Nearly half of Americans try to lose weight by reducing caloric intake each year; however, most of these attempts fail to sustain weight loss in the long term. Time-restricted eating (TRE), a form of intermittent fasting, has emerged as a promising intervention to combat overeating, weight gain, and metabolic disorders. Patients who restrict their eating to a 6-8 hour window during their active circadian phase lose weight, improve glucose tolerance, and increase insulin sensitivity. Additionally, these diet regimens enhance circadian health, positively influencing neurological functions such as sleep and cognition. Therefore, identifying the molecular mechanisms involved in circadian entrainment and well-being is crucial for developing informed lifestyle strategies that diminish diseases exacerbated by modernity.
Our recent research has begun to uncover these mechanisms. Using single-nucleus RNA sequencing during scheduled feeding, we identified a population of leptin receptor–expressing neurons in the dorsomedial hypothalamus (DMHLepR neurons) that upregulate circadian entrainment genes and exhibit calcium activity before anticipated meals. Manipulating these neurons through exogenous leptin, silencing, or chemogenetic stimulation disrupted the development of molecular and behavioral food entrainment. Repetitive activation of DMHLepR neurons led to a secondary bout of circadian locomotor activity in phase with the stimulation, dependent on an intact suprachiasmatic nucleus (SCN). A subset of these neurons projects directly to the SCN, integrating metabolic and circadian systems and facilitating mealtime anticipation.
Additionally, the p75 neurotrophic factor receptor (p75NTR), known for its role in developmental events and adult homeostatic processes like injury response, synaptic plasticity, and metabolic balance, has been established—through our collaboration with the Deppmann Lab—as a novel regulator of time-restricted eating. We are currently leveraging these findings to strengthen circadian rhythmicity and promote metabolic health.
Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network Q Tang, E Godschall, CD Brennan, Q Zhang, RJ Abraham-Fan, ... Science Advances 9 (34), eadh9570
The p75 neurotrophin receptor in AgRP neurons is necessary for homeostatic feeding and food anticipation B Podyma, DA Johnson, L Sipe, TP Remcho, K Battin, Y Liu, SO Yoon, ... eLife 9, e52623
