Interestingly our transgenic mouse model with macrophages ex

Interestingly, our transgenic mouse model with macrophages expressing AdipoR1 showed not only improved insulin sensitivity and inflammation in skeletal muscle and adipose tissues, but fat mass, macrophage and plasma lipid accumulation and foam cell formation was also favorably reduced resulting from the enhanced adiponectin actions either in mouse macrophage Cell Counting Kit-8 or mouse metabolically active tissues. Thus, using macrophages as the carriers for in vivo enhanced actions of adiponectin, which is an anti-diabetic, anti-inflammatory and anti-atherogenic cytokine, may provide a novel, unique strategy (Fig. 8) to develop a new therapeutic application for the treatment of human Metabolic Syndrome or metabolic disorders. The molecular basis of the cell/tissue interactions among AdipoR1 overexpressed macrophages and other metabolically active tissues is still not fully understood. It is not clear how the macrophage AdipoR1 overexpression directly influences productions of proinflammatory cytokines in macrophages, adipose, skeletal muscle, and liver tissues; though these tissues have the similar expression levels of cytokines and macrophage markers with those in the AdipoR1 modified macrophages (data not shown). It is not clear if these favorable changes result from the secretion of other anti-inflammatory molecules from these adiponectin receptor modified macrophages or if the reduced lipid accumulation and inflammatory response in these macrophages results in reduced negative impact when these macrophages reside in other tissues or circulate inside other tissues via circulation system. Clearly, additional studies are required and the potential for other cellular or molecular physiological effects among these metabolically active tissues should be further pursed in the future. Our macrophage AdipoR1 transgenic mouse model provides an excellent research system for investigating and evaluating the potential role of these physiological mechanisms in vivo. Our current results from these unique mouse models also provide new insight into the prevention and therapy of metabolic disorders in humans.
Conflict of interest
Acknowledgments We thank Dr. Chris Glass (University of California at San Diego) for kindly providing the plasmid vector containing the human scavenger receptor A-I gene (SR-AI) enhancer/promoter. We are grateful to the UAB Diabetes Research and Training Center for providing outstanding core services (NIH P30 DK-56336); especially the helpful technical assistance on en face artery dissections from Ms. Melissa Sammy and Dr. Scott Ballinger in the core facility. This work was supported by grants from American Diabetes Association (1-07-RA-49) and the UAB Diabetes Research and Training Center to YF, and grant from NIH (DK-083562) to TG.
Introduction Adiponectin [1–4] is an adipokine with antidiabetic and antiatherogenic effects. Adiponectin decreases insulin resistance and type 2 diabetes caused by obesity, supports fatty acid utilization, reduces the triglyceride content in cells and exhibits an anti-inflammatory effect [5–7]. Several transcriptional regulators, such as the peroxisome proliferator-activated receptors (PPARs) [8], peroxisome proliferator-activated receptor coactivator 1 (PGC-1) [9], adenosine monophosphate-activated protein kinase (AMPK) [10], and consecutive pathways, are activated by adiponectin [11]. The physiological effects of these transcriptional regulators include increased mitochondrial biogenesis and oxidative metabolism in muscle cells, which induces a pseudo-exercise effect. Pharmaceuticals with pseudo-exercise effects are known as endurance exercise mimetics [12]. Adiponectin has binding affinities to at least two known receptors: adiponectin receptor 1 and 2 (adipoR1, adipoR2) [13]. Two synthetic adiponectin receptor agonists, AdipoRon and 112254, have been identified by others [14]. AdipoRon, the more potent agonist of the two, increases phosphorylation of AMPK, the expression of PGC-1α and, subsequently, mitochondrial DNA content in vitro. Oral administration of AdipoRon, has been shown to improve health and lifespan in vivo and is a potential pharmaceutical for treating obesity-related disorders, such as type 2 diabetes [14]. Moreover, AdipoRon has proven to be a vasodilator in a more effective manner than adiponectin [15]. Treatment of reperfusion injuries with AdipoRon improves cardiac functional recovery after myocardial apoptosis [16] and, like adiponectin, has a hepatoprotective effect [17]. Taken together, AdipoRon shows several beneficial effects that could be leveraged either for better health or advantage in professional sport. In the context of preventive anti-doping research, AdipoRon and, to a lesser extent, 112254 demonstrate physiological effects similar to adiponectin in regard to mimicking exercise. Hence, it is of particular relevance to enable sports drug testing laboratories to accurately test for AdipoRon and 112254 in routine doping controls.