Binge-eating disorder (BED) is the most common eating disorder worldwide and carries life-altering comorbidities. While genetic and environmental risk factors have been identified, the mechanisms that determine inter-individual susceptibility to BED remain largely unknown. Here, we demonstrate that developmental dosage of the DNA hydroxymethylase Tet1 defines stable inter-individual differences in binge-eating susceptibility. In mice, midbrain dopaminergic neurons of the ventral tegmental area (VTADA) are essential for the induction of addictive binge-eating behavior, express high levels of Tet1, and undergo rapid and widespread DNA hydroxymethylation remodeling upon experimental binge-eating. Strikingly, Tet1 haploinsufficiency creates pronounced inter-individual variation in binge-eating susceptibility even among genetically identical mice, which we trace to reduced connectivity between the prelimbic medial prefrontal cortex (mPFCPL) and the VTA. Chemogenetic inhibition of mPFCPLtextrightarrowVTA projections reduces binge-eating susceptibility, whereas EGR1-guided re-activation of TET1 in VTA dopaminergic neurons restores susceptibility, supporting a causal role for this axis. Importantly, TET1 promoter methylation in patients associates with binge-eating behavior and reward-circuit function, suggesting conservation of this regulatory network in humans. Collectively, these findings identify Tet1 dosage as a novel regulator of binge-eating susceptibility and provide a mechanistic basis for how inter-individual differences in behavior are established.

The past decades have witnessed the rise and fall of several, largely unsuccessful, therapeutic attempts to bring the escalating obesity pandemic to a halt. Looking back to look ahead, the field has now put its highest hopes in translating insights from how the gastrointestinal (GI) tract communicates with the brain to calibrate be- havior, physiology, and metabolism. A major focus of this review is to summarize the latest advances in comprehending the neuroendocrine aspects of this so-called ‘gut–brain axis’ and to explore novel concepts, cutting-edge tech- nologies, and recent paradigm-shifting experiments. These exciting insights continue to refine our understanding of gut–brain crosstalk and are poised to promote the development of additional therapeutic avenues at the dawn of a new era of antiobesity therapeutics.

Oxytocin-expressing paraventricular hypothalamic neurons (PVN^OT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVN^OT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVN^OT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVN^OT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK’s anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVN^OT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVN^OT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Summary Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1$α$-vascular endothelial growth factor (HIF1$α$-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1$α$-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1$α$-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.