Since AdipoR1 and AdipoR2 belong to the 11-member PAQR family of transmembrane proteins 27, it is speculated that other PAQR family members may constitute CTRP receptors 26. AdipoR1 and AdipoR2 serve as physiologically the most important receptors for adiponectin and play crucial roles in the regulation of glucose and lipid metabolism, as well as in inflammation and oxidative stress, in vivo 25.ĪdipoR1 may partially mediate the effects of CTRP9 on vascular endothelial cells and cardiomyocytes 22, 26. AdipoR1 and AdipoR2 were assumed to have a seven-transmembrane (7TM) topology with an internal N-terminus and an external C-terminus, opposite to that of G-protein-coupled receptors (GPCRs) 24. We previously reported cloning of AdipoR1 and AdipoR2 as receptors for adiponectin 24. Recent studies have suggested that CTRPs may also form heteromeric complexes, and that adiponectin can form heteromeric proteins with CTRP2 and CTRP9 17, 22, 23. Plasma levels of adiponectin have been shown to be decreased in obesity, insulin resistance, and type 2 diabetes, while adiponectin replenishment has been shown to improve insulin resistance and impaired glucose tolerance in mice 18, 19, 20, 21. Adiponectin, a member of the C1q/TNF related protein (CTRP) family that includes at least 15 other members (CTRP1-15) including some shown to regulate metabolism, has attracted much interest because of its anti-inflammatory and insulin-sensitizing effects 17. Obesity is known to cause insulin resistance, which is associated with type 2 diabetes and cardiovascular disease 4, 5, 6, where it has become clear that decreased plasma adiponectin levels in obesity are causally implicated in these obesity-linked diseases 7, 8, 9.Īdiponectin 10, 11, 12, 13 is a secreted protein highly expressed specifically in adipose tissue known as an adipokine 14, 15, 16. Lack of exercise 1 associated with increasing societal automation, as well as changes in dietary habits, has led to a drastic increase in the number of overweight individuals worldwide 2, 3. 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. ![]() 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. Moreover, we created AdipoR-humanized mice which express human AdipoR1 in muscle of AdipoR1 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. 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. Adiponectin receptors, AdipoR1 and AdipoR2 exert anti-diabetic effects.
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