Rev-erb in GABAergic Neurons Controls Diurnal Hepatic Insulin Sensitivity

Systemic insulin sensitivity shows diurnal rhythm with a peak at wakening(1,2). The molecular mechanism underlying such a temporal pattern is unclear. Here we demonstrate that nuclear receptors Rev-erbα/β in the GABAergic neurons in the suprachiasmatic nucleus (SCN(GABA)) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviors under the regular light-dark cycles. Rev-erb regulates the rhythmic expression of genes involved in neurotransmission in the SCN and modulates the oscillatory firing activity of SCN(GABA) neurons. Chemogenetic stimulation of SCN(GABA) neurons at wakening causes glucose intolerance, while restoration of the temporal pattern of either SCN(GABA) neuron firing or Rev-erb expression rescues the time-dependent glucose metabolic phenotype due to Rev-erb depletion. The elevated blood glucose level after awakening is a defining feature of the extended dawn phenomenon (DP) in diabetes patients(3,4). Type 2 diabetes (T2D) patients with the extended DP display a differential temporal pattern of Rev-erb gene expression compared to T2D patients without DP. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, which has implications in the extended DP in T2D.