Adipokines

Cardiometabolic risk and associated dysfunctions contribute largely to the recent rise in mortality globally. Advancements in multi-omics in recent years promise a better understanding of potential biomarkers that enable an early diagnosis of cardiometabolic dysfunction. However, the molecular mechanisms driving the onset and progression of cardiometabolic disorders remain poorly understood. Adipokines are adipocyte-specific cytokines that are central to deleterious cardiometabolic alterations. They exhibit both pro-inflammatory and anti-inflammatory effects, complicating their association with cardiometabolic disturbances. Thus, understanding the cardiometabolic association of adipokines from a molecular and signaling perspective assumes great importance. This review presents a comprehensive outline of the most prominent adipokines exhibiting pro-inflammatory and/or anti-inflammatory functions in cardiometabolic dysfunction. The review also presents an insight into the pathophysiological implications of such adipokines in different cardiometabolic dysfunction conditions, the status of adipokine druggability, and future studies that can be undertaken to address the existing scientific gap. A clear understanding of the functional and mechanistic role of adipokines can potentially improve our understanding of cardiovascular disease pathophysiology and enhance our current therapeutic regimen in the years to come.

Hypothalamic neuroinflammation plays a pivotal role in the development of metabolic disorders, contributing to obesity and insulin resistance. Hypercaloric diets rich, particularly high-fat diets (HFDs) induce hypothalamic neuroinflammation, which has been shown to precede peripheral inflammation, even after short-term exposure. However, the mechanisms initiating this central inflammatory response, especially the mediators involved, remain incompletely understood. In this study, we demonstrate that HFD consumption induces the expression of resistin in the hypothalamus. Resistin, an adipokine known to promote inflammation and insulin resistance, was found to modulate the expression profile of microRNAs in the hypothalamus. Notably, intracerebroventricular administration of resistin led to the upregulation of miR-155-5p in a TLR4-dependent manner. Consistently, HFD feeding elevated miR-155-5p levels in the mediobasal hypothalamus. Given the established role of miR-155-5p in promoting macrophage activation in peripheral tissues, we examined its expression in microglial cells. We found that both resistin and palmitate, a saturated fatty acid that mimics HFD-induced metabolic stress, increased miR-155-5p expression in the SIM-A9 microglial cell line, which is derived from mouse cerebral cortex tissue without transformation or artificial immortalization. Our findings reveal a novel resistin/TLR4/miR-155-5p signaling axis that may initiate hypothalamic neuroinflammation. Moreover, we show that the induction of miR-155-5p by resistin depends on activation of the NF-κB, JNK, and p38 MAPK signaling pathways. To further explore this pathway, we performed High-Throughput Sequencing of RNA isolated by Cross-Linking Immunoprecipitation (HITS-CLIP) to identify miR-155-5p targets in SIM-A9 microglia and in the hypothalami of both male and female mice. This approach revealed several common targets, including Quaking and Elmo1, genes implicated in microglial phagocytosis and engulfment. These targets were validated, as transfection of SIM-A9 cells with a miR-155-5p mimic led to downregulation of their expression. Importantly, hypothalamic knockdown of miR-155-5p in both male and female mice improved glucose tolerance and restored Quaking expression in hypothalamic microglia. In conclusion, our data show that HFD promotes hypothalamic resistin expression, which in turn upregulates miR-155-5p via TLR4 and downstream signaling pathways, thereby contributing to hypothalamic neuroinflammation and disrupted glucose homeostasis. We identify the resistin/TLR4/miR-155-5p axis as a novel and critical pathway in the early events of diet-induced neuroinflammation.

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.

BackgroundCardiovascular disease remains the leading cause of death worldwide, with coronary artery disease being the primary contributor. Our recent studies suggest that activation of LepRs (leptin receptors) in the brain can improve cardiac function after myocardial infarction. However, the mechanism by which this cardioprotective effect is transmitted from the brain to the heart remains unclear. We hypothesize that brain LepR activation stimulates brown adipose tissue (BAT) to secrete extracellular vesicles (EVs) enriched with cardioprotective factors. These EVs may safeguard the heart by modulating cardiac mitochondrial function and collagen deposition.MethodsSprague-Dawley rats with BAT intact, BAT ablation, or BAT sympathetic denervation were implanted with an intracerebroventricular cannula for continuous leptin or vehicle delivery over 28 days after cardiac ischemia-reperfusion injury. Cardiac function was assessed weekly via echocardiography and by ventricular catheterization at the end of the protocol. EVs were isolated from BAT for analysis. Rab27a (Ras-related protein Rab-27A), a protein required for EV release, was knocked down using adeno-associated virus, and EV tracking was conducted using a double fluorescent reporter mouse model.ResultsOur findings indicate that BAT ablation or BAT sympathetic denervation diminishes the cardioprotective effects of brain LepR activation. We also observed an increased concentration of EVs within the BAT of rats treated with intracerebroventricular leptin compared with vehicle-treated controls, an effect abolished by BAT denervation. Furthermore, knockdown of Rab27a in BAT reduced the cardioprotective benefits of brain LepR activation. MicroRNA miR-29c-3p was identified as a cargo of leptin-stimulated BAT-derived EVs and appears to play a key role in mitigating cardiac fibrosis after ischemia-reperfusion injury in leptin-treated animals.ConclusionsActivation of LepR in the brain protects the heart after ischemia-reperfusion injury via sympathetic-mediated BAT-derived EVs enriched with miR-29c-3p.