AdipoR agonist increases insulin sensitivity and exercise endurance in AdipoR-humanized mice.

Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects. Although muscle-specific disruption of AdipoR1 has been shown to result in decreased insulin sensitivity and decreased exercise endurance, it remains to be determined whether upregulation of AdipoR1 could reverse them in obese diabetic mice. Here, we show that muscle-specific expression of human AdipoR1 increased expression levels of genes involved in mitochondrial biogenesis and oxidative stress-detoxification to almost the same extents as treadmill exercise, and concomitantly increased insulin sensitivity and exercise endurance in obese diabetic mice. Moreover, we created AdipoR-humanized mice which express human AdipoR1 in muscle of AdipoR1·R2 double-knockout mice. Most importantly, the small-molecule AdipoR agonist AdipoRon could exert its beneficial effects in muscle via human AdipoR, and increased insulin sensitivity and exercise endurance in AdipoR-humanized mice. This study suggests that expression of human AdipoR1 in skeletal muscle could be exercise-mimetics, and that AdipoRon could exert its beneficial effects via human AdipoR1.

Allograft inflammatory factor-1 augments macrophage phagocytotic activity and accelerates the progression of atherosclerosis in ApoE-/- mice.

Allograft inflammatory factor (AIF)-1, originally cloned from a rat heart allograft under chronic rejection, is induced in various inflammatory conditions including atherosclerosis. Using mouse AIF-1 transfected macrophages and AIF-1 transgenic (AIF-1 Tg) mice, we analyzed the influence of AIF-1 overexpression on macrophage phagocytosis and the development of atherosclerosis. The AIF-1 transfectants showed significantly increased phagocytosis of latex beads and E. coli BioParticles as well as incorporation of acetylated low-density lipoprotein (LDL) compared to those of vector controls. Concordant results were obtained with elicited peritoneal exudate cells from AIF-1 Tg mice. When AIF-1 Tg mice were crossbred with apolipoprotein E knockout mice (ApoE-/-), these AIF-1 Tg ApoE-/- mice developed significantly increased atherosclerotic lesions compared to ApoE-/- mice. These results suggest that enhanced AIF-1 expression leads to augmented incorporation of degenerated LDL by macrophages and promotes development of atherosclerotic vasculopathy.