# Setmelanotide-mediated MC4R activation improves hypothalamic obesity via CaMKK2/AMPK pathways

## TL;DR

Setmelanotide helps treat hypothalamic obesity by activating MC4R through CaMKK2/AMPK pathways, reducing food intake and weight gain.

## Contribution

This study demonstrates setmelanotide's efficacy in treating hypothalamic obesity via MC4R activation and CaMKK2/AMPK signaling.

## Key findings

- Setmelanotide reduced food intake by 60% and caused 23% weight loss in obese rats.
- HO disrupts PVN neuropeptides and inhibits MC4R via CaMKK2/AMPK signaling.
- Setmelanotide restored CaMKK2/AMPK activity and reactivated MC4R neurons.

## Abstract

Hypothalamic obesity (HO) is a disabling disease caused by central nervous system (CNS) damage due to neurosurgery, trauma, or tumors, especially in hypothalamus. The pathological mechanism of its neural circuits is still unclear, and there is currently no corresponding drug due to the complex etiology. G protein-coupled receptors (GPCRs) regulate neural function in many CNS diseases. Among them, melanocortin 4 receptor (MC4R) regulate metabolism and appetite in the hypothalamus. Setmelanotide, an MC4R agonist, has demonstrated anti-obesity effects in genetic forms of obesity; however, its efficacy and mechanisms in HO remain unexplored. This study explored the potential of treating HO by setmelanotide-targeted activation of MC4R in the paraventricular nucleus (PVN). We established a rat hypothalamic injury model to replicate human HO symptoms, such as hyperphagia (50% increase in food intake), elevated Lee index, and more than 25% weight gain. Immunofluorescence and immunoblot analysis showed that HO disrupted the PVN neuropeptides, leading to the inhibition of MC4R via calmodulin-dependent protein kinase kinase 2 (CaMKK2) and AMP-activated protein kinase (AMPK) signaling. Crucially, administration of setmelanotide restored CaMKK2/AMPK activity, reactivated MC4R neurons, and normalized appetite and feeding behavior during fasting-refeeding and the long-term treatment of obese rats (60% reduction in food intake), ultimately reversing obesity (23% weight loss). These findings underscore the critical role of MC4R dysfunction in hypothalamic injury and highlight the strategies to pharmacologically activate MC4R via CaMKK2/AMPK signaling to restore metabolic homeostasis, proposing a translatable therapeutic agent to manage obesity caused by CNS injury.

Illustration comparing POMC and MC4R neuron activity in HO rats before and after Setmelanotide treatment. Left panel shows inactive MC4R receptors with decreased metabolism and increased food intake due to inactive AMPK. Right panel shows active MC4R receptors with Setmelanotide, leading to increased metabolism, decreased food intake, and active AMPK, resulting in expression activation.