Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety

Abstract

SUMMARYLiraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these areTrh+Arc neurons (TrhArc), which express theGlp1rgene and are activated by the GLP-1RA liraglutide. Activating TrhArcneurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArcneurons increases feeding and body weight and reduces liraglutide’s satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.

Incretin hormones and pharmacomimetics rapidly inhibit AgRP neuron activity to suppress appetite

“…While hypothalamic or hindbrain knockdown of GLP-1R reduces liraglutide efficacy, no brain region has been shown to be solely responsible for the weight loss efficacy of this drug 17,45,46 . A recent study described a population of GLP-1R agonist-activated neurons in the arcuate nucleus that inhibit AgRP neurons; however, whether direct GLP-1R activation of this cell type contributes to incretin-mimetic induced weight loss has yet to be illuminated 47 . The GLP-1R is also expressed in a large population of vagal afferent neurons 48–51 , and chemogenetic activation of these distension-sensing nodose ganglion neurons is sufficient to inhibit AgRP neurons 50 .…”

Thyrotropin-Releasing Hormone and Food Intake in Mammals: An Update

“…Activation of GABA/ Trh ARC neurons inhibits AgRP ARC neurons’ activity and decreases food intake, while inhibition of GABA/ Trh ARC neurons’ activity increases food intake. The synaptic effects are explained by GABA action on AgRP ARC neurons [ 173 ].…”