomitantly, HFD disrupts the intestinal barrier, permitting translocation of gut bacterial compounds into circulation. It has been hypothesized that these compounds, along with certain lipids, activate macrophages to a pro-inflammatory polarized phenotype, resulting in production of pro-inflammatory cytokines that directly interfere with insulin signalling in parenchymal cells of metabolism-defining tissues. However, the identity of the lipids and gut-derived factors that influence macrophage polarization, along with the underlying mechanisms, remain to be elucidated. In contrast to saturated fats, consumption of certain unsaturated fatty acids has beneficial effects on glucose homeostasis. Using isolated bone marrow-derived macrophages cultured ex vivo, we find that the monounsaturated fatty acid cis-palmitoleate promotes anti-inflammatory macrophage polarization. Specifically, cis-palmitoleate counteracts pro-inflammatory polarization induced by long-term HFD in vivo or by acute exposure to the saturated fatty acid palmitate in vitro. Further, we show that these anti-inflammatory effects are partially mediated by AMPK. When characterizing other diet-linked factors with immunoregulatory activity, we identify that activators of NOD1, a receptor for bacterial peptidoglycan, increase in circulation of HFD-fed mice. Moreover depleting NOD1 specifically in hematopoietic cells limits pro-inflammatory macrophage polarization within adipose tissue, and simultaneously improves whole-body insulin responsiveness without affecting body weight or adiposity. Collectively, our findings highlight that specific fatty acids and innate immune receptors have critical involvement in macrophage polarization under obesogenic conditions. These results suggest that cell-targeted anti-inflammatory strategies may have therapeutic promise in the alleviation of insulin resistance preceding T2D.
Source: TSpace (University of Toronto)
Author: Kenny L. Chan
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2789247778