Dissociable hindbrain GLP1R circuits for satiety and aversion.

The most successful obesity therapeutics, glucagon-like peptide-1 receptor (GLP1R) agonists, cause aversive responses such as nausea and vomiting1,2, effects that may contribute to their efficacy. Here, we investigated the brain circuits that link satiety to aversion, and unexpectedly discovered that the neural circuits mediating these effects are functionally separable. Systematic investigation across drug-accessible GLP1R populations revealed that only hindbrain neurons are required for the efficacy of GLP1-based obesity drugs. In vivo two-photon imaging of hindbrain GLP1R neurons demonstrated that most neurons are tuned to either nutritive or aversive stimuli, but not both. Furthermore, simultaneous imaging of hindbrain subregions indicated that area postrema (AP) GLP1R neurons are broadly responsive, whereas nucleus of the solitary tract (NTS) GLP1R neurons are biased towards nutritive stimuli. Strikingly, separate manipulation of these populations demonstrated that activation of NTSGLP1R neurons triggers satiety in the absence of aversion, whereas activation of APGLP1R neurons triggers strong aversion with food intake reduction. Anatomical and behavioural analyses revealed that NTSGLP1R and APGLP1R neurons send projections to different downstream brain regions to drive satiety and aversion, respectively. Importantly, GLP1R agonists reduce food intake even when the aversion pathway is inhibited. Overall, these findings highlight NTSGLP1R neurons as a population that could be selectively targeted to promote weight loss while avoiding the adverse side effects that limit treatment adherence.

Oral mometasone furoate administration preserves anti-inflammatory action with fewer metabolic adverse effects in rats.

BACKGROUND: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. METHODS: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control. RESULTS: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic ß-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible. CONCLUSION: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology.