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The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor. The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite—sphingosine-1-phosphate (S1P)—independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

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.

Skin wounds comprise a serious medical issue for which few pharmacological interventions are available. Moreover, the inflammatory, angiogenic, and proliferative facets of a typical response to a wound each have broader relevance in other pathological conditions. Here we describe a genomics-driven approach to identify secreted proteins that modulate wound healing in a mouse ear punch model. We show that adiponectin, when injected into the wound edge, accelerates wound healing. Notably, adiponectin injection causes upregulation of keratin gene transcripts within hours of treatment, and subsequently promotes collagen organization, formation of pilosebaceous units, and proliferation of cells in the basal epithelial cell layer and pilosebaceous units of healing tissue. The globular domain of adiponectin is sufficient to mediate accelerated dorsal skin wound closure, and the effects are lost in mice that are homozygous null for the adiponectin receptor 1 gene. These findings extend recent observations of a protective role of adiponectin in other tissue injury settings, suggest modulation of AdipoR1 for the clinical management of wounds, and demonstrate a new approach to the identification of regulators of a wound healing response.

Energy-sensing pathways, normally coordinated by 5′ AMP-activated protein kinase (AMPK), are dysregulated in renal cell carcinoma (RCC). Obesity can accentuate the pre-existing pro-tumorigenic metabolic machinery in RCC cells through its associated obesogenic hormonal milieu, characterized by lower circulating levels of adiponectin. In RCC patients, low adiponectin levels associate clinically with more aggressive disease. We investigated the adiponectin signaling pathway in RCC, focusing on adiponectin receptor 1 (AdipoR1) and associated activation of AMPK. AdipoR1 protein in RCC and normal surrounding renal tissues was determined by Western blot analysis and immunohistochemistry. Anti-tumorigenic effects of adiponectin in RCC cells in vitro were investigated via VEGF and MMP ELISA and invasion assays. Using in vivo models of RCC, the effect of AdipoR1-knockdown (shRNA) on tumor latency, growth and dissemination were determined. AdipoR1 protein was significantly reduced in clear cell RCC specimens. Adiponectin treatment inhibited VEGF, MMP-2 and MMP-9 secretion and activity and invasive and migratory capacities of RCC cells. AMPKα1-knockdown (shRNA) attenuated adiponectin’s effects. In cells stably expressing AdipoR1-specific shRNA, AMPK activation by adiponectin was significantly reduced compared to cells expressing control shRNA. In vivo, AdipoR1 knockdown increased the growth, dissemination and angiogenesis of RCC. These findings suggest that deficiencies in the entire adiponectin hormonal axis (the hormone and its receptor) result in underactivation of AMPK leading to increased angiogenic and invasive capacities of RCC. The established link between obesity and RCC can therefore be further explained by the adiponectin deficiency in obese individuals together with reduced AdipoR1 protein in RCC.

Background Recent evidence suggests that obesity is associated with hypo-adiponectinmia and chronic inflammation. Adiponectin regulates fat storage, energy expenditure, and inflammation. We propose that high fat diet induces steatohepatitis, reduces serum adiponectin, and liver adiponectin receptors. Methods A 4-week-old C57BL male mice were fed high fat diet ( n  = 8) or regular chow (control; n  = 6) for 7 weeks. Body weight, liver weight, and serum adiponectin were measured. Liver sections were stained with hematoxylin and eosin and oil red for fat content. Liver homogenates were used for protein (immunoblotting) and mRNA (reverse transcription PCR) of Toll-like receptor 4 (TLR4), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, sterol regulatory element-binding proteins (SREBP)-1c, and adiponectin receptors (AdipoR1/AdipoR2) in addition to nuclear phorsphorylated p65NF-κB. Gels were quantified using densitometry; t test was used, and p  < 0.05 was significant. Results High fat diet increased body (50%) and liver weight (33%), as well as hepatocyte fat content and ballooning. Mice fed high fat diet exhibited reduced serum adiponectin and liver AdipoR2. High fat diet increased hepatic levels of SREBP-1c, TLR4, TNF-α, and IL-6 protein and mRNA and increased activation of p65NF-κB. Conclusions Diet-induced liver steatosis is associated with increased lipogensis, upregulation of pro-inflammatory cytokines, and transcription factors as well as downregulation of AdipoR2. Reduction in serum adiponectin suggests that adiponectin signaling may be the crosslink between high fat diet, hepatic inflammation, and nonalcoholic fatty liver disease.

Key Points Various endocrine factors are known to exhibit time-of-day-dependent oscillations in both humans and animals Endocrine factor rhythms are driven not only by environmental and behavioural influences, but also by intrinsic circadian clocks Circadian dyssynchrony is associated with multiple pathologic states, including cardiometabolic diseases and cancer Reinstatement of circadian synchrony through time-of-day-restricted feeding and pharmacologic strategies improves metabolic homeostasis Adequate circadian oscillation of endocrine factors is essential in the maintenance of metabolic homeostasis. The authors of this Review explain the influence of extrinsic and intrinsic factors on endocrine circadian rhythms and how dysregulation of these rhythms can lead to disease in animals and humans. They also discuss therapeutic strategies to restore circadian rhythmicity and improve metabolism. Organisms experience dramatic fluctuations in demands and stresses over the course of the day. In order to maintain biological processes within physiological boundaries, mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors have an integral role in homeostasis. Not only do circulating levels of various endocrine factors oscillate over the 24 h period, but so too does responsiveness of target tissues to these signals or stimuli. Emerging evidence suggests that these daily endocrine oscillations do not occur solely in response to behavioural fluctuations associated with sleep–wake and feeding–fasting cycles, but are orchestrated by an intrinsic timekeeping mechanism known as the circadian clock. Disruption of circadian clocks by genetic and/or environmental factors seems to precipitate numerous common disorders, including the metabolic syndrome and cancer. Collectively, these observations suggest that strategies designed to realign normal circadian rhythmicities hold potential for the treatment of various endocrine-related disorders.

Obesity is increasing in the developed world, and epidemiological studies indicate that this is accompanied by an increased risk of cancer. This Opinion article discusses the possible mechanisms by which obesity might promote tumorigenesis. The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population.

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

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.