Orally active osteoanabolic agent GTDF binds to adiponectin receptors, with a preference for AdipoR1, induces adiponectin-associated signaling, and improves metabolic health in a rodent model of diabetes (original) (raw)
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An Adiponectin-Like Molecule with Antidiabetic Properties
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Adiponectin increases glucose transport, reduces inflammation, and controls vascular functions. Hence, we propose that treatment with a recombinant globular domain of adiponectin (rgAd110-244) has significant therapeutic potential to treat insulin resistance. Mice were fed for 3 months on a high-fat diet (HFD) to induce insulin resistance, diabetes, and moderate weight gain. The mice were first infused iv with different doses of rgAd110-244 (0.12, 0.4, and 1.2 μg/kg · min) for 5 h. Basal and insulin-sensitive glucose use rates were assessed by the use of a submaximal rate of insulin in the awake free-moving mouse. rgAd110-244 reduced, with dose dependence, epinephrine-induced hyperglycemia and HFD-induced insulin resistance by increasing whole-body glucose use (35% at the highest dose) and glycolysis rates. Similarly, the reduction of plasma free fatty acid concentrations by insulin was dramatically improved. Basal hepatic glucose production was unchanged by rgAd110-244 infusion. Th...
Discovery of a novel potent peptide agonist to adiponectin receptor 1
PloS one, 2018
Activation of adiponectin receptors (AdipoRs) by its natural ligand, adiponectin has been known to be involved in modulating critical metabolic processes such as glucose metabolism and fatty acid oxidation as demonstrated by a number of in vitro and in vivo studies over last two decades. These findings suggest that AdipoRs' agonists could be developed into a potential therapeutic agent for metabolic diseases, such as diabetes mellitus, especially for type II diabetes, a long-term metabolic disorder characterized by high blood sugar, insulin resistance, and relative lack of insulin. Because of limitations in production of biologically active adiponectin, adiponectin-mimetic AdipoRs' agonists have been suggested as alternative ways to expand the opportunity to develop anti-diabetic agents. Based on crystal structure of AdipoR1, we designed AdipoR1's peptide agonists using protein-peptide docking simulation and screened their receptor binding abilities and biological functi...
Adiponectin: A Promising Target for the Treatment of Diabetes and Its Complications
Life
Diabetes mellitus, a chronic metabolic disorder characterized by hyperglycemia, presents a formidable global health challenge with its associated complications. Adiponectin, an adipocyte-derived hormone, has emerged as a significant player in glucose metabolism and insulin sensitivity. Beyond its metabolic effects, adiponectin exerts anti-inflammatory, anti-oxidative, and vasoprotective properties, making it an appealing therapeutic target for mitigating diabetic complications. The molecular mechanisms by which adiponectin impacts critical pathways implicated in diabetic nephropathy, retinopathy, neuropathy, and cardiovascular problems are thoroughly examined in this study. In addition, we explore possible treatment options for increasing adiponectin levels or improving its downstream signaling. The multifaceted protective roles of adiponectin in diabetic complications suggest its potential as a novel therapeutic avenue. However, further translational studies and clinical trials are...
Modulation of adiponectin as a potential therapeutic strategy
Atherosclerosis, 2014
Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular...
Biointerface Research in Applied Chemistry
Obesity, Diabetes, and Cancer are major health concerns worldwide. Studies are ongoing to find a molecular drug target that simultaneously regulates these diseases. One such protein is adiponectin which modulates numerous physiological processes and regulates pathways associated with these diseases. Here we have reviewed the potential of adiponectin as a drug target and discussed possible mechanisms by which herbal compounds can modulate its function. Adiponectin exerts its function by binding to its transmembrane receptors (adipoR1 and adipoR2), which stimulate signaling cascades involved in regulating these diseases. Adiponectin activity can be enhanced by the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), or several natural compounds(like curcumin). The mechanism by which these phytocompounds influence adiponectin activity at the molecular level is unclear. Here we have summarized various natural compounds that can modulate adiponectin activity an...
Current Pharmaceutical Design
Adiponectin, a secretory protein specifically expressed by adipose tissue, has been shown to play a critical role in the maintenance of metabolic homeostasis. A deficiency of adiponectin has been linked to a wide variety of metabolic abnormalities, including obesity and associated disorders such as insulin resistance, hyperglycemia, dyslipidemia, hypertension and nonalcoholic fatty liver disease, collectively referred to as the “metabolic syndrome”. Conversely, increased expression of adiponectin corrects these abnormalities, as revealed by the positive metabolic effects observed in genetic over expression studies or by administration of recombinant adiponectin. This has led to widespread interest in its role as a therapeutic target for treatment of a range of metabolic disorders such as diabetes mellitus, obesity, inflammatory and cardiovascular diseases. Various therapeutic approaches targeted at increasing adiponectin levels, or its activity, are being explored. These consist of increasing expression of adiponectin or its receptors by inducers, increasing circulating levels of adiponectin by administering recombinant protein, peptide mimetic approaches, or increasing expression/activity of its downstream effectors such as AMPK or PPAR alpha. Many of these approaches have achieved therapeutic benefits in animal models of metabolic diseases. Despite the profusion of research on adiponectin and ways to modulate it, there are limited number of studies focused on smallmolecule based-therapeutic approaches. In this review, we summarize what is currently known with respect to the therapeutic potential of adiponectin and discuss the challenges in designing small molecule-based therapies.
Adiponectin: an adipokine with protective features against metabolic syndrome
Iranian journal of basic medical sciences, 2015
Metabolic syndrome (MetS) as a collection of obesity-associated disorders is associated with inflammation, oxidative stress, pro-thrombotic state, elevated risk of developing cardiovascular disease and type 2 diabetes. Adiponectin is one of the most abundant peptide hormones derived from adipose tissue. This protein plays a major role in glucose and lipid metabolism and prevents development of vascular changes. Anti-oxidative and anti-inflammatory effects are the other features of adiponectin. Hypoadiponectinemia is associated with hypertension and pro-thrombotic state. In this review, we discuss the crucial role of adiponectin in prevention of metabolic syndrome considering its effects on the components of this syndrome. Pharmacological interventions and lifestyle modification may increase plasma adiponectin level or tissue sensitivity which seems to be a promising target for prevention and therapeutic approaches of MetS and related diseases.