Trim28 Gene Implicated in Fat Storage, Obesity, Mouse Study Reports
Deleting a gene called Trim28 in mice led to alterations in fat storage and metabolism, especially in female mice, who became significantly heavier, a study reported.
These findings demonstrate Trim28‘s role in genetic obesity and show that the gene may be a potential target for the prevention and treatment of obesity.
The study, “Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance,” was published in the journal Nature Communications.
Fat (lipid) intake through diet, or made in the body, plays a critical role in the long-term energy supply needed to survive. Fat that is not used as energy is transferred to adipose tissue, which acts as fat storage.
Complications in obesity arise when fat storage cells — called adipocytes — become saturated and incapable of storing additional fat. This leads to deposits of fats in other tissues, which results in health problems.
“The storing of fat is a normal and necessary function, which developed through evolution to allow our bodies to survive in periods of famine,” Brian Drew, PhD, the study’s lead author, said in a press release.
“However, in modern society, we very rarely have periods of famine and usually have an oversupply of fat and energy, where our adipose tissue becomes too full and overflows,” said Drew, the head of molecular metabolism and aging at the Baker Heart and Diabetes Institute, in Australia.
Studies have shown that stimulating the growth of new adipocytes can reduce obesity-induced complications, resulting in a metabolically healthy outcome. People who are obese but metabolically healthy have regular-sized adipocytes, whereas those who are not obese but are metabolically unhealthy have significantly larger adipocytes.
As such, identifying new molecules and pathways to promote adipocytes’ healthy growth may support the development of treatment strategies to benefit obese people.
Trim28 is a protein that controls gene activity and plays a vital role in regulating many aspects of mammalian physiology. Mutations in the Trim28 gene have been associated with increased fat mass in mice and humans, but its mechanisms remain largely undefined.
Now, researchers at Monash University, in Australia, and their collaborators bred a mouse model — called Trim28 adi-KO — in which the gene that encodes Trim28 was deleted specifically from adipocytes to investigate its function in adipose tissue and obesity.
“In Australia alone, over 65% of adults are either overweight or obese,” Drew said, noting that obesity now is linked to higher mortality rates than is smoking.
“Though we know quite a bit about how and why obesity causes disease, we still don’t fully understand why it varies so differently across the population, between different populations, and even between sexes,” Drew said.
“One theory is that these genes control how and where we store fat, and by identifying the genes that affect these processes such as the one in this study, it can help us find ways to treat people with obesity, or even prevent it in the first place,” he added.
Both male and female Trim28 adi-KO mice, along with healthy controls, were fed a chow diet for 24 weeks (about six months). Total body weight increased with time in all of the mice, but without a significant difference between the two groups.
Male mice showed a trend for increased fat mass, which began at about eight weeks. Likewise, female mice exhibited a significant and steady increase in fat mass from about eight weeks.
Fasting blood glucose levels were significantly lower in male and female KO mice at the end of the study. There were no differences in glucose tolerance — which is an impaired ability for glucose disposal by the body — at any time for either male or female mice.
Next, feeding another group of KO mice with a high-fat diet showed that the total body weight of male and female mice increased over 16 weeks (about four months), but with no overall differences compared with controls.
However, female Trim28 adi-KO mice were significantly heavier than control mice beginning at about seven weeks of age. Further, these females showed a significant increase in fat mass, which began at about four weeks.
In contrast with chow-fed animals, no differences in fasting blood glucose were seen between controls and Trim28 adi-KO mice of either sex at any time point in animals fed a high-fat diet.
While the team found no differences between male control and KO mice in whole-body metabolism, as measured by respiration and energy expenditure, female KO mice showed a significant reduction in respiration in both chow-fed and high-fat diet mice. These female KO mice also showed significant change in energy expenditure patterns relative to controls, “suggesting a sex-specific genotype effect on energy metabolism,” the team wrote.
The results also showed a consistent increase in triglycerides containing saturated fatty acids and a decrease in polyunsaturated fatty acids in animals with no Trim28 in adipocytes. Lipolysis — a process that breaks down triglycerides into fatty acids — was significantly reduced in Trim28 adi-KO female mice as compared with control mice.
A gene activity analysis on Trim28-related pathways in adipose tissue revealed that many genes were altered in the Trim28 adi-KO mice, including those associated with cancer and DNA replication, as well as pathways involved in lipid metabolism and fat storage.
Two genes — Olr1 and Klf14, both of which have been implicated in adipocyte function — were substantially affected by Trim28 deletion. The results showed an up to 40-fold increase in Olr1 gene activity in both male and female KO mice, and an almost complete absence of Klf14 activity in adipose tissue.
Of these two genes, Klf14 is linked to female-specific differences in adipocyte function and fat storage in both rodents and humans. That suggests that “Trim28 may be a core component of the [gene activation] machinery that regulates Klf14 expression,” the researchers wrote.
“These findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and [adipose] function,” the scientists concluded.
Overall, the study shed new light on some of the genetic mechanisms behind obesity. According to Drew, “genetics contributes about 50% of how our body develops and reacts to obesity.”
The researchers say there is an urgent need for treatment options for people with obesity.
“Whilst prevention is what we ultimately hope for, there are many people in our community with obesity who would benefit from an effective treatment,” said Wendy Brown, PhD, chair of the Monash University department of surgery.
“Only three percent of people with obesity are able to lose weight and keep it off with diet and exercise alone,” Brown said. “Findings such as this are the first step in developing effective treatment options, not only reducing weight but improving health.”