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Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-[alpha]-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance. C1 complement; gene expression doi:10.1152/ajpendo.00664.2006

Role of the nitric oxide pathway in AMPK-mediated glucose uptake and GLUT4 translocation in heart muscle. Am J Physiol Endocrinol Metab 287: E834-E841, 2004. First published July 20, 2004; doi:10.1152/ajpendo.00234.2004.--AMP-activated protein kinase (AMPK) is a serine-threonine kinase that regulates cellular metabolism and has an essential role in activating glucose transport during hypoxia and ischemia. The mechanisms responsible for AMPK stimulation of glucose transport are uncertain, but may involve interaction with other signaling pathways or direct effects on GLUT vesicular trafficking. One potential downstream mediator of AMPK signaling is the nitric oxide pathway. The aim of this study was to examine the extent to which AMPK mediates glucose transport through activation of the nitric oxide (NO)-signaling pathway in isolated heart muscles. Incubation with 1 mM 5-amino-4-imidazole-1-[beta]-carboxamide ribofuranoside (AICAR) activated AMPK (P < 0.01) and stimulated glucose uptake (P < 0.05) and translocation of the cardiomyocyte glucose transporter GLUT4 to the cell surface (P < 0.05). AICAR treatment increased phosphorylation of endothelial NO synthase (eNOS) ~1.8-fold (P < 0.05). eNOS, but not neuronal NOS, coimmunoprecipitated with both the [[alpha].sub.2] and [[alpha].sub.1] AMPK catalytic subunits in heart muscle. NO donors also increased glucose uptake and GLUT4 translocation (P < 0.05). Inhibition of NOS with [N.sup.[omega]]-nitro-L-arginine and [N.sup.[omega]]-methyl-L-arginine reduced AICAR-stimulated glucose uptake by 21 [+ or -] 3% (P < 0.05) and 25 [+ or -] 4% (P < 0.05), respectively. Inhibition of guanylate cyclase with ODQ and LY-83583 reduced AICAR-stimulated glucose uptake by 31 [+ or -] 4% (P < 0.05) and 22 [+ or -] 3% (P < 0.05), respectively, as well as GLUT4 translocation to the cell surface (P < 0.05). Taken together, these results indicate that activation of the NO-guanylate cyclase pathway contributes to, but is not the sole mediator of, AMPK stimulation of glucose uptake and GLUT4 translocation in heart muscle. nitric oxide synthase; AMP-activated protein kinase; glucose transporter

Research was conducted to examine the hypothesis that calorie restriction (CR) increases cell surface GLUT-4 in insulin-stimulated skeletal muscle. The effects of CR were tested on cell surface GLUT-4 content by exofacial photolabeling with 2-N-4-(1-azi,2,2,2-trifluoroethyl)-benzoyl-1,2-bis-(D-mannos-4-yloxy)-2-prop lamine in basal and insulin-stimulated muscles. Results indicate that CR enhances the ability of insulin to increase the number and the ability of glucose transporters at the cell surface.

Research was conducted to examine the potential importance of muscle glycogen in the inhibited glucose transport response to hypoxia. Glucose transport and glycogen responses to hypoxia were studied in rat skeletal muscle after muscle glycogen level was manipulated by food restriction and exercise training. Results indicate the existence of a strong inverse relationship between hypoxia-stimulated glucose transport activity and glycogen.

The relationship between glucose transport activity and cell surface glucose transporters after exercise was analyzed in fast- and slow-twitch muscles of obese Zucker rats that were subjected to in vitro contractions. The levels of glucose transporters such as GLUT-4 was significantly enhanced by exercise in the slow- and fast-twitch muscles of obese Zucker rats. However, cell surface GLUT-4 was not altered by exercise in the absence of insulin.

The epitrochlearis muscle was isolated from rats under a five-day exercise program and analyzed to determine the effects of exercise training on glucose transport activity in the skeletal muscles. Rat epitrochlearis muscle exhibited improved insulin-stimulated glucose transport activity that was mediated by increased levels of GLUT-4 on the cell surface from a larger total muscle GLUT-4 pool. However, high levels of muscle glycogen coupled with exercise inhibited hypoxia-stimulated glucose transport activity by reducing the increase in cell surface GLUT-4.

The inability to increase the cell surface GLUT-4 protein level decreases the glucose transport response to insulin in the soleus and epitrochlearis skeletal muscles of the obese Zucker rat. The glucose transport stimulated by insulin is lower in both muscles of the obese rat as compared to that in lean rats. Muscle contraction causes similar glucose transport increases in both lean and obese rats. The effect is more significant in the fast-twitch muscles as compared to that in slow-twitch muscles.

The thyroid hormone, 3,5,3'-triiodo-L-thyronine (T3), increases the transport of glucose in the ARL 15 cell line, derived from rat liver, by increasing the translocation of the GLUT-1 glucose transporter to the plasma membrane. T3 exposure for 48 hours also increases the concentration of GLUT-1 protein in the cell. This increase in the partitioning of GLUT-1 to the plasma membrane is probably by fusion of the GLUT-1 containing vesicles to the plasma membrane.

Tyrosine kinase-deficient mutant insulin receptors, expressed in high concentrations in transfected rat adipose cells, do not mediate GLUT4 translocation in the basal cell surface and shift the insulin dose-response curve. These properties assign the insulin receptor tyrosine kinase activity to insulin-stimulated glucose transport in the rat adipose cells and elucidate the insulin signal transduction pathway involved in the glucose transport.