Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks

Paschos, G. K.; Lordan, R.; Hollingsworth, T.; Lekkas, D.; Kelch, S.; Loro, E.; Verginadis, I.; Khurana, T.; Sengupta, A.; Weljie, A.; FitzGerald, G. A.

doi:10.1101/2024.10.28.620609

bioRxiv · 10.1101/2024.10.28.620609

Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks

Paschos, G. K.·Lordan, R.·Hollingsworth, T.·Lekkas, D.·Kelch, S.·Loro, E.·Verginadis, I.·Khurana, T.·Sengupta, A.·Weljie, A.·FitzGerald, G. A.

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Abstract

Circadian misalignment has been associated with obesity both in rodents and humans. Brown adipose tissue (BAT) thermogenesis contributes to energy expenditure and can be activated in adults to reduce body weight. Although previous studies suggest control of BAT thermogenesis by the circadian clock, the site and mechanisms of regulation remain unclear. We used mice with genetic disruption of the circadian clock in the suprachiasmatic nucleus (SCN) and peripheral tissues to delineate their role in BAT thermogenesis. Global post-natal deletion of Bmal1 in adult mice (Bmal1-/-) abolishes the rhythms of interscapular BAT temperature, a measure of thermogenesis, while normal locomotor activity rhythms are maintained under a regular 12h light-12h dark schedule. Activation of thermogenesis either by exposure to cold or adrenergic stimulation of BAT displays a diurnal rhythm with higher activation during the active period. Both the rhythm and the magnitude of the thermogenic response is preserved in Bmal1-/- mice. In contrast to mice with global deletion of Bmal1, mice with brown adipocyte (Ucp1-Bmal1-/-) or brown and white adipocyte (Ad-Bmal1-/-) deletion of Bmal1 show intact rhythms of BAT thermogenic activity. The capacity of Ucp1-Bmal1-/- mice to activate thermogenesis in response to exposure to cold is identical to WT mice, independent of time of stimulation. Circadian rhythmicity of interscapular BAT temperature is lost in mice with SCN deletion of Bmal1 (SCN-Bmal1-/-), indicating control of BAT thermogenesis rhythms by the SCN. Control mice exhibit rhythmic BAT glucose and fatty acid uptake - a rhythm that is not recapitulated in Bmal1-/- and SCN-Bmal1-/- mice but is present in Ucp1-Bmal1-/- and Ad-Bmal1-/- mice. BAT cAMP and phosphorylated hormone-sensitive lipase (pHSL) is reduced during the active period in Bmal1-/- and SCN-Bmal1-/- mice consistent with reduced sympathetic tone. Furthermore, sympathetic denervation of BAT ablates BAT temperature rhythms in WT mice. Taken together, our findings suggest that the SCN drives rhythms of BAT thermogenesis through adipocyte clock-independent, sympathetic signaling to the BAT.

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Paschos, G. K., Lordan, R., Hollingsworth, T., Lekkas, D., Kelch, S., Loro, E., Verginadis, I., Khurana, T., Sengupta, A., Weljie, A., FitzGerald, G. A.. 2024-10-28. Brown adipose tissue thermogenesis rhythms are driven by the SCN independent of adipocyte clocks. https://doi.org/10.1101/2024.10.28.620609

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