Epidemiological studies suggest that obesity increases the risk of developing several cancers, including melanoma. Obesity increases the expression of angiogenic factors, such as leptin, that may contribute to tumor growth. However, a direct cause and effect relationship between obesity and tumor growth has not been clearly established and the role of leptin in accelerating tumor growth is unclear. Our objective in the present study was to examine the rate of melanoma tumor growth in lean and obese mice with leptin deficiency or high levels of plasma leptin. We injected 1 × 106 B16F10 melanoma cells subcutaneously into lean wild type (WT), obese melanocortin receptor 4 knockout (MC4R−/−), which have high leptin levels, obese leptin-deficient(ob −/−), pair fed lean ob−/−, and lean ob+/− mice. Mean body weights were 29.7 ± 0.3 g (WT), 46.3 ± 1.9 g (MC4R−/−), 63.7 ± 0.9 g (ob−/−), 30.5 ± 1.0 g (pair fed ob−/−) and 31.6 ± 1.7 g (ob+/−). Tumors were much larger in the obese leptin deficientob−/− (5.1 ± 0.9 g) and obese MC4R−/− (5.1 ± 0.7 g) than in lean WT (1.9 ± 0.3 g) and ob+/− (2.8 ± 0.7 g) mice. prevention of obesity by pair feeding ob−/− mice dramatically reduced tumor weight (0.95 ± 0.2 g) to a level that was significantly lower than in WT mice of the same weight. Tumor VEGF levels were the highest in the obese mouse tumors (p < 0.05), regardless of the host leptin levels. Except for the lean ob+/−, MC4R−/− and ob−/− melanomas had the highest VEGF receptor 1 and VEGF receptor 2 protein expression (p < 0.01 and p < 0.05), respectively. These results indicate that obesity markedly increases melanoma tumor growth rate by mechanisms that may involve upregulation of VEGF pathways. although tumor growth does not require host leptin, melanoma tumor growth may be accelerated by leptin.

Abstract-Previous studies suggest that activation of the CNS melanocortin system reduces appetite while increasing sympathetic activity and arterial pressure. The present study tested whether endogenous activity of the CNS melanocortin 3/4 receptors (MC3/4-R) contributes to elevated arterial pressure in the spontaneously hypertensive rat (SHR), a model of hypertension with increased sympathetic activity. A cannula was placed in the lateral ventricle of male SHR and Wistar (WKY) rats for chronic intracerebroventricular (ICV) infusions (0.5 L/h). Mean arterial pressure (MAP) and heart rate (HR) were recorded 24 hour/d using telemetry. After 5-day control period, rats were infused with MC3/4-R antagonist (SHU-9119, 1 nmol/h-ICV) for 12 days, followed by 5-day posttreatment period. MC3/4-R antagonism increased food intake in SHR by 90% and in WKY by 125%, resulting in marked weight gain, insulin resistance, and hyperleptinemia in SHR and WKY. Despite weight gain, MC3/4-R antagonism reduced HR in SHR and WKY (Ϸ40 bpm), while lowering MAP to a greater extent in SHR (Ϫ22Ϯ4 mm Hg) than WKY (Ϫ4Ϯ3 mm Hg). SHU9119 treatment failed to cause further reductions in MAP during chronic adrenergic blockade with propranolol and terazosin. These results suggest that endogenous activity of the CNS melanocortin system contributes to the maintenance of adrenergic tone and elevated arterial pressure in SHR even though mRNA levels for POMC and MC4R in the mediobasal hypothalamus were not increased compared to WKY. These results also support the hypothesis that weight gain does not raise arterial pressure in the absence of a functional MC3/4-R. Key Words: leptin Ⅲ melanocortin Ⅲ hypertension Ⅲ food intake Ⅲ blood pressure Ⅲ POMC Ⅲ insulin P revious studies from our laboratory and others indicate that leptin, an adipocyte derived cytokine, may be an important link between obesity, sympathetic activation, and hypertension. Chronic leptin infusion in rodents not only reduces appetite but also raises arterial pressure and heart rate 1 by increasing sympathetic nervous system (SNS) activity. [2][3][4][5] Although the mechanisms involved in mediating the effects of leptin on SNS activity and cardiovascular function have not been fully elucidated, activation of proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulation of the melanocortin receptor types 3 and 4 (MC3/4-R) appear to play a key role. We recently showed that chronic blockade of the brain MC3/4R by intracerebroventricular (ICV) infusion of the antagonist, SHU-9119, completely prevented the effects of leptin to reduce food intake and to raise arterial pressure and heart rate. 6 SHU-9119 also blocked leptin-induced increases in renal SNS activity. 7,8 Furthermore, mice lacking a functional MC4-R receptor are totally unresponsive to the chronic effects of leptin to raise arterial pressure and reduce food intake. 9 These results suggest that an intact central MC3/4-R is required for leptin to exert its effects on food intake and cardiovascular fu...

Polymorphonuclear neutrophils (PMN) infiltrate the respiratory tract early after viral infection and can contribute to both host defence and pathology. Coronaviruses are important causes of respiratory tract infections, ranging from mild to severe depending on the viral strain. This study evaluated the role of PMN during a non-fatal pulmonary coronavirus infection in the natural host. Rat coronavirus (RCoV) causes respiratory disease in adult rats, characterized by an early PMN response, viral replication and inflammatory lesions in the lungs, mild weight loss and effective resolution of infection. To determine their role during RCoV infection, PMN were depleted and the effects on disease progression, viral replication, inflammatory response and lung pathology were analysed. Compared with RCoV infection in control animals, PMN-depleted rats had worsened disease with weight loss, clinical signs, mortality and prolonged pulmonary viral replication. PMNdepleted animals had fewer macrophages and lymphocytes in the respiratory tract, corresponding to lower chemokine levels. Combined with in vitro experiments showing that PMN express cytokines and chemokines in response to RCoV-infected alveolar epithelial cells, these findings support a role for PMN in eliciting an inflammatory response to RCoV infection. Despite their critical role in the protection from severe disease, the presence of PMN was correlated with haemorrhagic lesions, epithelial barrier permeability and cellular inflammation in the lungs. This study demonstrated that while PMN are required for an effective antiviral response, they also contribute to lung pathology during RCoV infection.