Scientists at Northwestern Medicine, led by Joseph Bass, have discovered how disruptions in the body’s internal clock known as the circadian rhythm can impair metabolic function in fat cells and contribute to the development of obesity and other metabolic disorders. The findings, published in Nature Metabolism, provide new insights into how the body’s energy systems function at the cellular level.

Circadian rhythm is the body’s natural 24-hour biological clock that regulates key physiological processes such as sleep-wake cycles, hormone secretion, and metabolism. At the molecular level, this clock operates through a feedback system involving specific proteins and genes, including CLOCK and the gene BMAL1, which control the activity of many other genes responsible for maintaining normal metabolic rhythms across tissues and organs.

In their study, researchers investigated how disruptions in this biological clock affect metabolism within adipocytes fat cells responsible for storing energy and regulating metabolic balance. By isolating mitochondria, the energy-producing structures within cells, the scientists observed how circadian rhythm influences oxidative metabolism, a cellular process that converts nutrients and oxygen into usable energy.

The research revealed that when the circadian clock is disrupted either by deleting the BMAL1 gene or by exposing mice to a high-fat diet mitochondrial function in fat cells becomes impaired. This disruption interferes with key metabolic pathways, including insulin signaling and peroxisome proliferator-activated receptor signaling, both of which play essential roles in maintaining metabolic health. As a result, the energy-handling mechanisms inside cells become inefficient, contributing to metabolic dysfunction even before significant weight gain occurs.

To further explore potential solutions, the researchers engineered mouse models expressing an enzyme from baker’s yeast called NDI1. This enzyme helps regenerate NAD+, a molecule essential for cellular energy production and ATP generation. Remarkably, adipocytes expressing this enzyme were able to restore metabolic balance and prevent diet- and circadian-related metabolic dysfunction, even though the overall body weight of the mice remained unchanged.

According to Bass, these findings demonstrate that metabolic disease is not caused solely by the accumulation of excess fat, but also by dysfunction in the cellular energy systems that manage and process stored energy. When the circadian clock fails to function properly, the energy-producing processes in mitochondria become disrupted, leading to metabolic imbalance.

The study suggests that targeting mitochondrial defects and restoring proper energy metabolism in fat cells may offer new therapeutic strategies for treating metabolic diseases without necessarily reducing fat storage.

Looking ahead, the research team plans to investigate how disruptions in circadian rhythm and mitochondrial function influence immune responses and inflammation in obesity. They are also exploring RNA-based therapeutic approaches that could potentially restore metabolic function in affected cells.

The study was led by Chelsea Hepler, a former postdoctoral fellow in the Bass laboratory and now an assistant professor at the University of Michigan Medical School, further advancing the understanding of how biological clocks regulate metabolism and overall health.

Source: https://news.feinberg.northwestern.edu/2026/03/09/circadian-rhythm-causes-metabolic-dysfunction-in-fat-cells/