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Human hepatocellular carcinoma (HCC) is a hypervascular tumor but the mechanisms underlying the process of angiogenesis are not fully understood. Angiopoietins (Ang) have been recently identified as ligands for Tie-2 receptor and are thought to be important factors in vascular maturation and stability during angiogenesis. In this study, we investigated the expression of Ang-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in surgically resected specimens from 46 patients with HCC to determine their potential role in tumor angiogenesis and its progression. VEGF messenger RNA (mRNA) was significantly up-regulated in HCC compared to normal liver tissue from patients with hepatic metastases. No differences were found between HCC and adjacent liver tissue. Meanwhile, Ang-2 mRNA expression in HCC was significantly increased when compared to adjacent liver tissue. On the other hand, Ang-1 and Tie-2 mRNA expression in HCC was not different from that in adjacent liver tissue. Immunohistochemical staining also showed increased Ang-2 protein in HCC. Furthermore, a high Ang-2/1 mRNA ratio in HCC was closely associated with tumor portal vein invasion, tumor diameter, and the microvessel density level as assessed by CD34 immunostaining. With regard to prognosis, the survival time for patients in the high Ang-2/1 mRNA ratio group was significantly poorer when compared with the low Ang-2/1 mRNA ratio group. In conclusion, an increased expression of Ang-2/1 in the presence of VEGF may play a critical role in promoting tumor angiogenesis and progression in human HCC. (HEPATOLOGY 2003;37:1105-1113

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The small intestine has been presumed to release citrulline as a precursor for the endogenous arginine synthesis. We studied the effect of intestinal resection and arginine-free diet on rat physiology. We maintained rats with massively resected small intestine (R rats) and those with transected intestines (T rats) on either control or an arginine-free diet. After 4 wk, R rats fed deficient diet [R(-)] lost weight by a mean of 46 g, whereas R rats fed control diet [R(+)] and T rats fed control [T(+)] and deficient diet [T(-)] gained 30-96 g. Average nitrogen balance was 150, 60, 110, and -33 mg/day for T(+), T(-), R(+), and R(-), respectively. The concentrations of arginine in skeletal muscle were 654, 163, 230, and 84 nmol/g, respectively, and those in plasma were 133, 50, 103, and 54 microM, respectively. The concentrations of citrulline in R rats were halved compared with T rats irrespective of diet. We conclude that arginine is synthesized in a small intestine-dependent manner in the rat.

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The mitochondrial uncoupling protein (UCP) has usually been found only in brown adipose tissue. We recently observed that a chronic administration of the β3-adrenergic agonist CL-316,243 (CL) induced the ectopic expression of UCP in white fat and skeletal muscle in genetic obese yellow KK mice. The aim of the present study was to examine whether UCP could be induced in nongenetic obese animals produced by neonatal injections of monosodiuml-glutamate (MSG). The daily subcutaneous injection of CL (0.1 mg/kg) to MSG-induced obese mice for 2 wk caused significant reductions of body weight (15%) and white fat pad weight (58%). Northern and Western blot analyses showed that CL induced significant expressions of UCP in the white fat and muscle, as well as in brown fat. Immunohistochemical observations revealed that the UCP stains in white fat were localized on multilocular cells and that those in muscle were localized on slow-twitch fibers rich in mitochondria. Immunoelectron microscopy confirmed the mitochondrial localization of UCP in the myocytes. The guanosine 5′-diphosphate (GDP) binding to mitochondria in brown fat doubled after the CL treatment. Moreover, significant GDP binding was detected in the white fat and muscle of the CL-treated mice, at about one-fourth and one-thirteenth the activity of brown fat, respectively, suggesting that ectopically expressed UCP is functionally active. We concluded that the β3-adrenergic agonist CL can induce functionally active UCP in white fat and slow-twitch muscle fibers of obese mice.

The effects of CL 316,243, a highly specific beta 3-adrenoceptor agonist (relative selectivities of 0, 1 and 100,000 for beta 1-, beta 2- and beta 3-receptors, respectively), were evaluated in mice with monosodium L-glutamate (MSG)-induced obesity as well as in control mice injected with physiological saline instead of MSG. Both MSG- and saline-treated mice were divided into three groups and at 8 weeks of age received either CL 316,243 (0.1 or 1.0 mg/kg) or distilled water through a gastric tube for 2 weeks. CL 316,243 not only reduced white adipose tissue mass but also activated brown adipose tissue and systemic metabolism, and hence reduced body mass without affecting food intake. Furthermore, CL 316,243 decreased hyperglycemia and hypertriglyceridemia in MSG-treated mice. However, at the higher dose, CL 316,243 also increased liver triglyceride in MSG-treated mice. These observations suggest that CL 316,243 exerts an anti-obesity effect in mice with MSG-induced obesity and consequently may prove efficacious in the treatment of human obesity.