Scientists report that they have discovered an enzyme that appears to regulate the physiology of fat in mice—decreasing inflammation in white fat tissue, while promoting the ability of brown fat to burn calories. Preliminary genetic evidence included in the study suggests that the enzyme, called SNRK, or sucrose nonfermenting related kinase, performs similar functions in humans, making it a potential new drug target in the battle against obesity and its complications.
“This study suggests that there may be dual benefits if we can find a way to enhance SNRK production in fat tissue,” said Simin Liu, M.D., Sc.D., professor of epidemiology in Brown's School of Public Health and professor of medicine at the Alpert School of Medicine. “Reducing inflammation in white fat may ease associated complications, such as insulin resistance, while at the same time, increasing brown fat metabolism may aid in weight loss. Those possibilities will need to be followed up in further studies in humans.”
The study (“Sucrose Non-Fermenting Related Kinase Regulates Both Adipose Inflammation and Energy Homeostasis in Mice and Humans”) appears in Diabetes.
“SNRK is essential for survival since SNRK global deficient pups die within 24 hours after birth. Heterozygous mice are characterized by inflamed WAT [white adipose tissue] and smaller BAT [brown adipose tissue]. Adipocyte specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impairment in adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, elevated body weight, and insulin resistance,” write the investigators.
“We further confirmed the significant association of common variants of [the] SNRK gene with obesity risk in human beings. Through applying [a] phosphoproteomic approach, we identified eukaryotic elongation factor 1 delta (EEF1D) and histone deacetylase 1/2 (HDAC1/2) as potential SNRK substrates. Taken together, we conclude that SNRK is a repressor for WAT inflammation and essential for maintaining BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated disorders.”
The presence of SNRK in fat tissue was first discovered by Haiyan Xu, M.D., Ph.D., while she was a researcher in the molecular epidemiology and nutrition lab of Brown's Center for Global Cardiometabolic Health. Her initial research suggested that the enzyme played a role in regulating inflammation, but this latest study was designed to get a more complete picture of its function in fat tissue.
The researchers bred mice that lack the gene for producing SNRK in fat cells. They could then compare fat tissue from those mice with tissue from normal mice. Mice lacking the SNRK gene had a significantly higher concentration of macrophages in white fat tissue compared with normal mice. Macrophages are commonly used as markers for inflammation, and their increased presence helps confirm that SNRK plays a role in regulating inflammation in white fat tissue.
It's an intriguing finding, Dr. Xu says, because her previous research has shown that inflammation in white fat is associated with insulin resistance, a risk factor for the development of diabetes.
In addition to its effects on white fat, the researchers showed that SNRK influences the physiology of brown fat tissue. Mice lacking the SNRK gene tended to be heavier than normal mice and were shown to have lower overall metabolic rates. The SNRK-lacking mice maintained their extra weight, even when treated with a drug known to induce weight loss in rodents by activating brown fat. That suggests that the lower metabolic rate and extra weight carried by the mice lacking the SNRK gene was due in part to reduced brown fat metabolism.
“What that tells us is that boosting SNRK production might have the effect of boosting overall metabolism, which might aid in weight loss,” Dr. Xu said.
Having established that SNRK appears to regulate fat tissue inflammation and metabolism in mice, the researchers then identified multiple germline mutations in the human genes responsible for SNRK production that were directly associated with higher body mass index, higher waist circumference, and risk of obesity in a cohort of 12,000 women who participated in the Women's Health Initiative.
“What's particularly noteworthy about this work is we were able to present an integrative link from genetics, cell- and animal-based experiments, all the way up to clinical outcomes in a large human population,” Dr. Liu said. “We hope that making that connection will quicken the process of multidisciplinary collaborations in translating lab-based discoveries to new therapies or targets for interventions.”