Recurrent Binge Eating (BE) episodes characterize several eating disorders. Here, we attempted to reassemble a condition closer to BE disorder, and we analyzed whether recurrent episodes might evoke molecular alterations in the hypothalamus of rats. The hypothalamus is a brain region which is sensitive to stress and relevant in motivated behaviors, such as food intake. A well-characterized animal model of BE, in which a history of intermittent food restriction and stress induce binge-like palatable food consumption, was used to analyze the transcriptional regulation of the endocannabinoid system (ECS). We detected, in rats showing the BE behavior, an up-regulated gene expression of cannabinoid type-1 receptor (CB1), sn-1-specific diacylglycerol lipase, as well as fatty acid amide hydrolase (Faah) and monoacylglycerol lipase. A selective reduction in DNA methylation was also observed at the promoter of Faah, which is consistent with the changes in the gene expression. Moreover, BE behavior in rats was associated with an increase in anandamide (AEA) levels. Our findings support the relevant role of the ECS in the regulation of food intake in rats subjected to repeated BE episodes, and, in particular, on AEA signaling, acting via CB1 and FAAH modulation. Notably, the epigenetic regulation of the Faah gene might suggest this enzyme as a possible target for developing new therapeutical approaches.

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

Advanced glycation end products (AGEs) exert a key pathogenic role in the development of obesity and insulin resistance. Thanks to its abundance in bioactive compounds, the microalga Arthrospira platensis (spirulina, SP) is proposed as a nutritional supplement. Here, we investigated the potential anti-glycating properties of SP enriched with zinc (Zn-SP) and the following impact on diet-induced metabolic derangements. Thirty male C57Bl6 mice were fed a standard diet (SD) or a high-fat high-sugar diet (HFHS) for 12 weeks, and a subgroup of HFHS mice received 350 mg/kg Zn-SP three times a week. A HFHS diet induced obesity and glucose intolerance and increased plasma levels of pro-inflammatory cytokines and transaminases. Zn-SP administration restored glucose homeostasis and reduced hepatic dysfunction and systemic inflammation. In the liver of HFHS mice, a robust accumulation of AGEs was detected, paralleled by increased expression of the main AGE receptor (RAGE) and depletion of glyoxalase-1, whereas Zn-SP administration efficiently prevented these alterations reducing local pro-inflammatory responses. 16S rRNA gene profiling of feces and ileum content revealed altered bacterial community structure in HFHS mice compared to both SD and HFHS + Zn-SP groups. Overall, our study demonstrates relevant anti-glycation properties of Zn-SP which contribute to preventing AGE production and/or stimulate AGE detoxification, leading to the improvement of diet-related dysbiosis and metabolic derangements.

Chronic low-grade inflammation (metaflammation) is a key contributor to obesity-associated metabolic disorders and their cardiovascular complications. This study investigated the effects of CXT29, a novel dual cyclooxygenase-2 (COX-2) inhibitor and thromboxane prostanoid receptor (TP) antagonist, in comparison with its parent compound etodolac, in a murine model of diet-induced metabolic dysfunction. Four-week-old male C57BL/6 mice were fed either a standard diet or a high-fat diet for 18 weeks and subsequently treated with etodolac (20 mg/kg/day) or CXT29 (25 mg/kg/day) by oral gavage for 5 weeks. High-fat-diet-fed mice developed increased body weight, impaired glucose tolerance, altered circulating metabolic hormones, liver dysfunction, steatosis, inflammatory cell infiltration, and systemic inflammation. Both treatments attenuated systemic inflammation and improved the metabolic alterations induced by the obesogenic diet. Notably, CXT29, but not etodolac, attenuated the increase in circulating plasminogen activator inhibitor-1 (PAI-1), a biomarker associated with cardiovascular risk. These findings indicate that pharmacological inhibition of COX-2 improves metabolic dysfunction associated with diet-induced obesity. Furthermore, the additional TP antagonism provided by CXT29 does not compromise the metabolic benefits associate with COX-2 inhibition, while displaying a distinct effect on circulating PAI-1, supporting further investigation of this dual-target approach in obesity-associated metabolic dysfunction.

Histone deacetylases (HDACs) are key epigenetic regulators that modulate chromatin accessibility and transcriptional programs controlling metabolism, energy balance, and reward-related behaviors. Aberrant HDACs activity contributes to metabolic dysfunction by altering adipogenesis, thermogenic capacity, lipid profile, and hypothalamic circuits governing appetite. In obesity, specific HDAC isoforms promote adipocyte hypertrophy, impair browning of white adipose tissue, disrupt mitochondrial function, and exacerbate inflammation and insulin resistance. HDAC inhibitors (HDACi) counteract these effects by enhancing oxidative metabolism, stimulating thermogenesis, reducing adipocyte size, and improving systemic glucose and lipid homeostasis in preclinical models. Beyond peripheral metabolism, HDACi can also modulate neural pathways implicated in food intake, highlighting their potential influence in eating disorders, an area of research currently largely limited to anorexia nervosa. Research on HDACs, HDACi, and eating disorders is relatively recent; therefore, the characterization of potential molecular alterations and the identification of specific HDAC targets remain areas of ongoing development. Collectively, current evidence suggests that selective targeting of HDACs may offer a promising therapeutic strategy to correct epigenetic dysfunctions underlying both obesity and maladaptive feeding behaviors; however, translating these findings into clinical practice will require overcoming key challenges, including achieving isoform-specific selectivity, minimizing central nervous system-related side effects, and establishing efficacy and safety in human studies.

Neuropeptide Y (NPY) is a key regulator of energy homeostasis, acting through various receptor subtypes in both central and peripheral systems. Increasing interest has been directed toward exploiting NPY as a pharmacological target in obesity. While the orexigenic role of NPY in the hypothalamus is well established, its downstream effects on peripheral metabolism remain less defined, particularly when perturbations to the system are introduced. Previously, we observed that female mice with limbic NPY-Y1 receptor gene (Npy1r) knockout (KO) under different dietary conditions (standard, SD, or high-fat diet, HFD) accumulated more subcutaneous white adipose tissue (WAT) compared to wild-type in the absence of gonadal hormones, despite no changes in food intake. To deepen the mechanisms underlying these effects, we conducted molecular analyses on WAT of these mice. We found that Npy gene expression was upregulated in WAT of HFD-fed mice, regardless of genotype. However, NPY peptide levels were reduced in both KO and HFD groups, suggesting post-transcriptional regulation of NPY under metabolic stress. NPY-Y2 receptor gene (Npy2r) expression in WAT was significantly increased in both KO and HFD while Npy1r expression in WAT remained unchanged across groups. Genes involved in WAT metabolism were similarly upregulated in both KO and HFD mice, indicating that limbic Npy1r KO mimics some of the metabolic effects induced by HFD. Correlation analysis suggests that dysregulated NPY signalling may promote increased lipid storage and reduce energy expenditure. Overall, these findings highlight the complex interplay between central and peripheral NPY signalling emphasizing the importance of caution when investigating therapeutic strategies targeting single NPY receptors. Overall, these findings highlight the complex interplay between central Npy1r signalling and peripheral adipose tissue regulation. They also emphasize the importance of caution when investigating new therapeutic strategies targeting single NPY receptors, as central interventions may provoke maladaptive metabolic responses in peripheral tissues.