Deletion of astrocytic BMAL1 results in metabolic imbalance and shorter lifespan in mice

Abstract

Disruption of the circadian cycle is strongly associated with metabolic imbalance and reduced longevity in humans. Also, rodent models of circadian arrhythmia, such as the constitutive knockout of the clock gene Bmal1, leads to metabolic disturbances and early death. Although astrocyte clock regulates molecular and behavioral circadian rhythms, its involvement in the regulation of energy balance and lifespan is unknown. Here, we show that astrocyte‐specific deletion of Bmal1 is sufficient to alter energy balance, glucose homeostasis, and reduce lifespan. Mutant animals displayed impaired hypothalamic molecular clock, age‐dependent astrogliosis, apoptosis of hypothalamic astrocytes, and increased glutamate and GABA levels. Importantly, modulation of GABAA‐receptor signaling completely restored glutamate levels, delayed the reactive gliosis as well as the metabolic phenotypes and expanded the lifespan of the mutants. Our results demonstrate that the astrocytic clock can influence many aspects of brain function and neurological disease and suggest astrocytes and GABAA receptor as pharmacological targets to prevent the metabolic dysfunctions and shortened lifespan associated with alterations of circadian rhythms.

Astrocyte Clocks and Glucose Homeostasis

“…Astrocytes have long lived in the shadow of the neurons as they were thought to have mainly a structural role in the central nervous system. The recent findings showing the critical role of the astrocyte clock in the control of SCN function and circadian behavior ( 39 – 43 ) is a game-changing discovery that offers radically new research directions for therapy of brain diseases originated by environmental miss functioning of circadian rhythms or genetic factors affecting clock genes or outputs. This glial cell type is highly diverse in its morphological appearance, functional properties, and distribution among and within different brain regions ( 44 , 45 ).…”

“…Moreover, the circadian locomotor activity but not the metabolic disturbances of Bmal1−/− mice were rescued by restoring BMAL1 expression in the SCN ( 125 ). Similarly, mice with astrocyte‐specific deletion of BMAL1 show altered energy balance and glucose homeostasis despite their circadian locomotor activity is not lost ( 39 – 43 ). Thus, peripheral and/or extra-SCN hypothalamic clocks, but not the SCN, might have a crucial role in developing glucose intolerance and INS resistance.…”

“…Whether astrocyte-neuron metabolism in hypothalamic glucose sensing and associated-systemic response in the normal or diabetic brain relies on the astrocyte molecular clock remains to be investigated. However, this idea is reinforced by the recent finding that deletion of Bmal1 in astrocytes impairs INS sensitivity and glucose homeostasis ( 39 ).…”

“…The uptake of glutamate by astrocytes, critical for neuronal activity ( 202 ), is metabolically expensive and requires an increase in glycolysis and lactate production ( 171 ). Remarkably, control of glutamate and GABA levels, coupled to astrocyte rhythms ( 40 – 43 , 203 ), is necessary for the generation of molecular and behavioral rhythms and, is also critically involved in the modulation of hypothalamic neural circuits controlling glucose homeostasis ( 39 , 204 , 205 ). However, excessive demands on astrocytes, in response to a decrease in glucose levels, impair glutamate uptake ( 206 ), altering the glutamatergic signaling to delay the onset of the normal counterregulatory response to hypoglycemia ( 206 ).…”

Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism

“…Circadian rhythms are involved in the regulation and maintenance of various physiological processes, including immune responses, energy metabolism, and memory formation (8)(9)(10). A growing body of literature shows that endogenous circadian clock function plays a crucial role in the control of many cellular processes that affect overall physiology (11)(12)(13)(14)(15)(16)(17). For example, macrophages or microglial clock gene modulates the production of cytokines, following an immune challenge (18)(19)(20).…”