- Chemical structure of Melanotan II by TheCook, made available under the terms of the Creative Commons Attribution-Share Alike 3.0 Unported license.

What is Melanotan II?

This is an analog of the alpha-melanocyte-stimulating hormone, and an agonist of the melanocortin receptor types 3 and 4 (MCR3 and MCR4)^1,2. The melanocortin system in the central nervous system is associated with the regulation of social, emotional and food intake behaviors. It is also associated with a role in mediating the beneficial effects of leptin in rats with uncontrolled diabetes³. The MCR4 receptor is also associated with the regulation of bodyweight⁴. Defective MCR4 is associated with disorders of satiety and with early-onset obesity⁵.

Studies of Melanotan II and its Functions

Social Functions

Melanotan II may be able to influence factors such as partner preference in monogamous animals. This molecule was found to enhance this behavior in prarie voles, but not in more polygamous meadow voles¹. This was found to be associated with the activation of oxytocin-releasing neurons in the hypothalamus and the enhancement of oxytocin release by melanotan II¹. Subcutaneous administration of 10 mg/kg melanotan II to males and female neonates of the same species for the first seven days of life resulted in reduced play-fighting in males compared to matched controls⁶. It also enhanced partner preference in the treated females in adulthood⁶.

Metabolic and Cardiovascular Functions

The administration of melanotan II in a rat model of diabetes did not appear to reduce hyperglycemia³. Intraperitoneal melanotan II was associated with rapid decreases in body temperature and energy expenditure⁴. This did not affect feeding, however⁴. The effect of melanotan II on body temperature was found to be independent of MCR4 receptor availability, and may be linked to activity at vasopressin V1a receptors instead⁴. The infusion of melanotan II into the medial preoptic nuclei of rat brains was associated with thermogenesis in brown adipose tissue². The molecule was also found to be associated with the expression of proteins involved in lipolysis and lipogenesis². These actions appear to be regulated by the dorsomedial hypothalamus². Knockdown studies in rats indicates that AMP-activated protein kinase (AMPK) may be involved in the mediation of melanotan II activity⁷.

The microinjection of melanotan II into the paraventricular nucleus of rat brains resulted in an increase in mean arterial pressure⁸. MCR3 and 4 antagonists reversed this effect⁸. Melanotan II also increased cAMP in the paraventricular nucleus⁸. Another study compared mice with MCR4 receptor deficiency to identical animals with selectively restored MCR4 in proopiomelanocortin neurons. (These are associated with the effects of leptin on energy homeostasis⁹. The knockout of PTP1B, the negative regulator of leptin in these cells, was associated with increased sensitivity to the effects of melanotan II on feeding, bodyweight and energy expenditure in KO mice compared to controls⁹.) This resulted in observations of increased bodyweight and decreased energy expenditure in the MCR4-deficient mice only, although feeding, blood pressure and heart rate were similar between the two groups¹⁰. This may further indicate the role of this receptor - and thus of melanotan II - in energy homeostasis and bodyweight control.

References: 

1. Modi ME, Inoue K, Barrett CE, et al. Melanocortin receptor agonists facilitate oxytocin-dependent partner preference formation in the prairie vole. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015.

2. Monge-Roffarello B, Labbe SM, Lenglos C, et al. The medial preoptic nucleus as a site of the thermogenic and metabolic actions of melanotan II in male rats. American journal of physiology. Regulatory, integrative and comparative physiology. 2014;307(2):R158-166.

3. Meek TH, Matsen ME, Damian V, Cubelo A, Chua SC, Jr., Morton GJ. Role of melanocortin signaling in neuroendocrine and metabolic actions of leptin in male rats with uncontrolled diabetes. Endocrinology. 2014;155(11):4157-4167.

4. Xu Y, Kim ER, Fan S, et al. Profound and rapid reduction in body temperature induced by the melanocortin receptor agonists. Biochemical and biophysical research communications. 2014;451(2):184-189.

5. Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. International journal of obesity (2005). 2014;38(2):163-169.

6. Barrett CE, Modi ME, Zhang BC, Walum H, Inoue K, Young LJ. Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner. Neuropharmacology. 2014;85:357-366.

7. Tanida M, Yamamoto N, Shibamoto T, Rahmouni K. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PloS one. 2013;8(2):e56660.

8. Li P, Cui BP, Zhang LL, Sun HJ, Liu TY, Zhu GQ. Melanocortin 3/4 receptors in paraventricular nucleus modulate sympathetic outflow and blood pressure. Experimental physiology. 2013;98(2):435-443.

9. De Jonghe BC, Hayes MR, Zimmer DJ, Kanoski SE, Grill HJ, Bence KK. Food intake reductions and increases in energetic responses by hindbrain leptin and melanotan II are enhanced in mice with POMC-specific PTP1B deficiency. American journal of physiology. Endocrinology and metabolism. 2012;303(5):E644-651.

10. do Carmo JM, da Silva AA, Rushing JS, Pace B, Hall JE. Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons. American journal of physiology. Regulatory, integrative and comparative physiology. 2013;305(4):R359-368.