4-Methylumbelliferone improves the thermogenic capacity of brown adipose tissue.

Therapeutic increase of brown adipose tissue (BAT) thermogenesis is of great interest as BAT activation counteracts obesity and insulin resistance. Hyaluronan (HA) is a glycosaminoglycan, found in the extracellular matrix, which is synthesized by HA synthases (Has1/Has2/Has3) from sugar precursors and accumulates in diabetic conditions. Its synthesis can be inhibited by the small molecule 4-methylumbelliferone (4-MU). Here, we show that the inhibition of HA-synthesis by 4-MU or genetic deletion of Has2/Has3 improves BAT`s thermogenic capacity, reduces body weight gain, and improves glucose homeostasis independently from adrenergic stimulation in mice on diabetogenic diet, as shown by a magnetic resonance T2 mapping approach. Inhibition of HA synthesis increases glycolysis, BAT respiration and uncoupling protein 1 expression. In addition, we show that 4-MU increases BAT capacity without inducing chronic stimulation and propose that 4-MU, a clinically approved prescription-free drug, could be repurposed to treat obesity and diabetes.

Effects of omni-directional noise-exposure during hearing onset and age on auditory spatial resolution in the Mongolian gerbil (Meriones unguiculatus) -- a behavioral approach.

Inhibitory inputs to the binaural brainstem nuclei medial and lateral superior olives (MSO and LSO, respectively) are thought to be important for sound localization in mammals. Here, we investigate whether aged gerbils that typically exhibit degenerative changes in auditory nuclei providing inhibition to MSO and LSO show diminished localization ability. We also tested the localization ability in gerbils reared in omni-directional white noise during hearing onset, a treatment that affects the adjustment of inhibitory inputs to MSO neurons possibly resulting in weakened sensitivity to interaural time difference. Localization ability of both groups was compared to that of young gerbils raised under control conditions. Stimuli had a duration of 125 ms and were pure tones of 0.5, 1, 2, 4 and 8 kHz, 300-Hz-bands of noise centered at 0.5, 2 and 8 kHz or broad-band noise. Gerbils trained in a two-alternative-forced-choice procedure indicated if sounds were presented from the left or from the right by choosing the respective response compartment of a Y-shaped experimental setup. The minimum resolvable angle (MRA) was calculated as the minimum angle between two loudspeaker locations that a gerbil was able to discriminate. MRAs for aged gerbils were higher compared to controls, whereas MRAs of noise-reared gerbils did not differ from those of the control group. Results are discussed with respect to the progressive degeneration affecting the gerbil's auditory system, changes in the anatomical arrangement of inhibitory inputs on binaural neurons in the MSO, and hearing thresholds.

Resolution in azimuth sound localization in the Mongolian gerbil (Meriones unguiculatus).

Minimum resolvable angles (MRAs) for sound localization in azimuth in the gerbil were determined in a behavioral study using tones, 300-Hz bands of noise centered at frequencies between 500 Hz and 8 kHz and broad-band noise of on average 60 dB SPL overall level. Using the method of constant stimuli, seven gerbils were trained in a two-alternative-forced-choice procedure to indicate if sounds were presented to them from the left or from the right by choosing the left or right arm of a Y-shaped cage. The MRA is the minimum angle between two loudspeaker locations that the gerbils discriminated. Animals were either stimulated from the front (N=4) or from the back (N=3). The MRA for broad-band noise randomly varying in level by +/- 6 dB was 23 degrees and 45 degrees for gerbils stimulated from the front or back, respectively. Generally a gerbil's MRA for tones declined up to 2 kHz reaching 20 degrees and 31 degrees for gerbils stimulated from the front or back, respectively, and the MRA was generally increased above this frequency. Results for narrow-band noise stimuli were similar. Results are discussed with respect to the available interaural cues and physiological mechanisms of sound localization in the gerbil.