How Ghrelin and Melanotan II Control Feeding Through an Energy Sensor in the Brain's Amygdala | Research

The takeaway

Ghrelin injection into the brain's central amygdala increased food intake and AMPK activation, while the melanocortin peptide Melanotan II reduced food intake and body weight over 7 days — identifying AMPK as a key signaling node for peptide-driven feeding control.

7-day MTII reduced body weight
Chronic Melanotan II injection into the central amygdala reduced body mass and food intake over 7 days, revealing a sustained melanocortin-AMPK appetite suppression axis in the brain's reward circuitry

What the researchers found

Fasting increased and refeeding decreased AMPK phosphorylation (AMPKThr172) in the central nucleus of the amygdala (CeA), confirming AMPK responds to nutritional status in this brain region.

Intra-CeA ghrelin injection increased both food intake and AMPKThr172 phosphorylation, establishing ghrelin-AMPK signaling as a feeding-promoting pathway in the amygdala. Glucose injection into the CeA decreased feeding, while 2-deoxy-D-glucose (a glucoprivation inducer) increased food intake and blood glucose.

Chronic intra-CeA injection of Melanotan II (MTII) over 7 days reduced body mass and food intake with a slight decrease in AMPKThr172, demonstrating that melanocortin peptide signaling opposes the ghrelin-AMPK feeding axis in this brain region.

Why it matters

The central amygdala is part of the brain's reward circuitry, which drives cravings for calorie-dense, palatable foods. Understanding how peptide hormones like ghrelin control feeding through AMPK in this region could explain why some people struggle with binge eating and food addiction. The finding that Melanotan II can suppress this circuit over 7 days suggests potential therapeutic targets for appetite control that work through the brain's reward system rather than just the hypothalamus.

How the study worked

Eight-week-old male Wistar rats on a chow diet were stereotaxically implanted with cannulas targeting the central amygdala. Researchers injected various modulators directly into the CeA: ghrelin (hunger peptide), glucose, 2-deoxy-D-glucose (glucoprivation agent), and Melanotan II (melanocortin agonist). Food intake was measured after acute injections. For MTII, chronic 7-day injections assessed sustained effects on body weight and food intake. AMPKThr172 phosphorylation was measured via molecular assays. Fasting and refeeding conditions were used to assess baseline AMPK regulation.

What this study cannot tell us

This is a rat study with direct brain injections, a highly invasive approach that doesn't translate directly to clinical treatment. Exact sample sizes per experimental group were not specified in the abstract. The 2DG-induced feeding increase was accompanied by only faint AMPK increases, suggesting AMPK may not be the only feeding signal in the CeA. The Melanotan II effect on AMPK was described as 'slight,' raising questions about whether AMPK fully mediates the melanocortin feeding suppression in this region.

How to read the evidence

This is a preclinical mechanistic study using direct brain injections in rats. While the experimental design is rigorous (stereotaxic cannulation, multiple modulators, both acute and chronic treatments), the invasive approach and animal model limit clinical translation. The findings are hypothesis-generating and contribute to basic neuroscience understanding.

When this study was published

Published in 2024, this study is recent and reflects current interest in understanding how metabolic peptides like ghrelin and melanocortins influence the brain's reward circuitry beyond the hypothalamus.

The bigger picture

Most appetite research focuses on the hypothalamus, but this study highlights the amygdala as another critical brain region for peptide-driven feeding control. By showing that ghrelin and melanocortin peptides (Melanotan II) regulate feeding through AMPK in the amygdala, it bridges the gap between metabolic hormone signaling and reward-driven eating. This is particularly relevant for understanding conditions like binge eating disorder, where food consumption is driven by pleasure and emotional circuits rather than hunger signals alone.

Questions still open

Could targeting AMPK in the central amygdala with systemic drugs reduce binge eating or food addiction behaviors?
How does the ghrelin-AMPK feeding pathway in the amygdala interact with the hypothalamic circuits already known to control appetite?
Do GLP-1 receptor agonists also modulate AMPK signaling in the central amygdala as part of their appetite-suppressing effects?

Common questions

What is the central amygdala's role in eating?

The central amygdala is part of the brain's reward system that makes eating feel pleasurable. This study showed it also contains an energy-sensing enzyme (AMPK) that responds to hunger hormones like ghrelin. When ghrelin activates AMPK here, it drives food intake — potentially explaining why we crave food even when we don't need the calories.

What is Melanotan II and how does it reduce appetite?

Melanotan II is a synthetic peptide that activates melanocortin receptors in the brain, which naturally suppress appetite. When injected directly into the amygdala's reward center, it reduced food intake and body weight over 7 days. This suggests the melanocortin system can override the reward-driven desire to eat through this specific brain region.

Read the original research

Multiple metabolic signals in the CeA regulate feeding: The role of AMPK.

Molecular and cellular endocrinology, 589, 112232

View on PubMed ↗Publisher’s paper ↗

Citation

Castro, Gisele; Mendes, Natália Ferreira; Weissmann, Laís; Quaresma, Paula Gabriele Fernandes; Saad, Mario Jose Abdalla; Prada, Patricia Oliveira. (2024). Multiple metabolic signals in the CeA regulate feeding: The role of AMPK.. Molecular and cellular endocrinology, 589, 112232. https://doi.org/10.1016/j.mce.2024.112232