resolvin-d1 and Insulin-Resistance

Insulin resistance and nonalcoholic steatohepatitis (NASH), characterized by hepatic steatosis combined with inflammation, are major sequelae of obesity. Currently, lifestyle modification (i.e., weight loss) is the first-line therapy for NASH. However, weight loss resolves steatosis but not inflammation. In this study, we tested the ability of resolvin D1 (RvD1), an anti-inflammatory and proresolving molecule, to promote the resolution initiated by calorie restriction in obese mice with NASH. Calorie restriction reduced adipose and liver weight (-56 and -13%, respectively; P<0.001), serum leptin and resistin levels, hepatic steatosis, and insulin resistance. In addition to these, mice receiving RvD1 during the dietary intervention showed increased adiponectin expression at both the mRNA and protein levels and reduced liver macrophage infiltration (-15%, P<0.01). Moreover, RvD1 skewed macrophages from an M1- to an M2-like anti-inflammatory phenotype, induced a specific hepatic miRNA signature (i.e., miR-219-5p and miR-199a-5p), and reduced inflammatory adipokine mRNA and protein expression and macrophage innate immune response. In precision-cut liver slices (PCLSs), which override the influence of circulating factors, RvD1 attenuated hypoxia-induced mRNA and protein expression of COX-2, IL-1β, IL-6, and CCR7. Of note, RvD1 anti-inflammatory actions were absent in macrophage-depleted PCLSs. In summary, RvD1 acts as a facilitator of the hepatic resolution process by reducing the inflammatory component of obesity-induced NASH.

Topics: Animals; Blotting, Western; Caloric Restriction; Docosahexaenoic Acids; Fatty Liver; Immunoenzyme Techniques; Immunohistochemistry; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; MicroRNAs; NF-kappa B; Obesity; Real-Time Polymerase Chain Reaction

Type 2 diabetes and obesity have emerged as global public health crises. Adipose tissue expansion in obesity promotes accumulation of classically activated macrophages that perpetuate chronic inflammation and sustain insulin resistance. Acute inflammation normally resolves in an actively orchestrated series of molecular and cellular events that ensures return to homeostasis after an inflammatory insult, a process regulated in part by endogenous lipid mediators such as the resolvins. In this study, we sought to determine whether stimulating resolution with resolvin D1 (RvD1) improves insulin sensitivity by resolving chronic inflammation associated with obesity. In male leptin receptor-deficient (db/db) mice, treatment with RvD1 (2 μg/kg) improved glucose tolerance, decreased fasting blood glucose, and increased insulin-stimulated Akt phosphorylation in adipose tissue relative to vehicle-treated mice. Treatment with RvD1 increased adiponectin production, while expression of IL-6 in adipose tissue was decreased. The formation of crown-like structures rich in inflammatory F4/80(+)CD11c(+) macrophages was reduced by >50% in adipose tissue by RvD1 and was associated with an increased percentage of F4/80(+) cells expressing macrophage galactose-type C-type lectin 1 (MGL-1), a marker of alternatively activated macrophages. These results suggest that stimulating resolution with the endogenous proresolving mediator RvD1 could provide a novel therapeutic strategy for treating obesity-induced diabetes.

Topics: Adiponectin; Adipose Tissue; Animals; Blood Glucose; Cytokines; Diabetes Mellitus, Type 2; Docosahexaenoic Acids; Glucose Tolerance Test; Hypoglycemic Agents; Immunoblotting; Inflammation Mediators; Insulin; Insulin Resistance; Macrophages; Male; Mice; Mice, Knockout; Obesity; Phosphorylation; PPAR gamma; Proto-Oncogene Proteins c-akt; Receptors, Formyl Peptide; Reverse Transcriptase Polymerase Chain Reaction