Nhlh2: a basic helix-loop-helix transcription factor controlling physical activity

Abstract

In mice, targeted deletion of the basic helix-loop-helix transcription factor, nescient helix-loop-helix 2 (Nhlh2), leads to adult-onset obesity and reduced physical activity. We propose the novel hypothesis that transcriptional activity by Nhlh2 (NHLH2 in humans) controls either the ability or the motivation for exercise.

Figure 1

Screenshot from NCBI map viewer showing region of human chromosome 1 containing nescient helix-loop-helix 2 (NHLH2, human) and marker D1S189. National Center for Biotechnology Information website (http://www.ncbi.nlm.nih.gov/) map viewer was used to visualize the region of human chromosome 1 containing nescient helix-loop-helix 2 (NHLH2, human) and marker locus D1S189. A screenshot of the region was modified for use in this figure to highlight the two loci of interest and the distance between them.

Figure 2

Home-cage activity levels for male and female N2KO mice. A laser beam-based home-cage activity system for mice (Columbus Instruments International, Columbus, OH) was used to assess general activity of the nescient helix-loop-helix 2 (Nhlh2)-deleted (N2KO) mice and normal (WT) age- and sex-matched mice. Data are based on the total average activity per 24-h period, measured over 3 d. Data are reported as the mean × SEM, n = 7 male WT, 7 male N2KO, 4 female WT, and 4 female N2KO. *P ≤ 0.05, **P ≤ 0.01

Figure 3

The effect of food deprivation on wheel running activity in N2KO mice. Mice were acclimated for 3 d to cages containing computerized running wheels (Columbus Instruments International). Wheel running was then measured for 24 h during ad libitum access to food. At 11 a.m. the following day, food was removed, and wheel running was accessed for 24 h of food deprivation. At 11 a.m. the following day, ad libitum food was returned to the animals, and wheel running was accessed for 24 h of food return. The data are reported as the percent of activity levels during ad libitum feeding for each genotype. Note that nescient helix-loop-helix 2 (Nhlh2)-deleted (N2KO) show a lower ad libitum activity level (2470 ± 175 turns per day, WT, compared with 1037 ± 141 turns per day, N2KO). N = 3 normal (WT) males, 4 N2KO males. *P ≤ 0.05, **P ≤ 0.01

Figure 4

Diagram showing the possible role of nescient helix-loop-helix 2 (Nhlh2) in mediating brain and skeletal muscle function and exercise levels. Nescient helix-loop-helix 2 (Nhlh2) activity in the brain could control the motivation to exercise through either β-endorphin processing or melanocortin signaling, In skeletal muscle tissue, Nhlh2 could control the differentiation and/or regeneration of muscle tissue after exercise or muscle metabolism of glucose and fatty acid substrates.