Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice

Abstract

Immune components can bridge inflammatory triggers to metabolic dysfunction. Scavenger receptors sense lipoproteins, but it is not clear how different scavenger receptors alter carbohydrate metabolism during obesity. Macrophage scavenger receptor 1 (MSR1) and macrophage receptor with collagenous structure (MARCO) are scavenger receptors that have been implicated in lipoprotein metabolism and cardiovascular disease. We assessed glucose control, tissue‐specific insulin sensitivity, and inflammation in Msr1‐ and Marco‐deficient mice fed with obesogenic diets. Compared to wild‐type (WT) mice, Msr1 −/− mice had worse blood glucose control that was only revealed after diet‐induced obesity, not in lean mice. Obese Msr1 −/− mice had worse insulin‐stimulated glucose uptake in the adipose tissue, which occurred in the absence of overt differences in adipose inflammation compared to obese WT mice. Msr1 deletion worsened dysglycemia independently from bacterial cell wall insulin sensitizers, such as muramyl dipeptide. MARCO was dispensable for glycemic control in obese mice. Oral administration of the polysaccharide fucoidan worsened glucose control in obese WT mice, but fucoidan had no effect on glycemia in obese Msr1 −/− mice. Therefore, MSR1 is a scavenger receptor responsible for changes in glucose control in response to the environmental ligand fucoidan. Given the interest in dietary supplements and natural products reducing inflammation or insulin resistance in metabolic disease during obesity, our results highlight the importance of understanding which ligand–receptor relationships promote versus those that protect against metabolic disease factors. Our results show that ligand or gene targeting of MSR1 exacerbates insulin resistance in obese mice.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to High Fructose Consumption in Mice

“…In contrast to B6, fructose responsive microbiota in DBA was more associated with lipid and inflammatory genes in the adipose tissue (Table 2, Supplementary table 1). Abhd3 is a crucial factor for insulin resistance in adipose tissue (43); Sema3e contributes to inflammation and insulin resistance in obese mice (44); Msr1 is macrophage scavenger receptor 1, provides a protection from excessive insulin resistance in obese mice (45); Creb promotes expression of transcriptional factors of adipogenesis and insulin resistance in obesity (46); Fas contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity (47).…”

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice

“…In contrast to B6 mice, fructose-responsive microbiota in DBA mice were associated with lipid and inflammatory genes in the adipose tissue (Table 2; Supplemental Table 2). Abhd3 is a crucial factor for insulin resistance in adipose tissue (47); Sema3e contributes to inflammation and insulin resistance in obese mice (48); Msr1 is macrophage scavenger receptor 1 and provides protection from excessive insulin resistance in obese mice (49); Creb1 promotes expression of transcriptional factors of adipogenesis and insulin resistance in obesity (50); Fas contributes to adipose tissue inflammation, hepatic steatosis, and insulin resistance induced by obesity (51).…”

Adipose Tissue Inflammation Is Directly Linked to Obesity-Induced Insulin Resistance, while Gut Dysbiosis and Mitochondrial Dysfunction Are Not Required

“…Total RNA was obtained from frozen WAT as previously described. 31 Transcript expression was measured using TaqMan Assays with AmpliTaq Gold DNA polymerase (Thermo Fisher Scientific) in a Rotor-Gene Q real-time polymerase chain reaction (PCR) cycler (Qiagen). Target genes ( Tnf, Ccl2, Cxcl1, Cxcl9, Cxcl10, Il1b, Il4, Il10, Emr1, Ccr7, Cd4, Cb8, and Cd11b ) were compared to the Rplp0 housekeeping gene using the ΔΔC T method as previously described.…”