ダイエット:脳は空腹シナプスのシグナルを増幅する(Dieting: brain amplifies signal of hunger synapses)

ヨーヨー効果に対抗する薬剤のターゲットになる可能性 Possible target for drugs to combat the yo-yo effect

2023-03-24 マックス・プランク研究所

<関連情報>

• https://www.mpg.de/20048019/0322-neur-dieting-brain-amplifies-signal-of-hunger-synapses-153735-x
• https://www.sciencedirect.com/science/article/pii/S1550413123000803?via%3Dihub

視床下部における体重回復のための飢餓のシナプス増幅器 A synaptic amplifier of hunger for regaining body weight in the hypothalamus

Katarzyna Grzelka, Hannah Wilhelms, Stephan Dodt, Marie-Luise Dreisow, Joseph C. Madara, Samuel J. Walker, Chen Wu, Daqing Wang, Bradford B. Lowell, Henning Fenselau
Cell Metabolism  Published: March 24, 2023
DOI:https://doi.org/10.1016/j.cmet.2023.03.002

Highlights

•Weight loss upon caloric deprivation activates PVH^TRH neurons that co-express PACAP

•Activated PVH^TRH neurons increase the number of active PVH^TRH → AgRP neuron synapses

•Potentiation of excitatory PVH^TRH → AgRP synapses lasts until lost weight is regained

•PVH^TRH → AgRP circuit activity is necessary and sufficient for driving weight (re)gain

Summary

Restricting caloric intake effectively reduces body weight, but most dieters fail long-term adherence to caloric deficit and eventually regain lost weight. Hypothalamic circuits that control hunger drive critically determine body weight; yet, how weight loss sculpts these circuits to motivate food consumption until lost weight is regained remains unclear. Here, we probe the contribution of synaptic plasticity in discrete excitatory afferents on hunger-promoting AgRP neurons. We reveal a crucial role for activity-dependent, remarkably long-lasting amplification of synaptic activity originating from paraventricular hypothalamus thyrotropin-releasing (PVH^TRH) neurons in long-term body weight control. Silencing PVH^TRH neurons inhibits the potentiation of excitatory input to AgRP neurons and diminishes concomitant regain of lost weight. Brief stimulation of the pathway is sufficient to enduringly potentiate this glutamatergic hunger synapse and triggers an NMDAR-dependent gaining of body weight that enduringly persists. Identification of this activity-dependent synaptic amplifier provides a previously unrecognized target to combat regain of lost weight.