Time restricted feeding improves health through the adipose-liver axis

The National Institute of Diabetes and Digestive and Kidney Diseases awarded Northwestern University $152,600 on December 31, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to conduct research on time-restricted feeding and its effects on metabolic health through the adipose-liver axis.

The research investigates how circadian rhythm disruption contributes to insulin resistance, obesity, and steatotic liver disease. The study tests the hypothesis that aligning feeding time with adipose tissue thermogenic cycles enhances liver metabolism and mitigates metabolic dysfunction. The recipient will characterize metabolic effects in mice fed a high-fat diet during different circadian phases and examine the interrelationship between adipose thermogenesis cycles and hepatic lipid metabolism, including de novo lipogenesis and steatosis.

Northwestern University's Sponsored Research Division is the recipient. Performance takes place in Chicago, Illinois. The award period extends from December 31, 2026, through June 30, 2029.

Abstract

Circadian rhythms are intrinsic 24-hour cycles of behavior and metabolism that coordinate anabolic and catabolic cycles of physiology in anticipation of the rotation of the earth. Epidemiologic and experimental genetic studies show that disruption of circadian rhythms is associated with insulin resistance, accelerated diet-induced obesity, and steatotic liver disease (masld) through mechanisms that remain incompletely understood. Recent research from our lab has demonstrated that feeding animals a high-FAT diet (HFD) ad libitum leads to disordered feeding and disrupts behavioral and molecular circadian rhythms. However, time-restricted feeding in which access to high-FAT diet is limited to the active phase (dark period) reinstates natural feeding patterns and markedly improves metabolic health. This process involves the increased metabolism of food to produce heat through adipose thermogenesis which peaks during the nighttime in mice. In exciting preliminary data, i find that disordered feeding (in the light cycle) also leads to increased DE novo lipogenesis (DNL) and steatosis whereas limiting access to high-FAT food during the nighttime, or naturalistic feeding, mitigates metabolic syndrome and obesity. These data lead me to postulate that desynchrony of feeding and cycles of adipose thermogenesis elevates hepatic DNL. In this proposal, i seek to unravel the interrelationship between the adipose thermogenesis cycle and hepatic lipid metabolism. My central hypothesis is that reinstating naturalistic feeding during the dark phase enhances liver metabolism due alignment of nutrient metabolism with adipose tissue thermogenesis. In aim 1 i will test the hypothesis that misalignment of feeding time with adipose tissue thermogenic rhythms induces insulin resistance and steatosis. I will characterize the metabolic effects of feeding mice a HFD during either the dark-cycle or light-cycle with a focus on hepatic lipid metabolism and DNL. Additionally, i will test if enhancing adipose tissue thermogenesis prevents steatosis by using novel adipose-directed antisense oligonucleotides against the thermogenic repressor ZFP423. Finally, i will use a liver-specific pan acetyl COA carboxylase (ACC) inhibitor to determine if the increase in DNL is required for light-cycle feeding to cause hepatic steatosis. In aim 2 i will test the hypothesis that time-restricted feeding protects against steatosis through a mechanism requiring the adipocyte molecular clock. I will use genetic strategies to delete or overexpress the circadian clock gene BMAL1 in adipocytes to determine if the adipocyte circadian clock is protective against hepatic metabolic dysfunction. The work presented in this proposal will dissect the contributions of meal timing, adipocyte thermogenesis, and the adipocyte circadian clock in regulating hepatic lipid metabolism and metabolic health. These studies will provide a training environment to foster my development as an independent investigator at the frontier of circadian studies of feeding behavior and metabolism.