RESEARCH: ENERGY STATE TO TRANSCRIPTION DURING TIME-RESTRICTED FEEDING

Joseph Bass, MD, PhD's research publication,
"Time-restricted feeding mitigates obesity through adipocyte thermogenesis", has been published in the 2022 21st Issue of Science and is highlighted in the 2022 SciPak.

Episode Summary

Joseph Bass, MD, Ph.D. discusses the focus of his research on circadian rhythms and metabolic homeostasis. He tells us about the relationship between homeostasis and metabolism and the conclusions he has drawn from his recent study published in Nature Metabolism

He shares the significance of finding NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding and how he is incorporating these findings into his work at Northwestern Medicine.

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Time-restricted feeding mitigates obesity through adipocyte thermogenesis

Why it matters when mice eat
The timing of feeding relative to daily cycles of activity and sleep can determine whether mice fed the same high-fat diet (HFD) become obese. Hepler et al. clarified the mechanism behind such differential energy handling (see the Perspective by Lagarde and Kazak). In their experiments, mice fed an HFD consumed during the active phase of their daily cycle (nighttime for a mouse) had greater energy expenditure resulting from the metabolism of food to produce heat. Such thermogenesis depended on the circadian clock of adipocytes and on increased synthesis of creatine, fueling a futile cycle of ATP turnover in the mitochondria of adipocytes. These results help to explain the benefits of time-restricted feeding and how circadian disruption can contribute to metabolic disease. —LBR

Abstract
Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.

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This article was originally published in Science on October 20, 2022.

Joseph Bass, MD, PhD, the Charles F. Kettering Professor of Medicine, director of the Center for Diabetes and Metabolism and chief of Endocrinology in the Department of Medicine.