Summary: Researchers have made a significant advance in understanding how obesity alters mitochondrial function. A new study shows that a high-fat diet causes mitochondria in fat cells to fragment into smaller, less efficient units through a process controlled by a single gene. Removing that gene protected mice from diet-induced weight gain, pointing to a potential therapeutic target for obesity.
Scientists found that a high-fat diet drives mitochondrial fragmentation in adipose tissue, reducing the cells’ ability to oxidize fat. The effect is mediated by the small GTPase RalA, and deleting the gene for RalA in adipocytes preserved mitochondrial integrity and increased fat burning, preventing excess weight gain in mice fed an identical high-fat diet.
Key Facts:
- A high-fat diet triggers fragmentation of mitochondria in white adipocytes, which decreases their oxidative capacity and impairs fat burning.
- The small GTPase RalA was identified as a central regulator of this mitochondrial fragmentation and the associated metabolic dysfunction.
- Targeted deletion of the RalA gene in adipose tissue protected mice from diet-induced obesity, highlighting RalA as a candidate therapeutic target for human obesity and related metabolic disease.
Source: UCSD
Context: The global prevalence of obesity has risen sharply since 1975, creating a major public health challenge. While diet and physical activity clearly influence weight, obesity also involves intrinsic metabolic derangements. Understanding how these cellular and molecular changes begin is essential to developing more effective treatments.
Researchers at the University of California San Diego School of Medicine investigated how obesity affects mitochondria, the organelles that produce cellular energy. Their findings, published in Nature Metabolism, reveal that high-fat feeding causes mitochondria in white adipose tissue to undergo fragmentation—splitting into many smaller mitochondria that are less able to oxidize fatty acids. The team linked this change directly to increased expression and activity of RalA in adipocytes.
The investigators showed that RalA promotes mitochondrial fission by altering the phosphorylation state of the fission protein Drp1. Specifically, RalA activity reduces the inhibitory phosphorylation at Ser637 on Drp1, which increases Drp1-driven fission and shifts mitochondrial dynamics toward excessive fragmentation. This shift lowers oxidative capacity in adipocytes and suppresses energy expenditure, contributing to weight gain and other metabolic dysfunctions associated with obesity.
When the researchers selectively deleted RalA in white adipocytes, mitochondria retained larger, interconnected morphologies and showed improved fatty acid oxidation. Mice lacking adipocyte RalA gained less weight on a high-fat diet compared with control animals, despite consuming similar amounts of food. These protective effects support the idea that chronic RalA activation in adipose tissue plays a causal role in the metabolic decline observed in obesity.
Further biochemical analysis revealed that several proteins downstream of RalA in mice have human counterparts linked to obesity and insulin resistance. This molecular overlap suggests that RalA-driven mitochondrial dysfunction may also be relevant to human metabolic disease and that targeting this pathway could restore energy expenditure and improve metabolic health.
“Chronic activation of RalA appears to play a critical role in suppressing energy expenditure in obese adipose tissue,” said Alan Saltiel, PhD, professor in the Department of Medicine at UC San Diego School of Medicine. “Understanding this mechanism brings us closer to therapies that increase fat burning and counteract weight gain and metabolic disease.”
Co-authors of the study include Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey Rhyne, Jiaxin Qian, Ying Jones, Chao-Wei Hung, Zichen Wang, Hiroyuki Hakozaki, Johannes Schoneberg, Peng Zhao, Hui Gao, Mikael Ryden, Christopher Liddle, Ruth Yu, Michael Downes, Ronald Evans, Jianfeng Huang, Martin Wabitsch and Shannon Reilly.
Funding: This research received partial support from the National Institutes of Health (Grants P30DK063491, R01DK122804, R01DK124496, R01DK125820 and R01DK128796).
About this genetics and obesity research news
Author: Miles Martin
Source: UCSD
Contact: Miles Martin – UCSD
Image: The image is credited to Neuroscience News
Original Research: Open access. “Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation” by Alan Saltiel et al., Nature Metabolism.
Abstract
Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation
Mitochondrial dysfunction is a hallmark of obesity, insulin resistance and fatty liver disease in both humans and rodents. The study demonstrates that high-fat diet feeding induces mitochondrial fragmentation in inguinal white adipocytes of male mice, which reduces oxidative capacity through a mechanism dependent on the small GTPase RalA.
RalA expression and activity increase in white adipocytes after high-fat diet exposure. Targeted deletion of RalA in white adipocytes prevents mitochondrial fragmentation and mitigates high-fat diet–induced weight gain by enhancing fatty acid oxidation.
Mechanistically, RalA promotes mitochondrial fission in adipocytes by reversing Ser637 phosphorylation on the fission protein Drp1, producing greater mitochondrial fragmentation. Expression of the human Drp1 homolog (DNM1L) in adipose tissue correlates positively with obesity and insulin resistance.
Overall, chronic activation of RalA shifts mitochondrial dynamics toward excessive fission, reducing energy expenditure in obese adipose tissue and contributing to weight gain and metabolic dysfunction.