👤 Francisco Portillo

Obesity is one of the most prevalent chronic metabolic alterations worldwide being highly related to an increased risk for further associated co-morbidities. Current evidence indicates that subjects with obesity have a distinct gut microbiota signature, emphasizing gut microbiota composition as a potential mediating factor. The aim of this research is to evaluate the potential effects of viable and heat-inactivated Lactobacillus rhamnosus GG in the prevention of diet-induced obesity in a rat model. The administration of the probiotic or its heat-inactivated postbiotic partially prevented diet-induced WAT increase in a similar manner. While viable probiotic administration resulted in a reduced lipid uptake (LPL) and de novo lipogenesis (FAS), along with enhanced lipolysis (ATGL) in WAT, its heat-inactivated postbiotic mainly acted reducing de novo lipogenesis. Additionally, the obtained results demonstrated that probiotic administration enhanced thermogenesis (UCP1) and fatty acid oxidation (CPT-1b) on BAT, as well as upregulated several markers involved in mitochondrial biogenesis (p38 MAPK, NRF1 and CS). By contrast, despite the administration of the postbiotic upregulated thermogenesis and fatty acid oxidation in a comparable manner as the probiotic, these results were not accompanied by changes in mitochondrial biogenesis markers. These results indicate that under the specific experimental conditions tested, both the administration of viable and heat-inactivated Lactobacillus rhamnosus GG present valuable potential for preventing diet-induced WAT mass increase in rats. While both treatments exerted similar effects on WAT and BAT, subtle differences that may derive from bacterial viability were observed in the involved mechanisms of action. Show less

The melanocortin receptors (MCRs) are important for numerous biological pathways, including feeding behavior and energy homeostasis. In addition to endogenous peptide agonists, this receptor family has two naturally occurring endogenous antagonists, agouti and agouti-related protein (AGRP). At the melanocortin-4 receptor (MC4R), the AGRP ligand functions as an endogenous inverse agonist in the absence of agonist and as a competitive antagonist in the presence of agonist. At the melanocortin-3 receptor (MC3R), AGRP functions solely as a competitive antagonist in the presence of agonist. The molecular interactions that differentiate AGRP's inverse agonist activity at the MC4R have remained elusive until the findings reported herein. Upon the basis of homology molecular modeling approaches, we previously postulated a unique interaction between the D189 position of the hMC4R and Asn114 of AGRP. To further test this hypothesis, six D189 mutant hMC4Rs (D189A, D189E, D189N, D189Q, D189S, and D189K) were generated and pharmacologically characterized resulting in the discovery of differences in inverse agonist activity of AGRP and an 11 macrocyclic compound library. These data support the hypothesized interaction between the hMC4R D189 position and Asn114 residue of AGRP and define critical ligand-receptor molecular interactions responsible for the inverse agonist activity of AGRP at the hMC4R. Show less

Cancer stem cells (CSC) are considered responsible for tumor initiation, therapeutic resistance, and metastasis. A comprehensive knowledge of the mechanisms governing the acquisition and maintenance of cancer stemness is crucial for the development of new therapeutic approaches in oncology. E2A basic helix-loop-helix (bHLH) transcription factors are associated with epithelial-mesenchymal transition (EMT) and tumor progression, but knowledge of their functional contributions to cancer biology is still limited. Using a combination of Show less