image: (Mouse adipose tissue) The panel shows the protein amount in adipose tissue. Fasted mice exhibited a significant reduction in Rubicon in adipose tissue compared with fed mice. mTORC1 activity indicator p-S6K1 was also reduced in fasting conditions, which suggests that mTORC1 is inactivated with fasting. Lamin B was used as the loading control. view more
Credit: Tadashi Yamamuro et al.
Osaka, Japan – The coming of spring harkens spring cleaning; a time to de-clutter your home and discard things that are no longer needed. In the body, a cellular process calledautophagy occurs regularly to “de-clutter” our cells. Recently, researchers in Japan have shed new light on the relationship between this process and the body’s metabolic response to fasting.
In a new study published in Autophagy, researchers led by Osaka University investigated the role of autophagy. Autophagy is the process by which unwanted cellular components are eliminated via degradation, during fasting conditions.
Previous studies have shown that fasting causes fat tissue, also known as adipose tissue, to break down, which leads to hepatic steatosis (an accumulation of fat in the liver) and ketogenesis (the production of ketones, which are by-products of fat breakdown). A gene called Rubicon Autophagy Regulator (RUBCN) acts as a negative regulator of autophagy, meaning that it functions to suppress autophagy. The research team led by Osaka University previously demonstrated that the loss of RUBCN in fat tissue during aging leads to systemic fat loss. Because RUBCN levels are also reduced during fasting, the researchers hypothesized that this reduction may promote fat loss through the upregulation of autophagy.
“We wanted to further our understanding of how autophagy is involved in the body’s metabolic response to fasting,” says lead author Tadashi Yamamuro. “To do so, we evaluated the effects of modulating autophagy in the adipose cells of fed and fasting mice.”
The researchers used several mouse models to perform their investigation, including an adipose-specific model that lacked RUBCN and an adipose-specific model that lacked ATG5, a gene that is essential for autophagy to occur. Fat loss, triglyceride levels, and liver weight were evaluated in these mice and compared with control mice under fed and fasting conditions.
“In control mice, fat loss, hepatic steatosis, and ketonemia were observed under fasting conditions,” says senior author Tamotsu Yoshimori. “Fed RUBCN knockout mice exhibited responses that were similar to those of fasted control mice, while fasted ATG5 mice exhibited reduced fat loss, hepatic steatosis, and ketonemia.”
The researchers also found that fasted control mice exhibited a substantial decrease in the expression of adipogenic, or fat-promoting, genes. In ATG5 knockout mice, this reduction was not observed, indicating that autophagy plays a role in the reduction of adipogenic gene expression.
Taken together with the findings from the research team’s previous study, it appears that upregulation of autophagy in adipose tissue is a hallmark of both fasting and aging. In addition to revealing a previously unknown mechanism of the fasting response, these findings may have important implications for our understanding of metabolism during aging.
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The article, “Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response,” was published in Autophagy at DOI: https://doi.org/10.1080/15548627.2022.2047341
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en
Journal
Autophagy
Method of Research
Experimental study
Subject of Research
Animals
Article Title
Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response
Article Publication Date
14-Mar-2022
COI Statement
Iichiro Shimomura and Tamotsu Yoshimori have applied for a patent related to this work. Tamotsu Yoshimori is the founder of AutoPhagyGO. Atsunori Fukuhara belongs to a department endowed by the Takeda Pharmaceutical Company, the Rohto Pharmaceutical, the Sanwa Kagaku Kenkyusho, FUJI OIL HOLDINGS, and the Kobayashi Pharmaceutical. All other authors declare no competing interests.