Biology subjects

Adriaenssens, A. E.

Publications and source records attributed to Adriaenssens, A. E..

3 recordsLinked to original sources

bioRxiv2026

Opposing GIPR brainstem circuits differentially control feeding behaviour

Central glucose-dependent insulinotropic polypeptide receptor (GIPR) signalling is required for the efficacy of GIP-based obesity therapeutics, yet how distinct subpopulations of GIPR neurons shape appetite remains undefined. Here we show that GIPR neurons in adjacent brainstem nuclei, the area postrema (AP) and nucleus tractus solitarius (NTS), exert opposing control over ingestion. We find GIPRAP neurons dampen post-ingestive satiation, permitting hyperphagia, whereas GIPRNTS neurons are anorectic. In line with this model, we show Gipr expression in AP, but not NTS, neurons is necessary for appetite suppression following GIPR antagonism. Additionally, we reveal that GIPR neurons in the AP and NTS occupy distinct gut-brain circuits, and are differentially sensitive to obesity-driven circuit remodelling. These data offer a framework for understanding how current GIPR agonist and antagonist strategies elicit weight loss.

neuroscience↗

bioRxiv2026

Functional segregation of body-brain signals in the area postrema

Nausea arises from activation of specialized neurons in the area postrema (AP)1-8. The AP also mediates much of the satiety produced by GLP1R agonists9-12, suggesting a broader role in non-aversive physiology, yet the functions of AP cell types are not well understood. Here, we have used optical recordings in behaving mice to systematically define the natural regulation of an array of AP neurons, including the cell types that are principal targets of widely-used weight loss drugs. We discover that neurons expressing GFRAL, the receptor for the sickness-related hormone GDF15, are unexpectedly activated when mice consume food rich in fat. This fat-specific GFRAL neuron activation is required for fat satiation but does not involve GDF15 or canonical gut-brain pathways. Instead, "anti-nausea" neurons expressing GIPR, which directly inhibit GFRAL neurons, are selectively activated by sugar, enabling macronutrient-specific gating of GFRAL responses. In addition, we show that CALCR neurons link intestinal hyperosmolality to the suppression of feeding, whereas PRLHR neurons respond to changes in blood volume and pressure. These findings reveal a broad role for AP cell types in sensing and responding to physiologic signals unrelated to nausea. They also reveal that GFRAL and GIPR neurons, which are key targets of the weight-loss drug tirzepatide, have a natural function in sensing ingestion of fat and sugar, respectively.

neuroscience↗

bioRxiv2021

Relaxin/insulin-like family peptide receptor 4 (Rxfp4) expressing hypothalamic neurons modulate food intake and preference in mice

Relaxin/insulin-like-family peptide receptor-4 (RXFP4), the cognate receptor for insulin-like peptide 5 (INSL5), has been implicated in feeding behaviour as Rxfp4 knockout mice display shorter meal durations and reduced high fat diet (HFD) intake. Here, we generated transgenic Rxfp4-Cre mice to explore Rxfp4 expression and physiology. Using this model, we identified Rxfp4 expression in the central nervous system, including in the ventromedial hypothalamus (VMH). Intra-VMH infusion of INSL5 increased HFD and highly palatable liquid meal intake (HPM) of ad libitum fed wildtype mice. Single-cell RNA-sequencing of VMH Rxfp4-expressing cells (RXFP4VMH) defined a cluster of Rxfp4-labelled neurons expressing Esr1, Tac1 and Oxtr, alongside known appetite-modulating neuropeptide receptors (Mc4r, Cckar and Nmur2). Viral tracing demonstrated RXFP4VMH neural projections to the bed nucleus of the stria terminalis, paraventricular hypothalamus, paraventricular thalamus and central nucleus of the amygdala. Utilising designer receptors exclusively activated by designer drugs (DREADDs), we found that whole body chemogenetic inhibition (Di) of Rxfp4-expressing cells, mimicking native INSL5-RXFP4 signalling, increased intake of HFD and HPM, whilst activation (Dq), either at whole body level or specifically within the VMH, reduced HFD and HPM intake and altered food preference. Ablating VMH Rxfp4-expressing cells recapitulated the lower HFD intake phenotype of Rxfp4 knockout mice, resulting in reduced body weight. These findings identify a discrete Rxfp4-expressing neuronal population as a key regulator of food intake and preference and reveal hypothalamic RXFP4 signalling as a target for feeding behaviour manipulation.

physiology↗