Search

Obesity-associated low-grade inflammation in metabolically relevant tissues contributes to insulin resistance. We recently reported monocyte/macrophage infiltration in mouse and human skeletal muscles. However, the molecular triggers of this infiltration are unknown, and the role of muscle cells in this context is poorly understood. Animal studies are not amenable to the specific investigation of this vectorial cellular communication. Using cell cultures, we investigated the crosstalk between myotubes and monocytes exposed to physiological levels of saturated and unsaturated fatty acids. Media from L6 myotubes treated with palmitate--but not palmitoleate--induced THP1 monocyte migration across transwells. Palmitate activated the Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway in myotubes and elevated cytokine expression, but the monocyte chemoattracting agent was not a polypeptide. Instead, nucleotide degradation eliminated the chemoattracting properties of the myotube-conditioned media. Moreover, palmitate-induced expression and activity of pannexin-3 channels in myotubes were mediated by TLR4-NF-κB, and TLR4-NF-κB inhibition or pannexin-3 knockdown prevented monocyte chemoattraction. In mice, the expression of pannexin channels increased in adipose tissue and skeletal muscle in response to high-fat feeding. These findings identify pannexins as new targets of saturated fatty acid--induced inflammation in myotubes, and point to nucleotides as possible mediators of immune cell chemoattraction toward muscle in the context of obesity. [ABSTRACT FROM AUTHOR]

Recent studies show that acute and chronic hyperglycemia in rats treated with streptozotocin (STZ) caused an increase in the blood brain barrier (BBB) permeability. Additionally, it was shown that insulin treatment attenuated BBB disruption in the short term; however, as diabetes progressed, the microvascular damage occurred even as hyperglycemia was controlled. In the studies reported here, the time course of the disruption of the functional integrity of the BBB was defined with added granularity. Permeability of the BBB was determined by quantitatively measuring [sup 13]C[sub 6]-sucrose concentrations in brain and plasma using mass spectometry. In rats maintained on a high fat diet and treated with a sub-optimal dose of STZ, the plasma glucose concentrations were elevated to above 500 mg/dL, however plasma insulin concentrations remained the same as control. It was determined that in the model, the increase in BBB permeability occurred between five and twelve days post STZ treatment and remained constant through 21 days. BBB integrity was also compromised in ZDF rats at 10 weeks of age. Although these animals had plasma glucose concentrations of about 500 mg/dL, their plasma insulin concentrations were elevated to approximately 5.7 mg/dL. Therefore, we determined if amelioration of hyperglycemia with rosiglitazone, a small molecule thiazolidinedione, attenuated the BBB disruption. Data from these studies are compared with reported data that suggests hyperglycemia controlled with exogenous insulin still resulted in disruption of the BBB. [ABSTRACT FROM AUTHOR]