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A synaptic amplifier of hunger for regaining body weight in the hypothalamus

Grzelka K, Wilhelms H, Dodt S, Dreisow M-L, Madara JC, Walker SJ, Wu C, Wang D, Lowell BB, Fenselau H (2023) Cell Metabolism  Published online ahead of print. https://doi.org/10.1016/j.cmet.2023.03.002 

Web URL: Read or download this article via Cell Metabolism here. Free full text of this article is available

Abstract:

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 (PVHTRH) neurons in long-term body weight control.

Silencing PVHTRH 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.


Highlights

  • Weight loss upon caloric deprivation activates PVHTRH neurons that co-express PACAP
  • Activated PVHTRH neurons increase the number of active PVHTRH → AgRP neuron synapses
  • Potentiation of excitatory PVHTRH → AgRP synapses lasts until lost weight is regained
  • PVHTRH → AgRP circuit activity is necessary and sufficient for driving weight (re)gain

 

FAB RESEARCH COMMENT:

This animal study shows that a calorie-restricted diet (as typically recommended for weight loss) leads to amplified signalling of hunger in specific hypothalamic circuits already known to drive appetite and feeding.

What's more, this effect was found to be remarkably long-lasting, reflecting 'synaptic plasticity' - i.e. relatively permanent changes in the neuronal interconnections involved.

These findings help to illuminate the mechanisms responsible for the 'rebound weight gain' that so often follows any weight loss achieved via strictly calorie-controlled diets.

See the related news article for more information, and FAB comment.