The number and activity of brown adipocytes are linked to the ability of mammals to resist body fat accumulation. In some conditions, certain white adipose tissue (WAT) depots are readily convertible to a ‘‘brown-like’’ state, which is associated with weight loss. Irisin, a newly identified hormone, is secreted by skeletal muscles into circulation and promotes WAT “browning” with unknown mechanisms. In the current study, we demonstrated in mice that recombinant irisin decreased the body weight and improved glucose homeostasis. We further showed that irisin upregulated uncoupling protein-1 (UCP-1; a regulator of thermogenic capability of brown fat) expression. This effect was possibly mediated by irisin-induced phosphorylation of the p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal–related kinase (ERK) signaling pathways. Inhibition of the p38 MAPK by SB203580 and ERK by U0126 abolished the upregulatory effect of irisin on UCP-1. In addition, irisin also promoted the expression of betatrophin, another newly identified hormone that promotes pancreatic β-cell proliferation and improves glucose tolerance. In summary, our data suggest that irisin can potentially prevent obesity and associated type 2 diabetes by stimulating expression of WAT browning-specific genes via the p38 MAPK and ERK pathways.

Chlorogenic acid (CGA) is a type of polyphenol compound found in rich concentrations in many plants such as green coffee beans. As an active natural substance, CGA exerts diverse therapeutic effects in response to a variety of pathological challenges, particularly conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional functions, including neuroprotection for neurodegenerative disorders and diabetic peripheral neuropathy, anti-inflammation, anti-oxidation, anti-pathogens, mitigation of cardiovascular disorders, skin diseases, diabetes mellitus, liver and kidney injuries, and anti-tumor activities. Mechanistically, its integrative functions act through the modulation of anti-inflammation/oxidation and metabolic homeostasis. It can thwart inflammatory constituents at multiple levels such as curtailing NF-kB pathways to neutralize primitive inflammatory factors, hindering inflammatory propagation, and alleviating inflammation-related tissue injury. It concurrently raises pivotal antioxidants by activating the Nrf2 pathway, thus scavenging excessive cellular free radicals. It elevates AMPK pathways for the maintenance and restoration of metabolic homeostasis of glucose and lipids. Additionally, CGA shows functions of neuromodulation by targeting neuroreceptors and ion channels. In this review, we systematically recapitulate CGA’s pharmacological activities, medicinal properties, and mechanistic actions as a potential therapeutic agent. Further studies for defining its specific targeting molecules, improving its bioavailability, and validating its clinical efficacy are required to corroborate the therapeutic effects of CGA.

Nitroalkene derivatives of linoleic acid (nitrolinoleic acid, LNO ₂ ) are formed via nitric oxide-dependent oxidative inflammatory reactions and are found at concentrations of ≈500 nM in the blood of healthy individuals. We report that LNO ₂ is a potent endogenous ligand for peroxisome proliferator-activated receptor γ (PPARγ; K _i ≈133 nM) that acts within physiological concentration ranges. This nuclear hormone receptor (PPARγ) regulates glucose homeostasis, lipid metabolism, and inflammation. PPARγ ligand activity is specific for LNO ₂ and not mediated by LNO ₂ decay products, NO donors, linoleic acid (LA), or oxidized LA. LNO ₂ is a significantly more robust PPARγ ligand than other reported endogenous PPARγ ligands, including lysophosphatidic acid (16:0 and 18:1), 15-deoxy-Δ ^12,14 -PGJ ₂ , conjugated LA and azelaoyl-phosphocholine. LNO ₂ activation of PPARγ via CV-1 cell luciferase reporter gene expression analysis revealed a ligand activity that rivals or exceeds synthetic PPARγ agonists such as rosiglitazone and ciglitazone, is coactivated by 9 cis -retinoic acid and is inhibited by the PPARγ antagonist GW9662. LNO ₂ induces PPARγ-dependent macrophage CD-36 expression, adipocyte differentiation, and glucose uptake also at a potency rivaling thiazolidinediones. These observations reveal that NO-mediated cell signaling reactions can be transduced by fatty acid nitration products and PPAR-dependent gene expression.

OBJECTIVE: Oxidative stress is implicated in cardiac insulin resistance, a critical risk factor for cardiac failure, but the direct evidence remains missing. This study explored a causal link between oxidative stress and insulin resistance with a focus on a regulatory role of redox sensitive transcription factor NF-E2–related factor 2 (Nrf2) in the cardiac cells in vitro and in vivo.RESEARCH DESIGN AND METHODS: Chronic treatment of HL-1 adult cardiomyocyte with hydrogen peroxide led to insulin resistance, reflected by a significant suppression of the insulin-induced glucose uptake. This was associated with an exaggerated phosphorylation of extracellular signal–related kinase (ERK). Although U0126, an ERK inhibitor, enhanced insulin sensitivity and attenuated oxidative stress–induced insulin resistance, LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), worsened the insulin resistance. Moreover, insulin increased Nrf2 transcriptional activity, which was blocked by LY294002 but enhanced by U0126. Forced activation of Nrf2 by adenoviral over-expression of Nrf2 inhibited the increased ERK activity and recovered the blunted insulin sensitivity on glucose uptake in cardiomyocytes that were chronically treated with H2O2. In the hearts of streptozotocin-induced diabetic mice and diabetic patients Nrf2 expression significantly decreased along with significant increases in 3-nitrotyrosine accumulation and ERK phosphorylation, whereas these pathogenic changes were not observed in the heart of diabetic mice with cardiac-specific overexpression of a potent antioxidant metallothionein. Upregulation of Nrf2 by its activator, Dh404, in cardiomyocytes in vitro and in vivo prevented hydrogen peroxide– and diabetes-induced ERK activation and insulin-signaling downregulation.CONCLUSIONS: ERK-mediated suppression of Nrf2 activity leads to the oxidative stress–induced insulin resistance in adult cardiomyocytes and downregulated glucose utilization in the diabetic heart.

Nitroalkene derivatives of linoleic acid (LNO₂) and oleic acid (OA-NO₂) are present; however, their biological functions remain to be fully defined. Herein, we report that LNO₂ and OA-NO₂ inhibit lipopolysaccharide-induced secretion of proinflammatory cytokines in macrophages independent of nitric oxide formation, peroxisome proliferator-activated receptor-γ activation, or induction of heme oxygenase-1 expression. The electrophilic nature of fatty acid nitroalkene derivatives resulted in alkylation of recombinant NF-κB p65 protein in vitro and a similar reaction with p65 in intact macrophages. The nitroalkylation of p65 by fatty acid nitroalkene derivatives inhibited DNA binding activity and repressed NF-κB-dependent target gene expression. Moreover, nitroalkenes inhibited endothelial tumor necrosis factor-α-induced vascular cell adhesion molecule 1 expression and monocyte rolling and adhesion. These observations indicate that nitroalkenes such as LNO₂ and OA-NO₂, derived from reactions of unsaturated fatty acids and oxides of nitrogen, are a class of endogenous anti-inflammatory mediators.

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that plays a pivotal role in obesity and diabetes. PPARγ has two isoforms, PPARγ1 and PPARγ2. We investigated the functional differences between PPARγ1 and PPARγ2 by selectively disrupting PPARγ2 in mice. In contrast to the embryonic lethality of PPARγ-deficient mice, PPAR γ 2 ^{- / -} mice survived. Although normal development was identified in other tissues we examined, PPAR γ 2 ^{- / -} mice exhibited an overall reduction in white adipose tissue, less lipid accumulation, and decreased expression of adipogenic genes in adipose tissue. In addition, insulin sensitivity was impaired in male PPAR γ 2 ^{- / -} mice, with dramatically decreased expression of insulin receptor substrate 1 and glucose transporter 4 in the skeletal muscle, but thiazolidinediones were able to normalize this insulin resistance. Consistent with in vivo data, PPAR γ 2 ^{- / -} mouse embryonic fibroblasts showed a dramatically reduced capacity for adipogenesis in vitro compared with wild-type mouse embryonic fibroblasts. Taken together, our data demonstrate that PPAR γ 2 deficiency impairs the development of adipose tissue and insulin sensitivity. PPAR γ 2 ^{- / -} mice may provide a tool to study the role of PPARγ2 in obesity and diabetes.