Mice deficient in inducible nitric oxide synthase (iNOS) were generated to test the idea that iNOS defends the host against infectious agents and tumor cells at the risk of contributing to tissue damage and shock. iNOS-/-mice failed to restrain the replication of Listeria monocytogenes in vivo or lymphoma cells in vitro. Bacterial endotoxic lipopolysaccharide (LPS) caused shock and death in anesthetized wild-type mice, but in iNOS-/-mice, the fall in central arterial blood pressure was markedly attenuated and early death averted. However, unanesthetized iNOS-/-mice suffered as much LPS-induced liver damage as wild type, and when primed with Propionobacterium acnes and challenged with LPS, they succumbed at the same rate as wild type. Thus, there exist both iNOS-dependent and iNOS-independent routes to LPS-induced hypotension and death.

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.

For defining the mechanism of control of sex skin colour in male rhesus macaques (Macaca mulatta) by hormones, a spectrocolorimeter was used to monitor skin redness after administration of testosterone, dihydrotestosterone (a non-aromatizable androgen), oestradiol or fadrozole (an aromatase inhibitor that blocks the conversion of testosterone to oestrogen). Skin blood flow was measured by laser doppler. Eight 9-14 kg, 5-9 year old intact male rhesus macaques were given hormone, fadrozole or vehicle treatments in a cross-over experimental design. Baseline blood flow and colour measurements were taken in four paired tattoo defined areas on the back and legs of each animal (one pair in non-sex skin, three pairs in sex skin). Colour and blood flow measurements were taken 3-4 days after the first dose and, thereafter, once a week for 3-6 weeks. Measurements taken after treatments were compared with baseline and intra-animal comparisons were made between treatment and vehicle for each animal. In all animals after administration of 4 mg testosterone kg-1 (long-acting), redness in the sex skin areas increased (P = 0.032) by day 3 and returned to baseline values by day 7. Administration of 1 mg oestradiol kg-1 day-1 for 4 days caused increased redness in all animals (P = 0.007) similar in magnitude to that caused by testosterone. Administration of 0.1 mg dihydrotestosterone kg-1 day-1 for 4 days resulted in a nonsignificant decrease in redness (P = 0.09) on days 3-7. Treatment with fadrozole (0.25-0.5 mg kg-1 day-1) for 3 weeks caused sex skin to become significantly less red during treatment (P = 0.014). There was no significant change in redness in non-sex skin areas during any treatment. Sex skin blood flow increased in animals treated with testosterone, correlating with increased redness (R = 0.906), while blood flow in non-sex skin was unchanged. Increased redness after treatment with testosterone and oestrogen, no change in redness with treatment with dihydrotestosterone and a decrease in redness after treatment with fadrozole support the conclusion that oestrogen controls sex skin redness, and testosterone acts indirectly through conversion to oestrogen to cause increased sex skin redness in male rhesus macaques.

No abstract

Activation of ␤ 3 adrenergic receptors on the surface of adipocytes leads to increases in intracellular cAMP and stimulation of lipolysis. In brown adipose tissue, this serves to upregulate and activate the mitochondrial uncoupling protein 1, which mediates a proton conductance pathway that uncouples oxidative phosphorylation, leading to a net increase in energy expenditure. While chronic treatment with ␤ 3 agonists in nonprimate species leads to uncoupling protein 1 up-regulation and weight loss, the relevance of this mechanism to energy metabolism in primates, which have much lower levels of brown adipose tissue, has been questioned. With the discovery of L-755,507, a potent and selective partial agonist for both human and rhesus ␤ 3 receptors, we now demonstrate that acute exposure of rhesus monkeys to a ␤ 3 agonist elicits lipolysis and metabolic rate elevation, and that chronic exposure increases uncoupling protein 1 expression in rhesus brown adipose tissue. These data suggest a role for ␤ 3 agonists in the treatment of human obesity.