Fat-Burning Mice Go the Distance

As any fitness trainer will tell you, building muscle is the best way to burn fat: the number of lipid-rich mitochondria increases to provide sufficient energy to support the increased skeletal muscle mass. In addition, fatty acids are mobilized and contribute to increased physical endurance. For example, marathon runners, as compared to sprinters, preferentially burn fat over glucose. Remarkably, researchers have discovered molecular methods to manipulate fat utilization in the absence of athletic training. Previous studies have shown that the peroxisome proliferator-activated receptor (PPAR) transcription factors differentially stimulate and repress fatty acid oxidation, alter mitochondria content, and modify running endurance in laboratory mice (Evans et al. 2004, for review). In a new 2015 study, researchers in Japan demonstrate that another transcription factor, NF-kB, similarly can regulate fat utilization in mice and can improve their long-distance running endurance (Minegishi et al. 2015).

NF-kB regulates fat utilization

As a central player in the inflammatory response, NF-kB is a common and valuable drug target for treating maladies such as rheumatoid arthritis, atherosclerosis, cancer, and diabetes. Because it both regulates and is regulated by PPAR transcription factors, Minegishi et al investigated the role of NF-kB in lipid metabolism by characterizing mice deficient in the NF-kB subunit p50 (similar to strain B6.Cg-Nfkb1tm1Bal/J (006097)).

Under baseline conditions, p50 null and control mice were similar in weight, oxygen consumption, and activity level. However, p50 null mice exhibited higher fatty acid oxidation in liver and skeletal muscle and expressed higher levels of fatty acid oxidation enzyme transcripts, which are also targets of PPAR activity. Despite consuming similar amounts of a high-fat diet for 15 weeks, p50 null mice gained less weight than wild-type control mice and showed lower white and brown adipose tissue accumulation. In blood analyses, p50 null mice had consistently lower levels of cholesterol, leptin, glucose, and insulin than controls. Because the p50 null mice utilized fat more readily, the researchers tested whether the mice could use this as an advantage in distance running. Although p50 null mice consumed similar amounts of oxygen as controls, they could run for 30% longer, indicating that they were able to generate more energy, presumably through fatty acid oxidation rather than from glycolysis and aerobic respiration.

These results indicate that NF-kB promotes fat storage and prevents its breakdown. Consequently, constant stimulation of NF-kB through chronic inflammation may help to maintain accumulated fat and prevent its metabolism. This study suggests that therapies directed against proinflammatory molecules may be useful not only for treating inflammation-related diseases but also for mitigating obesity and enhancing physical endurance.