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Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro . AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes. An orally active small molecule, AdipRon, that binds to and activates both adiponectin receptors (AdipoR1 and AdipoR2) is identified; it ameliorates diabetes in mice on a high-fat diet and in genetically obese db / db mice, and if this can be extrapolated to humans, orally active agonists such as AdipoRon are a promising new approach to treat obesity-related diseases such as type 2 diabetes. AdipRon, a small molecule with antidiabetic activity Adiponectin is a fat-derived hormone that seems to have a crucial role in the protection from insulin resistance/diabetes and atherosclerosis. This study identifies an orally active compound, obtained by screening small molecules in the chemical library at the University of Tokyo's Open Innovation Center for Drug Discovery, that binds to and activates the AdipoR1 and AdipoR2 receptors that mediate adiponectin's antidiabetic action. Named AdipRon, the compound ameliorates insulin resistance and glucose intolerance in mice on a high-fat diet and in genetically obese mice. AdipoRon also extends the shortened lifespan of db / db mice on a high-fat diet. If this work can be extrapolated to humans, orally active agonists such as AdipoRon could offer a promising new approach to treat obesity-related diseases such as type 2 diabetes.

Adiponectin is the richest adipokine in human plasma, and it is mainly secreted from white adipose tissue. Adiponectin circulates in blood as high-molecular, middle-molecular, and low-molecular weight isoforms. Numerous studies have demonstrated its insulin-sensitizing, anti-atherogenic, and anti-inflammatory effects. Additionally, decreased serum levels of adiponectin is associated with chronic inflammation of metabolic disorders including Type 2 diabetes, obesity, and atherosclerosis. However, recent studies showed that adiponectin could have pro-inflammatory roles in patients with autoimmune diseases. In particular, its high serum level was positively associated with inflammation severity and pathological progression in rheumatoid arthritis, chronic kidney disease, and inflammatory bowel disease. Thus, adiponectin seems to have both pro-inflammatory and anti-inflammatory effects. This indirectly indicates that adiponectin has different physiological roles according to an isoform and effector tissue. Knowledge on the specific functions of isoforms would help develop potential anti-inflammatory therapeutics to target specific adiponectin isoforms against metabolic disorders and autoimmune diseases. This review summarizes the current roles of adiponectin in metabolic disorders and autoimmune diseases.

Adiponectin (ADN) is an adipocyte-secreted protein with insulin-sensitizing, antidiabetic, antiinflammatory, and antiatherogenic properties. Evidence is also accumulating that ADN has neuroprotective activities, yet the underlying mechanism remains elusive. Here we show that ADN could pass through the blood-brain barrier, and elevating its levels in the brain increased cell proliferation and decreased depression-like behaviors. ADN deficiency did not reduce the basal hippocampal neurogenesis or neuronal differentiation but diminished the effectiveness of exercise in increasing hippocampal neurogenesis. Furthermore, exerciseinduced reduction in depression-like behaviors was abrogated in ADN-deficient mice, and this impairment in ADN-deficient mice was accompanied by defective running-induced phosphorylation of AMP-activated protein kinase (AMPK) in the hippocampal tissue. In vitro analyses indicated that ADN itself could increase cell proliferation of both hippocampal progenitor cells and Neuro2a neuroblastoma cells. The neurogenic effects of ADN were mediated by the ADN receptor 1 (ADNR1), because siRNA targeting ADNR1, but not ADNR2, inhibited the capacity of ADN to enhance cell proliferation. These data suggest that adiponectin may play a significant role in mediating the effects of exercise on hippocampal neurogenesis and depression, possibly by activation of the ADNR1/AMPK signaling pathways, and also raise the possibility that adiponectin and its agonists may represent a promising therapeutic treatment for depression.

Adiponectin is an adipocyte-derived secretory protein that has been very widely studied over the past 15 years. A multitude of different functions have been attributed to this adipokine. It has been characterised in vitro at the level of tissue culture systems and in vivo through genetic manipulation of rodent models. It is also widely accepted as a biomarker in clinical studies. Originating in adipose tissue, generally positive metabolic effects have been attributed to adiponectin. In this review, we briefly discuss the key characteristics of this interesting but very complex molecule, highlight recent results in the context of its mechanism of action and summarise some of the key epidemiological data that helped establish adiponectin as a robust biomarker for insulin sensitivity, cardiovascular disease and many additional disease phenomena.

Adiponectin and adiponectin receptors (AdipoRs) have been found to play significant roles in the etiology of obesity-related chronic disease. Their discovery has been a long and complicated path, with many challenges. Developing methods to unravel the molecular secrets has been an informative process in itself. However, with both functional and genetic studies confirming adiponectin as a therapeutic target adipokine, many roles and interactions with certain other biomolecules have been clearly defined. We have found that decreased high molecular weight (HMW) adiponectin plays a crucial and causal role in obesity-linked insulin resistance and metabolic syndrome; that AdipoR1 and AdipoR2 serve as the major AdipoRs in vivo; and that AdipoR1 activates the AMP kinase (AMPK) pathway and AdipoR2, the peroxisome proliferator-activated receptor alpha (PPARα) pathway in the liver, to increase insulin sensitivity and decrease inflammation. Further conclusions are that decreased adiponectin action and increased monocyte chemoattractant protein-1 (MCP-1) form a vicious adipokine network causing obesity-linked insulin resistance and metabolic syndrome; PPARγ upregulates HMW adiponectin and PPARα upregulates AdipoRs; that dietary osmotin can serve as a naturally occurring adiponectin receptor agonist; and finally, that under starvation conditions, MMW adiponectin activates AMPK in hypothalamus, and promotes food intake, and at the same time HMW adiponectin activates AMPK in peripheral tissues, such as skeletal muscle, and stimulates fatty-acids combustion. Importantly, under pathophysiological conditions, such as obesity and diabetes, only HMW adiponectin was decreased; therefore, strategies to increase only HMW adiponectin may be a logical approach to provide a novel treatment modality for obesity-linked diseases, such as insulin resistance and type 2 diabetes. It is hoped that these data will be helpful in developing treatments to counteract the destructive, expensive and painful effects of obesity.

Adipose tissue has been recognized as a complex organ with endocrine and metabolic roles. The excess of fat mass, as occurs during overweight and obesity states, alters the regulation of adipose tissue, contributing to the development of obesity-related disorders. In this regard, many epidemiological studies shown an association between obesity and numerous types of malignancies, comprising those linked to the endocrine system (e.g., breast, endometrial, ovarian, thyroid and prostate cancers). Multiple factors may contribute to this phenomenon, such as hyperinsulinemia, dyslipidemia, oxidative stress, inflammation, abnormal adipokines secretion and metabolism. Among adipokines, growing interest has been placed in recent years on adiponectin (APN) and on its role in carcinogenesis. APN is secreted by adipose tissue and exerts both anti-inflammatory and anti-proliferative actions. It has been demonstrated that APN is drastically decreased in obese individuals and that it can play a crucial role in tumor growth. Although literature data on the impact of APN on carcinogenesis are sometimes conflicting, the most accredited hypothesis is that it has a protective action, preventing cancer development and progression. The aim of the present review is to summarize the currently available evidence on the involvement of APN and its signaling in the etiology of cancer, focusing on endocrine malignancies.

Although innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus , potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed increased mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-deficient AMs exhibited an inflammatory phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon rescued deficient killing in APN-/- AMs and was dependent on the presence of either receptor. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A.fumigatus .

Adiponectin (ADPN) is a plasma protein secreted by adipose tissue showing pleiotropic effects with anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Initially, it was thought that the main role was only the metabolism control. Later, ADPN receptors were also found in the central nervous system (CNS). In fact, the receptors AdipoR1 and AdipoR2 are expressed in various areas of the brain, including the hypothalamus, hippocampus, and cortex. While AdipoR1 regulates insulin sensitivity through the activation of the AMP-activated protein kinase (AMPK) pathway, AdipoR2 stimulates the neural plasticity through the activation of the peroxisome proliferator-activated receptor alpha (PPARα) pathway that inhibits inflammation and oxidative stress. Overall, based on its central and peripheral actions, ADPN appears to have neuroprotective effects by reducing inflammatory markers, such as C-reactive protein (PCR), interleukin 6 (IL6), and Tumor Necrosis Factor a (TNFa). Conversely, high levels of inflammatory cascade factors appear to inhibit the production of ADPN, suggesting bidirectional modulation. In addition, ADPN appears to have insulin-sensitizing action. It is known that a reduction in insulin signaling is associated with cognitive impairment. Based on this, it is of great interest to investigate the mechanism of restoration of the insulin signal in the brain as an action of ADPN, because it is useful for testing a possible pharmacological treatment for the improvement of cognitive decline. Anyway, if ADPN regulates neuronal functioning and cognitive performances by the glycemic metabolic system remains poorly explored. Moreover, although the mechanism is still unclear, women compared to men have a doubled risk of developing cognitive decline. Several studies have also supported that during the menopausal transition, the estrogen reduction can adversely affect the brain, in particular, verbal memory and verbal fluency. During the postmenopausal period, in obese and insulin-resistant individuals, ADPN serum levels are significantly reduced. Our recent study has evaluated the relationship between plasma ADPN levels and cognitive performances in menopausal women. Thus, the aim of this review is to summarize both the mechanisms and the effects of ADPN in the central nervous system and the relationship between plasma ADPN levels and cognitive performances, also in menopausal women.

Adiponectin, a key adipokine primarily secreted by adipocytes, plays crucial roles in metabolic homeostasis and inflammation, exhibiting anti-diabetic, anti-atherogenic, and anti-inflammatory properties. Its various isoforms and signaling via receptors like AdipoR1, AdipoR2, and T-cadherin contribute to its diverse biological functions. Sepsis is a life-threatening syndrome triggered by a dysregulated host response to infection, leading to systemic inflammation, multi-organ failure, and high mortality, currently lacking specific treatments. Preclinical studies largely suggest a protective role for adiponectin, demonstrating that its deficiency exacerbates inflammation and endothelial dysfunction, while its administration or agonism improves outcomes in experimental sepsis models. Clinical findings, however, present a complex picture, with inconsistent correlations between adiponectin levels and sepsis outcomes reported, suggesting its potential as a dynamic biomarker influenced by disease stage, patient heterogeneity, and isoforms, rather than a simple prognostic factor. Notably, glucagon-like peptide-1 receptor agonists (GLP-1RAs), used in obesity and diabetes management, have been shown to increase adiponectin levels, linking metabolic therapies to potential sepsis immunomodulation. Consequently, targeting adiponectin signaling, either directly with adiponectin mimics like AdipoRon or indirectly via strategies like GLP-1RA administration, represents a promising therapeutic approach for sepsis. Harnessing the adiponectin axis holds potential for advancing precision medicine in critical care, necessitating further research into adiponectin-based interventions and synergistic metabolic therapies to improve sepsis outcomes. Graphical abstract

How are haematopoietic stem cells (HSCs) protected from inflammation, which increases with age and can deplete HSCs? Adiponectin, an anti-inflammatory factor that is not required for HSC function or haematopoiesis, promotes stem/progenitor cell proliferation after bacterial infection and myeloablation. Adiponectin binds two receptors, AdipoR1 and AdipoR2, which have ceramidase activity that increases upon adiponectin binding. Here we found that adiponectin receptors are non-cell-autonomously required in haematopoietic cells to promote HSC quiescence and self-renewal. Adiponectin receptor signalling suppresses inflammatory cytokine expression by myeloid cells and T cells, including interferon-γ and tumour necrosis factor. Without adiponectin receptors, the levels of these factors increase, chronically activating HSCs, reducing their self-renewal potential and depleting them during ageing. Pathogen infection accelerates this loss of HSC self-renewal potential. Blocking interferon-γ or tumour necrosis factor signalling partially rescues these effects. Adiponectin receptors are thus required in immune cells to sustain HSC quiescence and to prevent premature HSC depletion by reducing inflammation. Meacham et al. report that adiponectin receptors suppress chronic inflammatory signalling by immune effector cells to prevent haematopoietic stem cell exit from quiescence and, thus, protect them from exhaustion.