👤 Stefan Trapp

Dual agonists targeting glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are breakthrough treatments for patients with type 2 diabetes and obesity. Compared to GLP1R agonists, dual agonists show superior efficacy for glucose lowering and weight reduction. However, delineation of dual agonist cell targets remains challenging. Here, we develop and test daLUXendin and daLUXendin+, non-lipidated and lipidated fluorescent GLP1R/GIPR dual agonist probes, and use them to visualize cellular targets. daLUXendins are potent GLP1R/GIPR dual agonists that advantageously show less functional selectivity for mouse GLP1R over mouse GIPR. daLUXendins label rodent and human pancreatic islet cells, with a signal intensity of β cells > α cells = δ cells. Systemic administration of daLUXendin strongly labels GLP1R Show less

Alcohol consumption across the lifespan contributes to mood fluctuations and cognitive dysfunction, two neurobehavioral features also associated with Alzheimer's Disease and Related Dementias (ADRD). Yet, few studies have used rodent models to determine how a history of ethanol consumption across the lifespan might contribute to neurobehavioral and neuropathological features of ADRD. We exposed Wild Type (WT) and transgenic Fischer 344 CE rats (TgF344-AD) that have been genetically modified to express the human Amyloid Precursor Protein (APP) and presenilin-1 genes with mutations, to ethanol using a chronic, intermittent ethanol consumption model. Beginning at P28, rats were given a single bottle 10 % ethanol solution for 2 consecutive days, followed by 2 days of tap water. This pattern (2 days on, days off) was repeated for a total of 12 cycles until rats reached the age of ∼ 3 months, and repeated at 6 (Exp 1 and Exp 2) and 9 months of age (Exp 2). In experiment 1, ethanol consumption decreased alternations in a spontaneous alternation task in females, only at the 3-month time point, whereas TgF344-AD females showed increased contextual fear conditioning in the test of retention and reinstatement tests at 6 months of age. In experiment 2, a battery of anxiety-like behaviors (Elevated Plus Maze, Marble Burying, and Novelty Induced Hypophagia) were assessed following a 2-week abstinence period at 3, 6, and 9 months of age in ethanol-consuming rats. Data from the EPM and marble burying tasks revealed evidence of heightened anxiety-like behavior in Tg-F344-AD rats that varied by sex and age, with no significant effects of ethanol. In the novelty-induced hypophagia task, males with a history of ethanol consumption had a lower latency to approach a familiar, salient reward at 3 months old, but effects of ethanol were overall minimal. Examination of dorsal hippocampal gene expression at 6 months of age under basal conditions also revealed predominantly genotype and sex-specific effects on inflammation- and AD-related genes (App, Il-6, Bace1, Rage, Lrp-1). When examined at 9 months old following LPS challenge, ethanol increased inflammatory genes in males (Il-1β, Il-6) in the hippocampus, whereas ethanol decreased several inflammatory and AD-related genes (Hmgb1, Rage, Bace1, Lrp-1) in TgF344-AD females. Overall, these data provide further evidence that females are especially vulnerable to AD, and that a history of ethanol consumption had selective, rather than global, effects on AD- and inflammation-related genes following an inflammatory stimulus. Show less

Examine Setmelanotide use in patients with rare genetic variants that disrupt the melanocortin pathway. Between February 2017 and September 2018, 10 participants with pro-opiomelanocortin (POMC)/ proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency and 11 participants with leptin receptor (LEPR) deficiency were enrolled in open-label, phase 3 trials at 10 centers in the United States and internationally to assess the efficacy and safety of the melanocortin-4 receptor (MC4R) agonist Setmelanotide. 80% of POMC participants and 45% of LEPR participants achieved at least 10% weight loss at 1 year. Significant changes in hunger scores were seen for both cohorts as well. Setmelanotide was well tolerated with injection site reactions and hyperpigmentation being the most common adverse events reported. As a result, Setmelanotide was approved by the U.S. FDA in 2020 for chronic weight management in adult and pediatric patients ≥6 years of age with POMC, LEPR, or PCSK1 deficiency. In 2022, its approval was extended to include patients with Bardet-Biedel syndrome (BBS) after phase 3 trial data showed that, on average, Setmelanotide treatment resulted in a BMI loss of 7.9% for the 44 BBS participants. Rare genetic variants such as POMC, LEPR, and PCSK1 deficiency disrupt MC4R pathway signaling, resulting in severe early-onset obesity, hyperphagia, and increased risk for metabolic co-morbidities. Patients with BBS also demonstrate severe early-onset obesity and hyperphagia, due in part to defective MC4R signaling. Setmelanotide has shown promising benefits in improving satiety scores and weight-related outcomes in patients with these early-life genetic obesity conditions, although longer-term studies are needed. Show less

Overweight and obesity are endemic in developed countries, with a substantial negative impact on human health. Medications developed to treat obesity include agonists for the G-protein coupled receptors glucagon-like peptide-1 (GLP-1R; e.g. liraglutide), serotonin 2C (5-HT We profiled PPG neurons in the nucleus of the solitary tract (PPG We found that 5-HT These findings identify a necessary mechanism through which obesity medication lorcaserin produces its therapeutic benefit, namely brainstem PPG Show less

The control of myelination by oligodendrocytes in the CNS is poorly understood. Here we show that LINGO-1 is an important negative regulator of this critical process. LINGO-1 is expressed in oligodendrocytes. Attenuation of its function by dominant-negative LINGO-1, LINGO-1 RNA-mediated interference (RNAi) or soluble human LINGO-1 (LINGO-1-Fc) leads to differentiation and increased myelination competence. Attenuation of LINGO-1 results in downregulation of RhoA activity, which has been implicated in oligodendrocyte differentiation. Conversely, overexpression of LINGO-1 leads to activation of RhoA and inhibition of oligodendrocyte differentiation and myelination. Treatment of oligodendrocyte and neuron cocultures with LINGO-1-Fc resulted in highly developed myelinated axons that have internodes and well-defined nodes of Ranvier. The contribution of LINGO-1 to myelination was verified in vivo through the analysis of LINGO-1 knockout mice. The ability to recapitulate CNS myelination in vitro using LINGO-1 antagonists and the in vivo effects seen in the LINGO-1 knockout indicate that LINGO-1 signaling may be critical for CNS myelination. Show less