GLP1R agonists(Regeneron)

Glucagon-like peptide-1 receptor (GLP1R) agonists (GLP1RAs) are widely used in type 2 diabetes mellitus (T2DM) management due to their glycemic and cardiorenal benefits, yet emerging evidence suggests potential renal adverse effects, particularly tubulo-interstitial nephritis (TIN). We conducted a 2-sample Mendelian randomization (MR) analysis to investigate causal relationships between GLP1RA use and TIN risks. Genetic proxies for GLP1RA effects were derived from cis-eQTLs for GLP1R. Proteome-wide MR and mediation analyses with UK Biobank Pharma Proteomics Project data were also used to identify mediating plasma proteins and biological pathways. MR analyses showed a significant causal link between GLP1RA use and chronic tubulo-interstitial nephritis (CTIN; OR = 2.32, 95% CI = 1.39–3.85, P = .001), with no significant association for acute tubulo-interstitial nephritis (ATIN; OR = 0.93, 95% CI = 0.83–1.04, P = .216). Colocalization analysis strongly supported the MR findings, showing a high posterior probability of shared genetic variants between GLP1R expression and CTIN (PP.H4 = 0.99). Mediation analysis identified 4 plasma proteins (HYAL1, NMNAT1, IL12RB2, and DPP6) as partial mediators of the effect. Genetic evidence from this study indicated an association between GLP1R agonists and higher risk of chronic tubulo-interstitial nephritis. Potential risks need to be evaluated when prescribing GLP1RAs in in clinical practice.

The innate attraction to sweet mediates appetitive and consummatory responses. Here, we dissected the circuit driving responses to sweet and showed that amygdala neurons tuned to sweet connect to the bed nucleus of the stria-terminalis (BNST) to promote sweet-evoked consumption. Next, we demonstrate that the BNST functions as a central hub, transforming appetitive signals into consumption and linking sensory inputs to the internal state, not only for sweet but also for other stimuli such as salt or food, to flexibly regulate consummatory behaviors. Using single-cell functional imaging, we show that ensemble activity in the BNST encodes stimulus identity and the animal's internal state. Finally, we demonstrate that manipulating BNST activity can bidirectionally transform consummatory responses. Together, these findings illustrate how the internal state modulates sensory responses, characterize a general brain dial for consumption, and provide fresh insights into sites of action of GLP1R agonists and a strategy to help promote weight gain in pathological states.