Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.

The recent discovery that hydrogen sulfide (H ₂ S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H ₂ S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H ₂ S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemia-reperfusion (MI-R). This observed cytoprotection is associated with an inhibition of myocardial inflammation and a preservation of both mitochondrial structure and function after I-R injury. Additionally, we show that modulation of endogenously produced H ₂ S by cardiac-specific overexpression of cystathionine γ-lyase (α-MHC-CGL-Tg mouse) significantly limits the extent of injury. These findings demonstrate that H ₂ S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H ₂ S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.

Cardiovascular disease accounts for an overwhelming proportion of the morbidity and mortality suffered by patients with obesity and type 2 diabetes mellitus, and recent work has elucidated several potential mechanisms by which increased adiposity enhances cardiovascular risk. Excess adipose tissue, especially in certain compartments, leads to reduced insulin sensitivity in metabolically responsive tissues, which is frequently associated with a set of cardiovascular risk factors, including hyperinsulinemia, hypertension, dyslipidemia, and glucose intolerance. Increasing attention has also been paid to the direct vascular effects of plasma proteins that originate from adipose tissue, especially adiponectin, which exhibits potent antiinflammatory and antiatherosclerotic effects. This brief review will summarize recent work on the vascular actions of adiponectin, which complements the growing body of information on its insulin-sensitizing effects in glucose and lipid metabolism. Adiponectin is now a recognized component of a novel signaling network among adipocytes, insulin-sensitive tissues, and vascular function that has important consequences for cardiovascular risk.

Adiponectin is an abundant adipocyte-derived plasma protein with anti-atherosclerotic and insulin-sensitizing properties that suppresses hepatic glucose production and enhances glucose uptake into skeletal muscle. To characterize the potential effects of adiponectin on glucose uptake into adipose cells, we incubated isolated epididymal rat adipocytes with the globular domain of recombinant adiponectin purified from an E. coli expression system. Globular adiponectin increased glucose uptake in adipocytes without stimulating tyrosine phosphorylation of the insulin receptor or insulin receptor substrate-1, and without enhancing phosphorylation of Akt on Ser-473. Globular adiponectin further enhanced insulin-stimulated glucose uptake at submaximal insulin concentrations and reversed the inhibitory effect of tumor necrosis factor-α on insulin-stimulated glucose uptake. Cellular treatment with globular adiponectin increased the Thr-172 phosphorylation and catalytic activity of AMP-activated protein kinase and enhanced the Ser-79 phosphorylation of acetyl CoA carboxylase, an enzyme downstream of AMP kinase in adipose cells. Inhibition of AMP kinase activation using two pharmacological inhibitors (adenine 9-β-d-arabinofuranoside and compound C) completely abrogated the increase in glucose uptake stimulated by globular adiponectin, indicating that AMP kinase is integrally involved in the adiponectin signal transduction pathway. Coupled with recent evidence that the effects of adiponectin are mediated via AMP kinase activation in liver and skeletal muscle, the findings reported here provide an important mechanistic link in the signaling effects of adiponectin in diverse metabolically responsive tissues.

Objective— Rho-Kinase activity is increased in cardiovascular diseases and in patients with cardiovascular risk factors. However, it is not known whether inhibition of Rho-kinase could lead to cardiovascular protection and, if so, by what mechanism. Methods and Results— In human endothelial cells, the Rho-kinase inhibitor, hydroxyfasudil (HF) (1 to 100 μmol/L), increased Akt serine-473 phosphorylation within 15 minutes, leading to a 2.2-fold and 4.0-fold increase in Akt kinase activity and nitric oxide (NO) release, respectively. Activation of Akt and eNOS by HF was completely blocked by the phosphatidylinositol 3-kinase (PI3-kinase) inhibitor, LY294002 (10 μmol/L). To determine the physiological relevance of this pathway, we used 2 models of ischemia-reperfusion (I/R) injury. Acute administration of fasudil (10 mg/kg, intraperitoneal, 1 hour before ischemia) decreased leukocyte recruitment and adhesion to the mesenteric endothelium after I/R injury in wild-type but not eNOS ^−/− mice. Similarly, treatment with fasudil decreased myocardial infarct size by 38% in rats subjected to transient coronary artery occlusion. Cotreatment with 2 PI3-kinase inhibitors, wortmannin and LY294002, or the eNOS inhibitor, l -NAME, blocked the cardiovascular protective effects of fasudil. Conclusions— Inhibition of Rho-kinase leads to the activation of the PI3-kinase/Akt/eNOS pathway and cardiovascular protection. These findings suggest that Rho-kinase may play an important role in mediating the inflammatory response to I/R injury.