Long‐term Body Weight Regulation by The Central Melanocortin System Appears to Be Dissociated from Food Intake
Authors: Cote Isabelle , Sakarya Yasemin , Kirichenko Nataliya , Morgan Drake , Carter Christy , Tumer Nihal , Scarpace Philip 
Published: November 2023

The melanocortinergic peptide Melanotan II (MTII) is a potent appetite suppressor that rapidly promotes body weight loss when administered in the brain. Given the rapid loss of anorexic response upon chronic MTII treatment, most investigations focused on the initial physiological adaptations. However, other evidence supports the central melanocortin system as a long‐term modulator of energy balance that yet remains to be addressed. Consequently, we centrally infused either MTII (high dose; 1 μg/day or low dose; 0.04 μg/day) or artificial cerebrospinal fluid (aCSF) in 6 month‐old F344xBN rats (n = 6–7/group) for 40 days to examine the chronic effects of MTII on food intake, body weight, body composition, muscle function, and hypothalamic melanocortin receptor signaling. Central delivery of MTII suppressed appetite for five days in a dose‐dependent manner (P < 0.05). Despite that food intake promptly rose back to control level, body weight remained significantly reduced in MTII groups throughout the duration of the treatment (P < 0.01). Notably, at day 14, lean body mass was increased in rats administered aCSF relative to their respective basal value, whereas lean body mass remained stable (low dose) or decreased (high dose) in animals receiving MTII. At the end of the experiment, both MTII groups displayed approximately 40% smaller intra‐abdominal fat pads (P < 0.01) compared to the aCSF group, indicating that chronic MTII treatment targets white adipose tissues. Interestingly, although rats given MTII high dose had significantly reduced skeletal muscle mass (P < 0.05) compared to aCSF animals, neither spontaneous voluntary exercise and nor grip strength differed between groups, suggesting that MTII did not impair muscle function. At day 40, the hypothalamus of rats treated with MTII high dose was enriched with key molecules from two distinct melanocortin receptor signaling pathways. In fact, hypothalamic Phospho‐p44/42 Mitogen‐Activated Protein Kinase (P‐p44/42 MAPKs) levels of MTII high dose treated animals were six‐fold those of aCSF infused rats. Consistently, Phospho‐cAMP response element (P‐CREB) protein expression was higher (P < 0.01) in rats administered MTII high dose than in control animals. Collectively, the long‐term effects on body weight, intra‐abdominal fat mass, along with the enrichment in key signaling elements suggest that MTII induces durable physiological responses through persistent receptor activation. In conclusion, this study shows that MTII reduces body weight and intra‐abdominal adiposity through a mechanism that appears to be dissociated from changes in food intake. Our study proposes that caloric restriction efficaciously initiates body weight loss; however, combined with a secondary action that preserves a negative energy balance state over time would be a valuable approach to combat obesity.

Support or Funding Information

Supported by the NIH DK091710