Loss of brain melanocortin receptors (Mc3rKO and Mc4rKO) causes increased adiposity and exacerbates diet-induced obesity (DIO). Little is known about how Mc3r or Mc4r genotype, diet, and obesity affect insulin sensitivity. Insulin resistance, assessed by insulin and glucose tolerance tests, Ser(307) phosphorylation of insulin receptor substrate 1, and activation of protein kinase B, was examined in control and DIO wild-type (WT), Mc3rKO and Mc4rKO C57BL/6J mice. Mc4rKO mice were hyperphagic and had increased metabolic efficiency (weight gain per kilojoule consumed) relative to WT; both parameters increased further on high-fat diet. Obesity of Mc3rKO was more dependent on fat intake, involving increased metabolic efficiency. Fat mass of DIO Mc3rKO and Mc4rKO was similar, although Mc4rKO gained weight more rapidly. Mc4rKO develop hepatic insulin resistance and severe hepatic steatosis with obesity, independent of diet. DIO caused further deterioration of insulin action in Mc4rKO of either sex and, in male Mc3rKO, compared with controls, associated with increased fasting insulin, severe glucose intolerance, and reduced insulin signaling in muscle and adipose tissue. DIO female Mc3rKO exhibited very modest perturbations in glucose metabolism and insulin sensitivity. Consistent with previous data suggesting impaired fat oxidation, both Mc3rKO and Mc4rKO had reduced muscle oxidative metabolism, a risk factor for weight gain and insulin resistance. Energy expenditure was, however, increased in Mc4rKO compared with Mc3rKO and controls, perhaps due to hyperphagia and metabolic costs associated with rapid growth. In summary, DIO affects insulin sensitivity more severely in Mc4rKO compared with Mc3rKO, perhaps due to a more positive energy balance.

Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r, Mc4r). PG946 is a derivative of a hybrid of alpha-and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.

To induce deliberate hypotension during anesthesia, nicardipine was administered to patients undergoing total hip arthroplasty and was randomly compared with nitroprusside. Hemodynamic measurements were performed before and 10, 20, 30, and 60 min after starting to administer either nicardipine (n = 12) or nitroprusside (n = 12) (B, T1, T2, T3, and T4, respectively); at the end of drug infusion (T5); and 10, 20, and 60 min later (T6, T7, and T8, respectively). Plasma renin activity and catecholamine levels were measured at B, T1, T5, T6, and T7. In addition, plasma nicardipine concentration was measured in five patients at T1, T2, T5, T7, and T8. As with nitroprusside, nicardipine administration (1-3 micrograms.kg-1.min-1, after a titration dose of 4.7 +/- 1.5 mg) resulted in hypotension (up to -34% +/- 3%), a decrease in systemic vascular resistances (up to -49% +/- 4%), and increases in heart rate (up to +17% +/- 6%), cardiac index (up to +37% +/- 8%), plasma norepinephrine (up to +63% +/- 17%) and epinephrine (up to +232% +/- 68%) levels, and plasma renin activity (up to +336% +/- 207%). Ten and 20 minutes after discontinuation of the hypotensive drug, nicardipine led to persistent vasodilation and hypotension, which differed significantly from the hypertensive rebound observed after nitroprusside discontinuation, despite a similar increase in plasma renin activity and catecholamine levels. Our results indicate that after the infusion was terminated, the nicardipine-induced vasodilation was opposed to the vasoconstrictive effects of angiotensin II and catecholamines, thus avoiding hypertensive rebound.(ABSTRACT TRUNCATED AT 250 WORDS)

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