Adiporon, an adiponectin receptor agonist acts as an antidepressant and metabolic regulator in a mouse model of depression

Abstract

Major depression is a psychiatric disorder with complex etiology. About 30% of depressive patients are resistant to antidepressants that are currently available, likely because they only target the monoaminergic systems. Thus, identification of novel antidepressants with a larger action spectrum is urgently required. Epidemiological data indicate high comorbidity between metabolic and psychiatric disorders, particularly obesity and depression. We used a well-characterized anxiety/depressive-like mouse model consisting of continuous input of corticosterone for seven consecutive weeks. A panel of reliable behavioral tests were conducted to assessing numerous facets of the depression-like state, including anxiety, resignation, reduced motivation, loss of pleasure, and social withdrawal. Furthermore, metabolic features including weight, adiposity, and plasma biological parameters (lipids, adipokines, and cytokines) were investigated in corticosterone-treated mice. Our data show that chronic administration of corticosterone induced the parallel onset of metabolic and behavioral dysfunctions in mice. AdipoRon, a potent adiponectin receptor agonist, prevented the corticosterone-induced early onset of moderate obesity and metabolic syndromes. Moreover, in all the behavioral tests, daily treatment with AdipoRon successfully reversed the corticosterone-induced depression-like state in mice. AdipoRon exerted its pleiotropic actions on various systems including hippocampal neurogenesis, serotonergic neurotransmission, neuroinflammation, and the tryptophan metabolic pathway, which can explain its antidepressant properties. Our study highlights the pivotal role of the adiponergic system in the development of both metabolic and psychiatric disorders. AdipoRon may constitute a promising novel antidepressant.

AdipoRon Affects Cell Cycle Progression and Inhibits Proliferation in Human Osteosarcoma Cells

“…erefore,looking for other innovative and more e ective pharmacological strategies represents the unique weapon to ght this malignancy. Recently, the rst oral adiponectin receptor agonist AdipoRon has been identi ed, but its potential pharmacological usage has marginally been explored [22][23][24]. In this regard, initial evidence candidates AdipoR as a potential antineoplastic molecule in various preclinical models, including pancreatic and ovarian cancer [28][29][30].…”

“…AdipoRon (AdipoR) is the first oral adiponectin receptor agonist capable of binding and activating AdipoR1 and AdipoR2 [21]. Over the past few years, AdipoR is emerging as a possible candidate for the treatment of different pathological conditions, including metabolic, cardiovascular, and psychiatric disorders, specifically comorbidity between depression and obesity [22][23][24]. According to the antitumor effects observed in response to Acrp30 [25,26] and the opposite relation between its circulating levels and risk of developing cancer [27], initial reports have also investigated the possible anticancer role of AdipoRon in preclinical models, especially in pancreatic and ovarian cancer [28][29][30].…”

Examining the Potential of Developing and Implementing Use of Adiponectin-Targeted Therapeutics for Metabolic and Cardiovascular Diseases

“…AdipoRON effectively improved insulin sensitivity and restored glucose homeostasis via the activation of AdipoR1-AMPK-PGC1α and AdipoR2-PPARα signaling pathways (162). AdipoRON treatment also mimicked adiponectin's established anti-diabetic effects (163) and ability to enhance cellular capacity for mitigating oxidative-stress (162,164), enhancing lipid/glucose oxidation in mitochondria (162,164), anti-inflammatory responses (162,(164)(165)(166)(167), lifeprolonging effect (162,163), anti-cancer effects (168,169), procell survival and anti-apoptotic effect (170,171), neuronal- (172,173), reno- (174,175), and cardio-/vascular-protective effects (165,(176)(177)(178)(179). However, exciting AdipoRON research in animal models has not been translated to establishment of a drug for human use and the search continues for additional small molecule AdipoR agonists which have little or no toxicity.…”

Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?

“…ApN/AdipoRon could well be strong alternatives to GCs due to their pleomorphic protective properties. These medications could even counter some GC side effects by enhancing insulin sensitivity [105,106], preventing obesity [107], hypertension [108] and mood disturbances [107].…”

“…Last but not least, the most compelling mimic to date is AdipoRon, an orally active synthetic small-molecule AdipoRs agonist identified in 2013 by Okada-Iwabu et al after screening a compound library to identify those that bind to AdipoRs and greatly activate AMPK [106]. AdipoRon has first been proposed for the treatment of type 2 diabetes and other obesity-related disorders in mice [32,[106][107][108]137,138]. It could even prolong the lifespan of obese treated mice [105,106].…”