Animal only
This animal study investigated whether two synthetic analogs of the ACTH(4-10) peptide fragment — Semax (ACTH(4-7)-Pro-Gly-Pro) and Melanotan II (MTII), a melanocortin receptor agonist — possess antidepressant-like and antistress properties in a chronic unpredictable stress (CUS) rat model of depression. Male adult Sprague-Dawley rats were subjected to CUS and received daily intraperitoneal injections of either saline or a low dose of Semax or MTII. Outcomes assessed included body weight, hedonic status via the sucrose preference test, adrenal gland weight, hippocampal BDNF levels, and immobility in the forced swim test. The study found that both Semax and MTII reversed or substantially reduced CUS-induced anhedonia, suppressed body weight gain, adrenal hypertrophy, and decreased hippocampal BDNF levels. Neither the CUS procedure nor the peptide treatments produced significant effects on immobility in the forced swim test. The authors concluded that systemically administered ACTH(4-10) analogs may have therapeutic potential for depression and stress-related conditions. Key limitations include the exclusive use of male rats, an animal-only design with no human data, and restriction to a single dose level.
European journal of pharmacology · Oct 2024DOI ↗ Animal only
This mouse study investigated therapeutic strategies for hyperphagia, hyperglycemia, and obesity caused by a loss-of-function mutation in the Htr2c gene (Htr2cF327L/Y), which encodes the serotonin 2C receptor (5-HT2CR). Researchers tested three main approaches in male mice fed a high-fat diet. First, they used viral re-expression of functional 5-HT2CR specifically in hypothalamic POMC neurons, finding this was sufficient to reduce food intake and body weight, and restored neuronal responsiveness to lorcaserin (a selective 5-HT2CR agonist). Second, they administered melanotan II, an MC4R agonist, which effectively suppressed feeding and weight gain. Third, they promoted voluntary wheel-running exercise, which reduced high-fat diet consumption and improved glucose homeostasis. The study highlights the importance of the 5-HT2CR–melanocortin pathway in energy balance regulation and suggests MC4R agonists and physical activity may be relevant strategies for individuals carrying rare Htr2c variants. Key limitations include exclusive use of a single male mouse model, a specific engineered mutation, and the gap between rodent models and human metabolic disease.
Endocrinology · May 2024DOI ↗ Animal only
This animal study investigated whether AMP-activated protein kinase (AMPK) in the central nucleus of the amygdala (CeA) serves as an intracellular signaling mediator linking metabolic cues—ghrelin, fasting, and glucoprivation—to food intake regulation. Male Wistar rats were surgically implanted with cannulas in the CeA and received intra-CeA injections of various modulators, including glucose, 2-deoxy-D-glucose (2DG), ghrelin, and Melanotan II (MTII). The study measured AMPK phosphorylation at Thr172 (AMPKThr172) alongside food intake and body weight. Key findings attributed to the study include: fasting increased and refeeding reduced CeA AMPKThr172; intra-CeA glucose reduced food intake while 2DG (a glucoprivation inducer) increased food intake and blood glucose with modest AMPKThr172 elevation; intra-CeA ghrelin increased both food intake and AMPKThr172; and chronic intra-CeA MTII injection reduced body mass and food intake over seven days alongside a slight reduction in AMPKThr172. Limitations include use of a single rodent model, small and unspecified sample sizes per group, and the inability to establish direct causality between AMPK activation and feeding behavior. No human data were collected.
Molecular and cellular endocrinology · Apr 2024DOI ↗ Animal only
This animal study investigated how the melanocortin receptor agonist Melanotan II (MTII) affects brain activity in prairie voles, with a focus on whether its effects depend on social context and the oxytocin system. Researchers administered MTII to male and female prairie voles either before social interactions or in non-social conditions, then used Fos expression (a marker of neuronal activation) to map brain activity. In non-social contexts, MTII activated only the hypothalamic paraventricular nucleus (PVN), the brain's primary site of oxytocin production. However, when MTII was given before social interactions, it selectively increased oxytocin-dependent activation in the nucleus accumbens — a region critical for social learning and reward. The authors propose this mechanism may explain how MTII accelerates partner preference formation (a model of social bonding) seen in earlier studies. The study frames these findings as supportive of a treatment model where endogenous oxytocin is pharmacologically stimulated during behavioral therapy, rather than via chronic exogenous oxytocin supplementation. Limitations include the use of a single animal species, an animal-only design, and the inherent challenges of translating prairie vole social bonding models to human psychiatric conditions such as autism.
Neuropharmacology · Jan 2024DOI ↗ Animal only
This study investigated whether a short-term high-fat (HF) diet could impair neurobehavioral outcomes in zebrafish (Danio rerio) and whether treatment with Melanotan-II (MT-II), a melanotropin receptor agonist, could reverse those effects. Zebrafish were fed an HF diet for approximately three weeks — roughly 1% of their lifespan — and then assessed for recognition memory, anxiety levels, and exploratory behavior. The researchers found that zebrafish on the HF diet showed measurable impairments in recognition memory, elevated anxiety, and reduced exploratory behavior compared to control-diet animals. Notably, HF-diet zebrafish that also received MT-II treatment demonstrated memory, anxiety, and exploratory behavior comparable to the control group, suggesting a reversal of HF diet-induced changes. The authors describe this as the first study demonstrating MT-II's ability to reverse short-term HF diet-induced neurobehavioral abnormalities. Key limitations include the use of a non-mammalian animal model (zebrafish), which limits direct translation to human neurology, and the absence of mechanistic data clarifying how MT-II acts on the relevant brain pathways. No human or clinical data are presented.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · Jul 2023DOI ↗ Animal only
This animal study investigated how the central nervous system melanocortin (CNS-MC) system influences feed intake, metabolic hormones, and insulin sensitivity in sheep. Ewes were surgically fitted with intracerebroventricular (ICV) cannulas and infused with artificial cerebrospinal fluid (aCSF), the α-MSH analog melanotan-I (MTI), or agouti-related peptide (AGRP) directly into the third ventricle. The study found that ICV MTI infusion significantly reduced voluntary feed intake, while AGRP infusion modestly increased it. MTI also elevated plasma triiodothyronine and thyroxine independently of changes in food intake, suggesting a direct central effect on thyroid hormone regulation. Notably, MTI did not affect plasma glucose, insulin, or cortisol under normal feeding conditions. However, during hyperinsulinemic-euglycemic clamp experiments in energy-restricted ewes, MTI impaired insulin's ability to suppress endogenous glucose production, indicating reduced hepatic insulin sensitivity. MTI also tended to lower plasma leptin in a feeding-level-dependent manner, with no effect on adiponectin. AGRP infusion did not significantly alter any measured plasma metabolic variables. The authors concluded that the CNS-MC system plays a role in regulating metabolic efficiency and peripheral insulin action in ruminants. Limitations include small sample sizes, a single non-human species, and the invasive ICV delivery route.
Journal of animal science · Jan 2023DOI ↗ Animal only
This preclinical study investigated the neurological mechanisms by which obesity medications suppress food intake, focusing on proglucagon (PPG)-expressing neurons in the nucleus of the solitary tract (PPG-NTS). Using single-nucleus RNA sequencing and histochemistry, researchers characterized gene expression profiles of PPG-NTS neurons in rodents, finding that serotonin 2C receptors (5-HT2CR) — the target of lorcaserin — were widely expressed in these neurons, while GLP-1 receptors and melanocortin-4 receptors were not. Lorcaserin was found to significantly activate PPG-NTS neurons. When PPG-NTS neurons were virally ablated, lorcaserin lost its ability to suppress food intake, whereas the MC4R agonist melanotan-II retained its effect, confirming the functional role of 5-HT2CR expression in these neurons. Additionally, combining lorcaserin with GLP-1R agonists liraglutide or exendin-4 produced greater food intake reduction than either drug alone. The study concludes that PPG-NTS neurons are a necessary mechanistic link for lorcaserin's appetite-suppressing effects and suggests that combining 5-HT2CR and GLP-1R agonists may enhance therapeutic outcomes. Key limitations include that all experiments were conducted in animals, and translational relevance to humans remains to be established.
Molecular metabolism · Dec 2022DOI ↗ Animal only
This study investigated the role of melanocortin signaling in the nucleus accumbens (NAcc) on food intake and motivation to eat in mice. Male C57BL/6J mice received bilateral microinjections of melanotan-II (MT-II), a melanocortin receptor 3/4 agonist, directly into the NAcc, and researchers measured effects on food consumption and operant responding for food. The study found that MT-II microinjected into the NAcc significantly reduced both the amount of food consumed (measured in home cage settings) and appetitive responding (measured by operant self-administration tasks requiring effort to obtain food). Importantly, these effects appeared to occur without inducing conditioned taste avoidance—suggesting the reductions were not due to nausea or aversion—and without measurable changes in metabolic rate. The authors concluded that melanocortin signaling in the NAcc may selectively regulate appetite and satiety independent of metabolism or aversive side effects. Key limitations include that this was an animal-only study conducted exclusively in male mice of a single inbred strain, limiting generalizability to other sexes, species, or humans. The microinjection approach is also not clinically translatable in its current form.
Neuropeptides · Sep 2022DOI ↗