Background: Overexpression of adiponectin receptor 1 in macrophages can physiologically modulate metabolic activities in vivo by enhancing adiponectin actions in distal metabolically active tissues. To investigate the effects of enhanced adiponectin actions in TALLYHO (TH) diabetic mouse model, we crossed the adiponectin receptor 1 macrophage-specific transgenic mice (AdR1-TG) with the TALLYHO diabetic mice (TH) to examine the changes of lipid accumulation and insulin sensitivity in these mice. Methods: AdR1-TG/TH and the control WT/TH mice were fed either normal diet or high fat diet for 28. weeks. Whole body weights of these mice were measured and mouse sera were analyzed for the levels of cholesterol, triglyceride, and free fatty acids. Glucose tolerance testing (GTT) and insulin tolerance testing (ITT) in these mice were performed to investigate systemic insulin sensitivity in vivo. Molecular markers for insulin signaling pathway in mouse skeletal muscle tissues, IRS-1 and AKT, were examined. Mouse serum insulin levels were measured and Sirt1 gene expression in mouse pancreatic tissues was also quantified related to the insulin secretion. The Caspase 3 protein levels were analyzed by Western blot methods. Results: Compared to the control WT/TH mice, AdR1-TG/TH mice showed significantly lower body weights under either normal diet or high fat diet and the mouse serum levels of cholesterol, triglyceride and free fatty acids were significantly decreased in the transgenic crossed mice when compared to those from the control mice. Improved GTT and ITT tests indicating increased systemic insulin sensitivity in the transgenic crossed mice demonstrated the enhanced adiponectin actions on the systemic metabolism in vivo. The increases of insulin secretion and its related gene expression were also detected in the transgenic crossed mice. In contrast, the control mice showed hypertrophy pancreases companying with high apoptosis gene expression. These results suggest that enhanced adiponectin actions by overexpressing adiponectin receptor 1 in macrophages can provide unique interactions with the metabolic tissues/cells, improving lipid accumulation and insulin sensitivity in TALLYHO diabetic mice. © 2013 Elsevier Inc.