Pro-opiomelanocortin gene transfer to the nucleus of the solitary track but not arcuate nucleus ameliorates chronic diet-induced obesity.

Short-term pharmacological melanocortin activation deters diet-induced obesity (DIO) effectively in rodents. However, whether central pro-opiomelanocortin (POMC) gene transfer targeted to the hypothalamus or hindbrain nucleus of the solitary track (NTS) can combat chronic dietary obesity has not been investigated. Four-weeks-old Sprague-Dawley rats were fed a high fat diet for 5 months, and then injected with either the POMC or control vector into the hypothalamus or NTS, and body weight and food intake recorded for 68 days. Insulin sensitivity, glucose metabolism and adrenal indicators of central sympathetic activation were measured, and voluntary wheel running (WR) assessed. Whereas the NTS POMC-treatment decreased cumulative food consumption and caused a sustained weight reduction over 68 days, the hypothalamic POMC-treatment did not alter cumulative food intake and produced weight loss only in the first 25 days. At death, only the NTS-POMC rats had a significant decrease in fat mass. They also displayed enhanced glucose tolerance, lowered fasting insulin and increased QUICK value, and elevated adrenal indicators of central sympathetic activation. Moreover, the NTS-POMC animals exhibited a near 20% increase in distance ran relative to the respective controls, but the ARC-POMC rats did not. In conclusion, POMC gene transfer to the NTS caused modest anorexia, persistent weight loss, improved insulin sensitivity, and increased propensity for WR in DIO rats. These metabolic improvements may involve stimulation of energy expenditure via centrally regulated sympathetic outflow. The similar POMC treatment in the hypothalamus had minimal long-term physiological or metabolic impact. Thus, melanocortin activation in the brainstem NTS region effectively ameliorates chronic dietary obesity whilst that in the hypothalamus fails to do so.

Insulin resistance and associated dysfunction of resistance vessels and arterial hypertension.

Insulin resistance (IR) has profound, negative effects on the function of arteries and arterioles throughout the body and leads to arterial hypertension and vascular occlusive diseases such as heart attacks and strokes. IR affects arteries and arterioles at both the endothelium and smooth muscle levels. One major, underlying mechanism of vascular dysfunction appears to involve the augmented generation, availability and subsequent actions of reactive oxygen species (ROS). Thus, application of superoxide dismutase (SOD), a specific scavenger of superoxide anion, is able to immediately restore normal dilator responsiveness in IR arteries. In some but not all circulations, however, other factors such as increased production of and actions by constrictor agents such as endothelin also appear to restrict normal dilator responses. The basis of ROS-mediated vascular dysfunction in IR is not completely understood, but inflammatory processes throughout the arterial wall appear to be involved. Treatments involving behavioral approaches, such as changes in diet, weight loss, and regular exercise, and pharmacological approaches, involving the use of insulin-sensitizing agents or statins, appear to offer benefits against the detrimental vascular effects of IR. Nonetheless, the most effective approach appears to involve prevention of IR via adoption of a healthy lifestyle by young people.

The cerebrocortical microcirculatory effect of nitric oxide synthase blockade is dependent upon baseline red blood cell flow in the rat.

The effects of nitric oxide synthase (NOS) blockade on the cerebrocortical microcirculation were investigated under physiological conditions in anesthetized ventilated rats using laser-Doppler (LD) flowmetry. LD flow values of the parietal cortex were determined before and after systemic administration of the NOS inhibitor N(G)-nitro-L-arginine-methyl-esther. NOS blockade reduced the LD flow significantly and the magnitude of the reduction was in close correlation with the baseline value. Synchronized sinus-wave-like LD flow oscillations were observed frequently after NOS inhibition and their appearance was also dependent on the high baseline flow values. These results indicate marked, baseline-dependent differences in the cerebrocortical blood flow response to the inhibition of the nitric oxide pathway, and may suggest that areas with high resting red blood cell flow express high NOS activity.