ABSTRACT
OBJECTIVES: Combinatorial therapies are under intense investigation to develop more efficient anti-obesity drugs; however, little is known about how they act in the brain to produce enhanced anorexia and weight loss. The goal of this study was to identify the brain sites and neuronal populations engaged during the co-administration of GLP-1R and CCK1R agonists, an efficient combination therapy in obese rodents. METHODS: We measured acute and long-term feeding and body weight responses and neuronal activation patterns throughout the neuraxis and in specific neuronal subsets in response to GLP-1R and CCK1R agonists administered alone or in combination in lean and high-fat diet fed mice. We used PhosphoTRAP to obtain unbiased molecular markers for neuronal populations selectively activated by the combination of the two agonists. RESULTS: The initial anorectic response to GLP-1R and CCK1R co-agonism was mediated by a reduction in meal size, but over a few hours, a reduction in meal number accounted for the sustained feeding suppressive effects. The nucleus of the solitary tract (NTS) is one of the few brain sites where GLP-1R and CCK1R signalling interact to produce enhanced neuronal activation. None of the previously categorised NTS neuronal subpopulations relevant to feeding behaviour were implicated in this increased activation. However, we identified NTS/AP Calcrl+ neurons as treatment targets. CONCLUSIONS: Collectively, these studies indicated that circuit-level integration of GLP-1R and CCK1R co-agonism in discrete brain nuclei including the NTS produces enhanced rapid and sustained appetite suppression and weight loss.
Subject(s)
Glucagon-Like Peptide-1 Receptor/metabolism , Obesity/drug therapy , Receptors, Cholecystokinin/metabolism , Animals , Anti-Obesity Agents/pharmacology , Appetite Regulation , Brain/metabolism , Diet, High-Fat , Eating/drug effects , Feeding Behavior/drug effects , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor/drug effects , Male , Mice , Mice, Inbred C57BL , Neurons/metabolism , Obesity/metabolism , Solitary Nucleus/metabolism , Weight Loss/drug effectsABSTRACT
Minimally-processed pineapple stored under refrigerated conditions is highly perishable. We aimed to characterize the evolution of physicochemical, sensory and microbiological quality during cold storage. Pineapple batches were sampled from several locations in Reunion Island and then minimally processed. In the processing step, the variability of firmness and counts of yeasts and molds were observed. Moreover, correlations between the sampling season and pH and b* color component, as well as between fungal population and b* parameter were observed. During storage, the visual aspect of pineapple cuts changed to brown and shiny, whereas olfactive descriptors shifted from fruity descriptors and fresh to fermented, alcoholic and milky. The values for pH, TA and TSS did not significantly vary according to storage time. A decrease in firmness and C* color parameter was observed. Yeast and mold counts were significantly higher after 7 days of storage. The diversity in yeasts and molds was mainly dependent on the considered batches observed from PCR-DGGE profiles. Fungal species were isolated from spoiled pineapple cuts. The implication of Penicilllium citrtrinum, Talaromyces amestolkiae, Rhodotorula mucilaginosa, Saccharomyces cerevisiae, and Meyerozyma caribbica in the spoilage of minimally-processed pineapple cuts was further demonstrated.
