Abstract
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.
Highlights
Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects
By genetically engineering muscle-specific human AdipoR1-transgenic (Tg) mice, we investigated whether augmentation of AdipoR1 expression in the muscle may have a similar role to exercise in muscle mitochondria synthesis and whether AdipoR1 signaling may be associated with anti-diabetic effects
We previously showed that orally active AdipoR agonist AdipoRon ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 DKO mice[39]
Summary
Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects. Musclespecific 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. 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. 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. AdipoR1 and AdipoR2 were assumed to have a seven-transmembrane (7TM) topology with an internal N-
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