Editors' ChoiceCircadian Biology

A food clock in the VMH

Sci. Signal.  22 Mar 2016:
Vol. 9, Issue 420, pp. ec70
DOI: 10.1126/scisignal.aaf7124

Special neuronal circuits in the hypothalamus control circadian rhythm and metabolism. In particular, the suprachiasmatic nucleus (SCN) is the site of the central circadian clock, which is controlled by light, and the ventral medial hypothalamus (VMH) controls metabolism by regulating eating. Components that control circadian output of the SCN, including the transcription factors Period (Per) and Bmal1, are also present in the VMH. Orozco-Solis et al. investigated how the VHM clock components controlled energy homeostasis by making a mouse with Bmal1 specifically deleted in steroidogenic factor 1 (SF1)–positive neurons of the VMH region (Sf1-Cre,Bmal1loxP/loxP). Bmal1 disruption in SF1 neurons had reduced Bmal1 expression and also affected circadian expression of Per1 and Per2 in other neurons in the VMH but did not affect circadian expression of Bmal1, Per1, and Per2 in SCN. Sf1-Cre,Bmal1loxP/loxP mice had reduced body weight compared with Bmal1loxP/loxP litter mates. During the dark (active) period, the Sf1-Cre,Bmal1loxP/loxP mice had increased energy expenditure (calorie burning) and the temperature of brown adipose tissue (BAT) was also higher when compared with these properties of Bmal1loxP/loxP mice during the same period. Expression of circadian clock components in brown adipocytes was not altered in Sf1-Cre,Bmal1loxP/loxP mice, which suggested that the increased temperature in the dark period is independent of the clock components of BAT. Gene expression analysis further revealed increased expression of the gene encoding β-adrenergic receptor 3 (Adrb3) and genes involved in thermogenesis, such as those encoding mitochondrial uncoupling proteins (Ucp1, Ucp2, and Ucp3) during the dark period in BAT of Sf1-Cre,Bmal1loxP/loxP mice. Free fatty acids, substrates for mitochondrial oxidation, were reduced in Sf1-Cre,Bmal1loxP/loxP mice, consistent with increased metabolism. Intraperitoneal injection of an ADRB3 antagonist caused a greater reduction in body temperature of Sf1-Cre,Bmal1loxP/loxP mice than in Bmal1loxP/loxP mice, and this antagonist also reduced the abundance of Ucp1, Ucp2, Ucp3 transcripts in BAT during the dark period. These observations suggested that VMH neurons controlled BAT through the sympathetic nervous system. The amplitude and phase of the change in oxygen consumption and heat production induced by exposing the mice to a prolonged period of constant darkness was greater in the Sf1-Cre,Bmal1loxP/loxP mice than in Bmal1loxP/loxP mice, whereas restricted feeding synchronized the oxygen consumption and heat production to mealtime, suggesting that, unlike the SCN clock that responds to change in light by shifts in the phase, the VMH clock responds to nutrient intake and light by regulating the amplitude and phase of its circadian output. Thus, this study identifies a nutrient status– and light-responsive circadian clock in the VMH that controls BAT metabolic activity through sympathetic signals.

R. Orozco-Solis, L. Aguilar-Arnal, M. Murakami, R. Peruquetti, G. Ramadori, R. Coppari, P. Sassone-Corsi, The circadian clock in the ventromedial hypothalamus controls cyclic energy expenditure. Cell Metab. 23, 467–478 (2016). [PubMed]