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Gene in Fat Plays Key Role in Insulin Resistance; “Getting Better Grasp on Function of KBTBD2 Could Open Completely New Window into How Insulin Sensitivity Is Regulated,” Says Nobelist Who Made Seminal “Innate Immunity” Discovery of Toll-Like Receptors

Deleting a key gene in mice in just their fat made tissues throughout these animals insulin-resistant, in addition to other effects, a new study by University of Texas Southwestern (UTSW) researchers shows. The findings, initially published online on May 7, 2020 in PNAS (https://www.pnas.org/content/117/21/11829), could shed light on Type 2 diabetes and other insulin-resistance disorders, which remain poorly understood, despite decades of study. The open-access article is titled “Tissue-Specific Disruption of Kbtbd2 Uncovers Adipocyte-Intrinsic and -Extrinsic Features of the teeny Lipodystrophy Syndrome.” In 2016, UTSW immunologist and geneticist and Nobel Laureate Bruce Beutler (photo), MD, (https://profiles.utsouthwestern.edu/profile/10593/bruce-beutler.html, Zhao Zhang, PhD (https://profiles.utsouthwestern.edu/profile/155419/zhao-zhang.html, and their colleagues reported a new mouse mutant that they named teeny (https://www.pnas.org/content/113/42/E6418), which resulted from inactivating a gene known as KBTBD2 that is widely expressed throughout the body in mice and humans. In addition to these animals’ small size – about half that of normal “wild-type” mice – the scientists quickly noticed that teeny mice produce a lot of urine, often a sign of diabetes. Dr. Beutler is a Regental Professor and Director of the Center for the Genetics of Host Defense (https://www.utsouthwestern.edu/education/medical-school/departments/gene...). Dr. Zhang is an Assistant Professor of Internal Medicine who also has an appointment in the Center. Sure enough, tests showed that these teeny animals had extremely high blood sugar, severe insulin resistance, and high insulin levels that peaked at 8 weeks of age and then gradually declined. They also had abnormally low amounts of body fat, but had fatty livers. Transplanting teeny mice with fat tissue from normal mice largely resolved these problems, a sign that KBTBD2 (Kelch repeat and BTB domain containing 2), in fat tissue in particular, is key to each of these problems. However, Dr. Beutler and Dr. Zhang say, it was unclear whether these problems were also rooted in KBTBD2 activity in other insulin-responsive tissues, such as muscle and liver.

To answer this question, the researchers created different mouse mutants in which KBTBD2 was selectively inactivated in the animals’ fat, muscle, or liver. Although each of these rodents grew to a normal size-- suggesting that this gene acts through other pathways to regulate body growth--only those with KBTBD2 inactivated in fat cells had some other hallmark characteristics of teeny.

These animals had extremely high insulin resistance, although only moderately high blood sugar levels. Although their blood insulin levels were also high, they didn’t decline after 8 weeks of age as they do in teeny mice.

In addition to having abnormally low body fat like their teeny counterparts, those animals missing KBTBD2 in just their fat cells also had fatty livers, suggesting communication between fat and liver tissue.

Together, Dr. Beutler and Dr. Zhang say, the findings confirm that KBTBD2 plays a key role in regulating insulin sensitivity, and a variety of other activities, through its role in fat. However, they also raise important questions about what this gene does elsewhere in the body.

KBTBD2 produces a protein that slices up another protein known as p85a, part of a larger protein complex that encourages insulin-sensitive cells to produce sugar transporters on their surfaces. Although it clearly performs this job when produced in fat cells, KBTBD2 doesn’t seem to do this in other parts of the body, even though it’s widely expressed in other cell types. It is also unclear what part KBTBD2 plays in keeping teeny mice so small. The researchers plan to explore these questions in future studies.

The researchers also plan to investigate the mechanisms behind why these animals have such extreme insulin resistance, which could have implications for Type 2 diabetes in humans, a disease marked by this characteristic.

“Although we know that insulin resistance is very rarely caused by mutations in the insulin receptor or genes responsible for making other proteins known to participate in glucose uptake, most of it is not understood,” says Dr. Beutler, a Nobel Laureate. “Getting a better grasp on the function of KBTBD2 could open a completely new window into how insulin sensitivity is regulated.”

Dr. Beutler, who developed a technology for instantly identifying induced germline mutations that cause phenotypes in mice, received the Nobel Prize in Physiology or Medicine in 2011 for his discovery of an important family of receptors (Toll-like receptors) that allow mammals to sense bacterial infections when they occur, triggering a powerful inflammatory response.

NOBEL PRIZE FOR TOLL, TOLL-LIKE RECEPTORS, & INNATE IMMUNITY

Below is a quote from the Nobel committee’s description of Dr. Beutler’s seminal discovery in the field of “innate immunity.”
“Bruce Beutler was searching for a receptor that could bind the bacterial product, lipopolysaccharide (LPS), which can cause septic shock, a life-threatening condition that involves overstimulation of the immune system. In 1998, Beutler and his colleagues discovered that mice resistant to LPS had a mutation in a gene that was quite similar to the Toll gene of the fruit fly. This Toll-like receptor (TLR) turned out to be the elusive LPS receptor. When it binds LPS, signals are activated that cause inflammation and, when LPS doses are excessive, septic shock. These findings showed that mammals and fruit flies use similar molecules to activate innate immunity when encountering pathogenic microorganisms. The sensors of innate immunity had finally been discovered.”

The discoveries of Dr. Beutler and co-Nobelist Dr. Jules Hoffman “triggered an explosion of research in innate immunity. Around a dozen different TLRs have now been identified in humans and mice. Each one of them recognizes certain types of molecules common in microorganisms. Individuals with certain mutations in these receptors carry an increased risk of infections while other genetic variants of TLR are associated with an increased risk for chronic inflammatory diseases.”

Other UTSW researchers who participated in this study include Thomas Gallagher and Philipp E. Scherer.

[Press release] [PNAS article]

IMAGE

The illustration shows the identification of KBTBD2 as a key gene in the maintenance of whole-body insulin sensitivity through its role in fat. Loss of KBTBD2 leads to the accumulation of the protein p85a that blocks insulin signaling in fat and secondary insulin resistance in other tissues such as liver and muscle.