Obesity, Is Melanotan II Effective?

Obesity and Melanotan II. Initially it was thought that Melanotan II could be an effective treatment for obesity, like this research paper from 2003 describes. It found that rats treated with MTII lost fat but not through conventional means. Conventionally, fat cells die in a process known as “apoptosis”. This process was not observed however, leading scientists to wonder what caused the fat loss?

DNA fragmentation assay did not support a role for MTII as an apoptotic signal in any of the fat tissues tested. These results show that in addition to reducing food intake and inhibiting body weight gain, intraperitoneal administration of MTII reduces fat mass, most likely by accelerated lipid mobilization, but not by apoptosis.

MTII administered peripherally reduces fat without invoking apoptosis in rats – ScienceDirect

One year later another study was published, this time showing that rats treated with Melanotan II showed lower levels of insulin and cholesterol. The research also demonstrated an improved metabolism in mice treated with the peptide.

This study has demonstrated that, despite reduced hypothalamic MC3/MC4 receptor expression, anorexic and thermogenic responses to MTII are unabated with an initial augmentation of energy expenditure in DIO versus CH rats. The HF-induced up-regulation of UCP1 in BAT may contribute to the immediate increase in MTII-stimulated thermogenesis in DIO rats. MTII also increased fat catabolism in the muscle of DIO rats and improved glucose and cholesterol metabolism in both groups.

Unabated anorexic and enhanced thermogenic responses to melanotan II in diet-induced obese rats despite reduced melanocortin 3 and 4 receptor expression – PubMed (nih.gov)

A year later another research paper offered more evidence that Melanotan II offers potential that rivals what leptin therapy can produce in reducing body fat.

Taken together, the data in the present study show that i3cv doses of leptin and MTII equated to produce similar reductions in food intake cause a similar degree of activation (assessed by cFLI and HPA axis activity) of PVN CRH neurons. Furthermore, reduced sensitivity to leptin might underlie DIO, but this does not rely on reduced sensitivity to or binding of MC receptor ligands. Thus, although leptin therapy has been disproved in this and other studies as an effective treatment strategy to counter DIO (14, 19, 63), MC receptor agonists may be more useful (50, 64–66). The success of the latter strategy may depend on interactions of MC receptor agonists with PVN CRH neurons.

Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats – PubMed (nih.gov)

It seemed as if a magic solution had finally been uncovered which could help millions of people every year feel confident in their own bodies. This 2008 paper discusses MTII as a potential new therapy for obesity.

Melanocortin 3 and 4 receptors (MC3R and MC4R) are widely distributed in the brain, particularly in regions of the hypothalamus implicated in appetite and body weight regulation.

Redalyc.Pharmacologic Treatment of Obesity: Pitfalls and New Promises

Yet, as clinical trials started to proceed, side-effects began to surface. One of the most concerning of these was an increase in hypertension, which is one of the primary concerns of obesity.

Collectively, our findings suggest that MC4R contributes to the elevated excitability of PVN presympathetic neurons, which may be involved in obesity-related hypertension.

Activation of the melanocortin-4 receptor causes enhanced excitation in presympathetic paraventricular neurons in obese Zucker rats – ScienceDirect

Evidence that certain factors must exist for MTII to be effective at managing obesity became apparent.

We also show that POMC-Ptp1b−/− mice show greater MC4R mRNA expression in both hypothalamus and hindbrain tissues, which may suggest altered melanocortinergic “tone” in these mice. To relate these data to our behavioral findings of enhanced 4th icv MTII-induced reductions in food intake in POMC-Ptp1b−/− mice, it is possible that elimination of PTP1B from POMC neurons results in an elevation of downstream MC4R levels possibly through an increase in endogenous α-MSH signaling endemic to the hindbrain.

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

And finally, in 2013, it seemed as if the hope for MTII being a magic bullet for obesity was starting to fade off. Reports from clinical trials indicated that high blood pressure was a problematic side-effect in humans that was not observed in rats.

The development of melanocortin agonists looked initially very promising as antiobesity drugs. However, the long-term administration of the agonist such as MT-II only induces a transient decrease in food intake that resolves within days. The exact explanation of this phenomenon referred to as ‘tachyphylaxis’ remains unknown. In this regard, the benefits of a long-term treatment based on melanocortin agonist drugs might potentially be affected. The very first clinical trials reported so far failed due to efficacy problems or side effects, such as an increase in blood pressure.

Melanotan II – an overview | ScienceDirect Topics

Subsequent research seemed the be the final nails for Melanotan 2 therapy and fat loss. For example, this research paper from 2015 demonstrates that fat content in food actually determines obesity in mice.

Rats on the fcHF diet show stronger food intake inhibition to the melanocortin receptor agonist MTII than rats on the CHOW, fcHS, and fcHFHS diet, which is independent of caloric intake and body weight gain. Our data point toward an important role for diet composition, particularly the dietary fat content, and not obesity in the sensitivity of the melanocortin system.

Frontiers | Inhibitory Effect of the Melanocortin Receptor Agonist Melanotan-II (MTII) on Feeding Depends on Dietary Fat Content and not Obesity in Rats on Free-Choice Diets | Behavioral Neuroscience (frontiersin.org)

Just when it seemed that there was no path forward to consider researching MTII as a possible fat loss therapy, new research surfaced in 2017 which blew the lid off and put Melanotan 2 back on the map as a promising breakthrough in obesity treatment. In fact, this new research showed that activation of the CNS with MTII.

In summary, this study demonstrates that MTII chronically reduces body mass and intraabdominal adiposity without the necessity of maintaining low caloric intake. Given the very low success rate of dietary approaches, targeting additional pathways to changes in feeding behaviours would support body mass loss maintenance. From a clinical point of view, our study suggests that caloric restriction efficaciously initiates body mass loss despite normalization of food intake; however, a combination with secondary actions that preserve a negative energy balance state over time, such as targeting melanocortin receptors, may be a valuable tool to combat obesity. Given the complexity of targeting neural receptors, future studies in our lab will aim at examining whether long-term peripheral administration of MTII, a more translational approach for humans, would yield similar physiological responses. Additional experiments could also assess whether intermittent peripheral administration may extend MTII efficacy over a longer period of time.

Activation of the central melanocortin system chronically reduces body mass without the necessity of long-term caloric restriction (nih.gov)

That hope was followed up a year later with research suggesting that diet scheduling has more impact on blood pressure than MTII independently.

Our studies indicate that restricting caloric intake to the active period may be a potential intervention to reduce blood pressure. Because overweight and obesity are associated with other health complications, losing weight should remain a major focus. However, caloric restriction in the treatment of obesity can be difficult to achieve in the long term (20) and can lead to eating pathologies (37). Therefore, focusing on feeding schedule and timed MTII therapy may constitute effective therapeutic strategies to obtain some clinical benefits such as blood pressure reduction, even in the absence of weight loss.

Limiting feeding to the active phase reduces blood pressure without the necessity of caloric reduction or fat mass loss | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology

Then in late 2020, new research appeared which looked at how MTII therapy can improve the thermogenic capabilities on mice who are deficient in a variety of peptides.

Results presented here provide physiological evidence to suggest that PACAP acts upstream of melanocortin receptors to facilitate sympathetically induced mechanisms of adaptive thermogenesis in response to cold acclimation.

Melanotan II, a melanocortin agonist, partially rescues the impaired thermogenic capacity of pituitary adenylate cyclase‐activating polypeptide deficient mice – McMillan – 2021 – Experimental Physiology – Wiley Online Library

Most recently research was published which collaborates these findings and demonstrate that Zebrafish who are deficient in alpha melanocyte stimulating hormone (the bodies endogenous MTII) suffered ravenous appetites, and an increased predisposition to store fat.

Our results show that α-MSH is a key regulator of POMC signaling in appetite regulation and energy expenditure, suggesting that it might be a potential therapeutic target for treating human obesity.

Biomedicines | Free Full-Text | Depletion of Alpha-Melanocyte-Stimulating Hormone Induces Insatiable Appetite and Gains in Energy Reserves and Body Weight in Zebrafish (mdpi.com)

So, with all this research is it safe to say MTII can treat obesity? No, it is still not appropriate or responsible to claim MTII can treat anything at this point except those instances where MTII has been approved by the FDA and marketed as a drug – like Clinuvel has done with Scenesse which is a treatment for photosensitivity disorder.

What this research DOES imply is that there is merit to researching MTII for its potential to be a weight control therapy. If you are looking to control your weight, we recommend seeing a dietitian or a trained nutritionist who can guide you towards positive eating habits. As some of the above research demonstrates, diet will have a significant effect on obesity.