Adiponectin

BackgroundAdiponectin, the most abundant adipokine derived from adipose tissue, exhibits a potent suppressive effect on the growth of breast cancer cells; however, the underlying molecular mechanisms for this effect are not completely understood. Fatty acid metabolic reprogramming has recently been recognized as a crucial driver of cancer progression. Adiponectin demonstrates a wide range of metabolic activities for the modulation of lipid metabolism under physiological conditions. However, the biological actions of adiponectin in cancer-specific lipid metabolism and its role in the regulation of cancer cell growth remain elusive.MethodsThe effects of adiponectin on fatty acid metabolism were evaluated by measuring the cellular neutral lipid pool, free fatty acid level, and fatty acid oxidation (FAO). Colocalization between fluorescent-labeled lipid droplets and LC3/lysosomes was employed to detect lipophagy activation. Cell viability and apoptosis were examined by MTS assay, caspase-3/7 activity measurement, TUNEL assay, and Annexin V binding assay. Gene expression was determined by real time-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The transcriptional activity of SREBP-1 was examined by a specific dsDNA binding assay. The modulatory roles of SIRT-1 and adiponectin-activated mediators were confirmed by gene silencing and/or using their pharmacological inhibitors. Observations from in vitro assays were further validated in an MDA-MB-231 orthotopic breast tumor model.ResultsGlobular adiponectin (gAcrp) prominently decreased the cellular lipid pool in different breast cancer cells. The cellular lipid deficiency promoted apoptosis by causing disruption of lipid rafts and blocking raft-associated signal transduction. Mechanistically, dysregulated cellular lipid homeostasis by adiponectin was induced by two concerted actions: 1) suppression of fatty acid synthesis (FAS) through downregulation of SREBP-1 and FAS-related enzymes, and 2) stimulation of lipophagy-mediated lipolysis and FAO. Notably, SIRT-1 induction critically contributed to the adiponectin-induced metabolic alterations. Finally, fatty acid metabolic remodeling by adiponectin and the key role of SIRT-1 were confirmed in nude mice bearing breast tumor xenografts.ConclusionThis study elucidates the multifaceted role of adiponectin in tumor fatty acid metabolic reprogramming and provides evidence for the connection between its metabolic actions and suppression of breast cancer.

Adiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet. In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.

Adiponectin (APN) deficiency has also been associated with Alzheimer-like pathologies. Recent studies have illuminated the importance of APN signaling in reducing Aβ accumulation, and the Aβ elimination mechanism remains rudimentary. Therefore, we aimed to elucidate the APN role in reducing Aβ accumulation and its associated abnormalities by targeting autophagy and lysosomal protein changes. To assess, we performed a combined pharmacological and genetic approach while using preclinical models and human samples. Our results demonstrated that the APN level significantly diminished in the plasma of patients with dementia and 5xFAD mice (6 months old), which positively correlated with Mini-Mental State Examination (MMSE), and negatively correlated with Clinical Dementia Rating (CDR), respectively. APN deficiency accelerated cognitive impairment, Aβ deposition, and neuroinflammation in 5xFAD mice (5xFAD*APN KO), which was significantly rescued by AdipoRon (AR) treatment. Furthermore, AR treatment also markedly reduced Aβ deposition and attenuated neuroinflammation in APP/PS1 mice without altering APP expression and processing. Interestingly, AR treatment triggered autophagy by mediating AMPK-mTOR pathway signaling. Most importantly, APN deficiency dysregulated lysosomal enzymes level, which was recovered by AR administration. We further validated these changes by proteomic analysis. These findings reveal that APN is the negative regulator of Aβ deposition and its associated pathophysiologies. To eliminate Aβ both extra- and intracellular deposition, APN contributes via the autophagic/lysosomal pathway. It presents a therapeutic avenue for AD therapy by targeting autophagic and lysosomal signaling.

BackgroundIrisin, an exercise-induced myokine and adiponectin, an adipocyte-derived hormone, are involved in energy metabolism and musculoskeletal health. However, their associations with obesity, abdominal obesity, sarcopenia and sarcopenic obesity remain unclear, and longitudinal evidence is limited. This study investigated the cross-sectional and longitudinal associations of these biomarkers with obesity- and sarcopenia-related outcomes.MethodsWe used data from the Hallym Aging Study, a cohort of Korean adults aged ≥ 45 years (45-64 years: 30%, ≥65 years: 70%). The cross-sectional analysis used the third wave (2010), while the longitudinal analysis included the second (2007, baseline) and third waves. In both analyses, sex-specific tertile groups (T1, T2 and T3) were defined based on baseline levels and changes in irisin and adiponectin over 3 years. Lean soft tissue and fat mass were assessed using dual-energy x-ray absorptiometry. Obesity was defined as body fat percentages > 29.7% for males and > 37.2% for females. For individuals without obesity, low ALST was defined as appendicular lean soft tissue (ALST)/height2 2 for males and 2 for females. For individuals with obesity, low ALST was defined as an ALST/body weight ResultsA total of 357 and 360 participants were included in the cross-sectional analyses of irisin and adiponectin, respectively, and 351 were included in the longitudinal analysis (baseline 2007; median age: 70 years; 54% female). In cross-sectional analysis, irisin was not significantly associated with obesity- and sarcopenia-related outcomes after adjustment for confounding variables. Longitudinally, the greatest irisin increase group (T3) over 3 years had higher odds of obesity [odds ratio (OR) 2.39, 95% confidence interval (CI) 1.24-4.71], abdominal obesity (OR 2.19, 95% CI 1.04-4.72), sarcopenia (OR 2.11, 95% CI 1.14-3.97), sarcopenic obesity (OR 3.40, 95% CI 1.43-8.61) and low ALST (OR 2.21, 95% CI 1.24-3.99) at the follow-up than the T1 group. In contrast, adiponectin levels showed inverse associations with obesity (OR 0.47, 95% CI 0.24-0.93) and abdominal obesity (OR 0.48, 95% CI 0.25-0.90) only in cross-sectional analysis.ConclusionsDespite irisin's proposed protective role against obesity and sarcopenia, our findings suggest that greater 3-year increases in irisin were associated with increased odds of obesity, abdominal obesity, sarcopenia and sarcopenic obesity at the follow-up. Conversely, adiponectin showed an inverse cross-sectional association with obesity and abdominal obesity.