JCI insightMar 28, 2020

Semaglutide lowers body weight in rodents through multiple brain systems

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Semaglutide induced weight loss and reduced food intake while maintaining energy expenditure.

Weight loss may be linked to changes in food preference and intake mediated by GLP-1 receptors in the brain.
Semaglutide accessed key brain regions involved in appetite regulation, including the brainstem and hypothalamus, without crossing the blood-brain barrier.
Activation of c-Fos was observed in 10 brain areas, indicating diverse neural pathways may be involved in its effects on food intake.
Upregulation of specific hormones and enzymes was noted in the area postrema following semaglutide treatment.
The interaction of semaglutide with various GLP-1 receptor populations could influence neural pathways related to food intake and energy management.

Simplified

Semaglutide, a glucagon-like peptide 1 (GLP-1) analog, induces weight loss, lowers glucose levels, and reduces cardiovascular risk in patients with diabetes. Mechanistic preclinical studies suggest weight loss is mediated through GLP-1 receptors (GLP-1Rs) in the brain. The findings presented here show that semaglutide modulated food preference, reduced food intake, and caused weight loss without decreasing energy expenditure. Semaglutide directly accessed the brainstem, septal nucleus, and hypothalamus but did not cross the blood-brain barrier; it interacted with the brain through the circumventricular organs and several select sites adjacent to the ventricles. Semaglutide induced central c-Fos activation in 10 brain areas, including hindbrain areas directly targeted by semaglutide, and secondary areas without direct GLP-1R interaction, such as the lateral parabrachial nucleus. Automated analysis of semaglutide access, c-Fos activity, GLP-1R distribution, and brain connectivity revealed that activation may involve meal termination controlled by neurons in the lateral parabrachial nucleus. Transcriptomic analysis of microdissected brain areas from semaglutide-treated rats showed upregulation of prolactin-releasing hormone and tyrosine hydroxylase in the area postrema. We suggest semaglutide lowers body weight by direct interaction with diverse GLP-1R populations and by directly and indirectly affecting the activity of neural pathways involved in food intake, reward, and energy expenditure.

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Competing interests

Conflict of interest: JAR, AFB, STB, KSF, JFJ, LMJ, CP, LS, AS, LBK, TTL, JP-W, HW, SG, CGS, GS, TA, HCCH, JN, and SJP are current or former Novo Nordisk employees and/or shareholders. CF and EF received research grants from Novo Nordisk to their institutions.

PubMed

Semaglutide lowers body weight in rodents through multiple brain systems

Abstract

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Funding

Competing interests

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Abstract

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