First sex-specific atlas of GLP-1 in the mouse brain shows striking male-female differences

Semaglutide, liraglutide, and their GLP-1 analog siblings have become some of the most prescribed drugs on the planet. They suppress appetite, improve blood sugar control, and produce significant weight loss. Clinical experience suggests they may work somewhat differently in women and men. But until now, nobody had a detailed map of where GLP-1 actually lives in the brain, let alone whether that map differs by sex.

A study from the Icahn School of Medicine at Mount Sinai, published in Brain Medicine, now provides that map, and the differences between females and males are more pronounced than anyone expected.

Counting individual mRNA transcripts across the whole brain

The research team, led by Vitaly Ryu, Anisa Gumerova, Georgii Pevnev, Tony Yuen, and senior author Mone Zaidi, used RNAscope, a technique capable of detecting single mRNA molecules, to map Glp1 gene expression across the entire mouse brain in three female and three male animals. The method hybridizes approximately 20 pairs of transcript-specific probes to thin whole-brain sections, achieving sensitivity that older analytical approaches could not reach. GLP-1 is produced in small quantities in the brain and rapidly degraded, which has historically made its detection difficult.

Two independent observers, blinded to the sex of the animals, manually counted transcripts in every tenth section. The result is a compendium of GLP-1 expression across 25 distinct brain nuclei, subnuclei, and regions in each sex.

The hindbrain divide

Both sexes showed the highest GLP-1 levels in the medulla and olfactory bulb. But the distribution within the medulla diverged sharply. In females, the three densest regions were the raphe obscurus nucleus, the ventral part of the nucleus of the solitary tract (SolV), and the medial solitary tract. In males, the densest regions were different subnuclei of the solitary tract entirely.

Several medullary nuclei showed expression in only one sex. The ambiguus nucleus, tectospinal tract, ventral cochlear nucleus, and cuneate nucleus expressed GLP-1 only in females. The dorsomedial spinal trigeminal nucleus, intercalated nucleus, paramedian reticular nucleus, and central solitary tract expressed it only in males. The number of GLP-1-expressing neurons in the SolV was significantly higher in females (P = 0.034).

An unexpected finding in the olfactory bulb

Males showed significantly higher GLP-1 density in the olfactory bulb than females (P = 0.024), driven by the granular cell layer. This is intriguing because GLP-1-releasing neurons in the olfactory bulb have been hypothesized to modulate appetite-related signals after eating, and recent work has shown that food odor triggers insulin release in lean and obese male mice.

The researchers propose a compensatory model: since females already have strong estrogen-mediated appetite suppression via olfactory bulb receptors, they may need less GLP-1 signaling in that region. Males, lacking that estrogen contribution, may rely more heavily on olfactory GLP-1 circuits. Whether this explains the clinical observation that GLP-1 drugs often produce stronger weight loss in women remains speculative but biologically plausible.

Reward, memory, and psychiatric circuits

Beyond metabolism, GLP-1 expression appeared in regions involved in reward processing and cognition. The ventral tegmental area, central to the brain's reward circuitry, showed GLP-1 expression only in females. The lateral hypothalamus, implicated in motivated behavior, showed expression only in males. GLP-1 was also detected in the hippocampus, hypothalamus, thalamus, and the ependymal layer of the third ventricle.

These findings are relevant to the growing interest in using GLP-1 analogs for conditions beyond obesity and diabetes, including addiction, depression, and cognitive decline. If the receptor's natural ligand is distributed differently in female and male brains, the drugs targeting that system might reasonably produce different neuropsychiatric effects in each sex.

What the atlas cannot tell us

The sample size of three animals per sex limits statistical power, particularly for detecting low-abundance expression in sparse regions. The authors are transparent about this: regions showing expression in only one sex could reflect genuine sex differences or could fall below the detection threshold in the other sex. These findings should be treated as hypothesis-generating rather than definitive.

Female mice were not staged for estrous cycle phase, introducing potential variability in the female group, though the authors argue this is unlikely to alter the main qualitative patterns. RNAscope detects gene expression at the mRNA level but does not directly measure peptide production, release, or functional activity. The presence of a transcript does not guarantee functional protein.

The atlas was built in mice, not humans, though the expression pattern of GLP-1-producing neurons in the brain is highly conserved between rodents and nonhuman primates, lending some translational relevance. Still, confirming these sex differences in human tissue would be an essential next step.

For the millions of people currently taking semaglutide or liraglutide, the atlas raises a practical question: should dosing, efficacy expectations, or side-effect monitoring differ between women and men? The biology suggests the answer may be yes, even if clinical practice has not yet caught up.