The melanocortin agonist melanotan II increases insulin sensitivity in OLETF rats
2004

In the present study, we examined the effects of the peripheral administration of melanocortin agonist MTII on insulin sensitivity and glucose tolerance in OLETF rats. Our data showed that food intake and body weight were decreased by chronic administration of MTII and that insulin sensitivity as well as glucose tolerance was improved by MTII in those rats. The serum TG levels were also decreased by MTII, and these effects persisted for at least 25 days. Thus, our data demonstrated that melanocortin agonists administered peripherally ameliorated obesity, insulin resistance and hypertriglyceridemia in OLETF rats.

The characteristic features of OLETF are late onset of hyperglycemia and hyperinsulinemia. The reported levels of fasted plasma insulin in 30–40 weeks aged OLETF were about 3000–5000 pg/ml in general, although some other reports indicated insulin levels of 700–1000 pg/ml, similar to our study. The reasons for these variations are not clear but could be attributed to the duration of fasting and/or the assay employed. In any case, the insulin levels in OLETF in the present study were about three-fold higher than in LETO rats, as in previous studies. In addition, plasma glucose levels after glucose tolerance in OLETF were significantly higher than in LETO. These data demonstrated that the OLETF rats used in the present study are valid as an animal model of insulin resistance.

The effects of MTII on food intake and body weight in OLETF rats are consistent with a previous study showing that peripheral administration of MTII with the mini-pumps reduced food intake and body weight for about a month in rats fed highly palatable food. As it is also shown that body weight started to increase after the guaranteed delivery time of the mini-pumps, it is likely that MTII in mini-pumps could retain bioactivity for at least a month. The decrease in body weight seems to be mainly due to a decrease in fat mass, as WATs in the MTII treatment group decreased significantly. While both MC3R and MC4R have been implicated in energy homeostasis, it is reported that systemic injection of MTII reduced food consumption to a similar extent in both wild-type and MC3R knockout mice. On the other hand, central or systemic administration of MTII had no effects on food intake or body weight in MC4R knockout mice. Although MTII has a limited brain penetration capability, MC4R is mainly expressed in the central nervous system. Thus, it is likely that peripherally administered MTII acted at MC4R in the brain to reduce food intake, although further study is warranted to prove this.

While it is suggested that central melanocorotin pathways regulate insulin sensitivity in the periphery, the effects of melanocortin agonists on insulin sensitivity are not consistent between studies. The discrepancy could be attributed to differences in the routes for injection, duration of injection and/or animal models employed. In the present study, we administered MTII peripherally to OLETF rats and examined the effects of the chronic administration on insulin sensitivity. Our data clearly demonstrated that insulin sensitivity was improved by MTII administration, which was shown by both ITT and HOMA. The improvement was not simply due to the decrease in food intake or body weight, since there was no such improvement in the pair-fed group in the ITT on day 9. In this regard, Obici et al. showed that central administration of MC4R agonist decreased the visceral fat and increased insulin sensitivity in Sprague–Dawley rats. In our study, while serum TG levels as well as WAT were finally decreased in both MTII and pair-fed groups in the end of the experiment, the serum TG levels on day 9 were dramatically decreased in MTII but not in pair-fed group. As serum TG levels are related with visceral adiposity, it is possible that MTII decreased the visceral adiposity independently of food intake, at least in part, and increased the insulin sensitivity in OLETF rats.

Our data showed that plasma insulin levels in GTT were lower in the MTII group than in the ad libitum OLETF group. These results could be attributed to either the inhibitory effects of MTII on insulin release as reported previously and/or the increase in insulin sensitivity. However, it should be noted that, while the insulin sensitivity was improved in the MTII group on day 9, blood glucose levels at 30 min in GTT were significantly higher in the MTII group than in the pair-fed group on day 11. These data suggest the possibility that, although the plasma insulin levels at 60 min in GTT were not significantly different between the MTII and ad libitum OLETF groups on day 11, insulin release before 60 min might be decreased in the MTII group. Nevertheless, glucose tolerance in MTII was improved to the levels of the pair-fed groups on day 23. The improvement could be, at least partially, due to the further increase in insulin sensitivity as HOMA values were significantly lower in the MTII group than in the ad libitum OLETF group only on day 23. Taken together, our data suggest that, while MTII might have inhibitory effects on insulin release, chronic administration of MTII improves glucose tolerance OLETF rats by increasing insulin sensitivity.

While the inhibitory effect of MTII on food intake persisted for at least 25 days in our studies, the effects were most remarkable during the first 4 days, which are consistent with the findings of Jonsson et al. The relatively short effects of MTII could be due to the down-regulation of the melanocortin receptors and the signal transduction as a result of adaptive process. Nevertheless, there was not full compensation in food intake, and body weight remained significantly lower for about a month in the present study. These data suggest that melanocortin agonists could well be a promising treatment for obesity in humans. Actually, administration of MSH/ACTH4-10, a MC4R agonist, was shown to decrease body weight and body fat in healthy and normal weight humans without apparent side effects.

In conclusion, we demonstrated that peripheral administration of MTII ameliorated insulin resistance, obesity and hypertriglyceridemia in OLETF rats. While further studies with several animal models for insulin resistance are warranted, our data suggest that to explore the possibility of the melanocorotin-agonists as a new therapeutic agent for insulin resistance is an important direction for future research