Adiponectin is a protein which in humans is encoded by the ADIPOQ gene. It is involved in regulating glucose levels as well as fatty acid breakdown. The hormone plays a role in the suppression of the metabolic derangements that may result intype 2 diabetes, obesity, atherosclerosis, non-alcoholic fatty liver disease and an independent risk factor for metabolic syndrome. The adiponectin receptors (AdipoRs) include the following two receptors, which are bound and activated by adiponectin: Adiponectin receptor 1 (AdipoR1, PAQR1) and Adiponectin receptor 2 (AdipoR2, PAQR2).
Adiponectin is one of the numerous adipokines secreted by adipocytes. It exerts favorable effects in the milieu of metabolic syndrome through anti-inflammatory, antifibrotic, and antioxidant effects. Adiponectin mediates fatty acid metabolism by inducing AMP-activated protein kinase (AMPK) phosphorylation and increasing peroxisome proliferative-activated receptor-α (PPARα) expression, which in turn upregulate the expression of acyl CoA oxidase and uncoupling proteins involved in energy consumption. Low circulating adiponectin levels in obese patients with a risk of insulin resistance, type 2 diabetes, and cardiovascular disease and increased adiponectin expression in state of albuminuria indicate the protective and compensatory role of adiponectin to mitigate further renal injury against the development of overt nephropathy. These beneficial effects of adiponectin have prompted research on drugs that mimic adiponectin, yet this manner of increasing the level of circulating adiponectin is not a panacea. Moreover, adiponectin overexpression is associated with adverse effects such as reduced bone density, left ventricular hypertrophy, weight gain, tumor growth, and infertility. Therefore, there is a need to develop a novel agent that could deliver the favorable effects of adiponectin but not the detrimental pitfalls due to adiponectin excess.
Adiponectin exerts its biological functions by binding to its receptor to trigger the downstream signaling pathways. Among the identifed adiponectin receptors (AdipoRs), AdipoR1 and AdipoR2 have been shown to be the most physiologically important for adiponectin functions in vivo. AdipoR1 is ubiquitously expressed, whereas AdipoR2 is mainly expressed by the liver. Physiologically, AdipoR1 and AdipoR2 have some common and different functions. Either of them can regulate glucose and lipid metabolism, inﬂammation, and oxidative stress in the liver. AdipoR1 defciency impairs adiponectin-induced AMP-activated protein kinase (AMPK) activation, whereas lack of AdipoR2 expression decreases PPARα (peroxisome proliferator-activated receptor α) activity. Simultaneous defciency of AdipoR1 and AdipoR2 expression greatly abolishes adiponectin functions, causing increased triglyceride content besides inﬂammation and oxidative stress.
Although adiponectin might be used for treatment of some diseases, the diffculty in converting the full-size adiponectin protein into a viable drug results in that no adiponectin-based therapeutics is available yet. Alternatively, AdipoR agonists with small molecular weight have been developed. For instance, AdipoRon is a selective, orally active, synthetic small-molecule agonist that can activate both AdipoR1 and AdipoR2 at high affnities (Kd = 1.8 and 3.1 μmol/L, respectively). It is developed by Okada-Iwabu et al. In db/db mice, AdipoRon binds to AdipoRs AdipoR1 and AdipoR2 to activate AMPK and PPARα, respectively, and induces such prometabolic effects as improved insulin sensitivity, weight neutrality, and expanded life span. Diminished adiponectin-associated metabolic effect in AdipoR1-/AdipoR2- knockout mice and restoration of obesity-induced metabolic alterations in high-fat-diet-fed mice by AdipoRon administrationwith implication on fatty acid combustion suggest that AdipoRon is a promising agent for treating type 2 diabetes. ADP355 is an adiponectin-derived active peptide with a sequence of H-DAsn-Ile-Pro-Nva-Leu-Tyr-DSerPhe-Ala-DSer-NH2. It can also activate both AdipoR1 and AdipoR2 with a greater effect on AdipoR1. In animal models, administration of AdipoRon to the high-fat diet-fed type 2 diabetic mice ameliorates insulin resistance and glucose intolerance. ADP355 has also shown benefcial effects on liver fbrosis in mice.
Sun, L., Yang, X., Li, Q., Zeng, P., Liu, Y., Liu, L., ... & Li, Y. (2017). Activation of Adiponectin Receptor Regulates Proprotein Convertase Subtilisin/Kexin Type 9 Expression and Inhibits Lesions in ApoE-Deficient MiceHighlights. Arteriosclerosis, thrombosis, and vascular biology, 37(7), 1290-1300.
Kim, Y., Lim, J. H., Kim, M. Y., Kim, E. N., Yoon, H. E., Shin, S. J., ... & Park, C. W. (2018). The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes. Journal of the American Society of Nephrology, ASN-2017060627.