OnDemand: April 2025 Grand Rounds - Hindbrain Contributions to the Neurologically Distributed Control of Feeding, Body Weight, and the actions of GLP1R Obesity Medication-April 2025 Grand Rounds - Hindbrain Contributions to the Neurologically Distributed Control of Feeding, Body Weight, and the actions of GLP1R Obesity Medication

April 2025 Grand Rounds - Hindbrain Contributions to the Neurologically Distributed Control of Feeding, Body Weight, and the actions of GLP1R Obesity Medication

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Professor Harvey Grill presented a comprehensive review of how the brain controls food intake and body weight, arguing against the old idea of a single “feeding center” in the hypothalamus. He emphasized that feeding is governed by a distributed network spanning the prefrontal cortex, hippocampus, ventral tegmental area, hypothalamus, parabrachial nucleus, nucleus of the solitary tract (NTS), and other regions. A major theme was that methodology matters: earlier lesion and stimulation studies often over-interpreted results, while modern genetic, chemogenetic, and optogenetic tools provide stronger evidence.<br /><br />Grill highlighted the hindbrain, especially the dorsal vagal complex and NTS, as a key site for integrating taste, satiation, and reward signals. He described experiments showing that isolated hindbrain preparations can still process taste, regulate meal size, gastric emptying, energy expenditure, and even temperature control. He also discussed specific neuron populations, such as LH VGAT/GABA neurons and NTS neurons expressing leptin and GLP-1 receptors, showing how activating or knocking down these neurons alters feeding motivation, meal size, and body weight.<br /><br />A major clinical focus was obesity pharmacotherapy. Grill explained that GLP-1 receptor agonists and GLP-1/GIP co-agonists produce major weight loss largely by suppressing feeding, but their use is limited by gastrointestinal side effects, including nausea and visceral malaise. He contrasted GLP-1 with GDF-15, which also reduces intake but appears to do so partly through aversive pathways. He proposed that identifying distinct hindbrain neuron subtypes, especially those linked to GFRAL-RET versus non-GFRAL GLP-1 signaling, may help develop more effective obesity drugs with fewer GI adverse effects.

Keywords

brain control of feeding

hypothalamus

hindbrain

nucleus of the solitary tract

dorsal vagal complex

GLP-1 receptor agonists

obesity pharmacotherapy

chemogenetics

optogenetics

GDF-15