A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs DOI Open Access
Elizabeth Godschall, Taha Buğra Güngül,

Isabelle R. Sajonia

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. The neural circuits through which these emerging therapeutics modulate feeding behavior remain undefined, particularly in comparison GLP1RAs. Here, we developed humanized GLP1R mouse models investigate how small- molecule influence behavior. Integrating genetic manipulations, calcium imaging, profiling, discovered that compounds regulate both homeostatic hedonic parallel circuits. Beyond engaging canonical hypothalamic hindbrain networks control homeostasis, recruit a discrete population of Glp1r-expressing neurons the central amygdala, selectively suppress consumption palatable foods by reducing dopamine release nucleus accumbens. Stimulating amygdalar curtail feeding, whereas targeted deletion this cell specifically diminishes anorectic efficacy for reward-driven intake. These findings reveal dedicated circuit small reward processing, suggesting broad therapeutic potential conditions dysregulated signaling including substance use disorder binge eating.

Language: Английский

Binding Kinetics, Bias, Receptor Internalization and Effects on Insulin Secretionin vitroandin vivoof a Novel GLP-1R/GIPR Dual Agonist, HISHS-2001 DOI Creative Commons
Yusman Manchanda, Ben Jones, Gaëlle Carrat

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract The use of incretin analogues has emerged in recent years as an effective approach to achieve both enhanced insulin secretion and weight loss type 2 diabetes (T2D) patients. Agonists which bind stimulate multiple receptors have shown particular promise. However, off target effects, including nausea diarrhoea, remain a complication using these agents, modified versions with optimized pharmacological profiles and/or biased signaling at the cognate are increasingly sought. Here, we describe synthesis properties molecule binds glucagon-like peptide-1 (GLP-1) glucose-dependent insulinotropic polypeptide (GIP) (GLP-1R GIPR) enhance secretion. HISHS-2001 shows increased affinity GLP-1R, well tendency towards reduced internalization recycling this receptor versus FDA-approved dual GLP-1R/GIPR agonist tirzepatide. also displayed significantly greater bias cAMP generation β-arrestin recruitment compared In contrast, G αs was lower tirzepatide but higher GIPR. Administered obese hyperglycaemic db/db mice, circulating whilst lowering body HbA1c similar efficacy substantially doses. Thus, represents novel improved profile.

Language: Английский

Citations

1
On the causes of obesity and its treatment: The end of the beginning DOI Creative Commons
Jeffrey M. Friedman

Cell Metabolism, Journal Year: 2025, Volume and Issue: 37(3), P. 570 - 577

Published: March 1, 2025

Over the last 30 years, our understanding of causes obesity has been transformed, and new, highly effective medicines for reducing weight have developed. This remarkable progress marks an end a beginning. By establishing that is biologic disorder amenable to scientific inquiry rational drug development, simplistic notions about its treatment should be laid rest. The future holds promise additional therapeutic approaches inducing or maintaining loss will developed, these treatments tailored different subgroups potentially address pathogenic mechanisms.

Language: Английский

Citations

1
Neural pathways of nausea and roles in energy balance DOI Creative Commons
Chuchu Zhang

Current Opinion in Neurobiology, Journal Year: 2025, Volume and Issue: 90, P. 102963 - 102963

Published: Jan. 6, 2025

Language: Английский

Citations

0
Glucagon-like peptide-1 DOI
Darleen A. Sandoval

Trends in Endocrinology and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Citations

0
Structural pharmacology and mechanisms of GLP-1R signaling DOI
Qingtong Zhou,

Fenghui Zhao,

Y Zhang

et al.

Trends in Pharmacological Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis DOI Creative Commons
Marie H. Solheim, Sima Stroganov, Weiyi Chen

et al.

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

Citations

0
Semaglutide effects on energy balance are mediated by Adcyap1+ neurons in the dorsal vagal complex DOI Creative Commons

Júlia Teixidor-Deulofeu,

Sebastian Blid Sköldheden,

Ferran Font‐Gironès

et al.

Cell Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: May 1, 2025

The use of the GLP-1R agonist semaglutide is revolutionizing treatment obesity, yet its mechanistic effects on energy balance remain elusive. Here, we demonstrate that reactivation semaglutide-responsive dorsal vagal complex neurons mimics drug's reducing food intake and body weight promoting fat utilization conditioned taste aversion. We observe many semaglutide-activated area postrema (AP) nucleus solitary tract (NTS) express Adcyap1 mRNA, ablation AP/NTS Adcyap1+ largely reverses semaglutide's acutely in lean mice subchronically treated obese mice. Semaglutide-activated promote loss rather than mass, with only a modest effect Furthermore, NTS are engaged by GLP-1R-expressing AP necessary for semaglutide-induced activation several downstream satiety-related structures. Selective targeting holds potential improved future anti-obesity treatments.

Language: Английский

Citations

0
A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs DOI Open Access
Elizabeth Godschall, Taha Buğra Güngül,

Isabelle R. Sajonia

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. The neural circuits through which these emerging therapeutics modulate feeding behavior remain undefined, particularly in comparison GLP1RAs. Here, we developed humanized GLP1R mouse models investigate how small- molecule influence behavior. Integrating genetic manipulations, calcium imaging, profiling, discovered that compounds regulate both homeostatic hedonic parallel circuits. Beyond engaging canonical hypothalamic hindbrain networks control homeostasis, recruit a discrete population of Glp1r-expressing neurons the central amygdala, selectively suppress consumption palatable foods by reducing dopamine release nucleus accumbens. Stimulating amygdalar curtail feeding, whereas targeted deletion this cell specifically diminishes anorectic efficacy for reward-driven intake. These findings reveal dedicated circuit small reward processing, suggesting broad therapeutic potential conditions dysregulated signaling including substance use disorder binge eating.

Language: Английский

Citations

1