SNIC
SUPR
SNIC SUPR
Body weight homeostasis RNAseq
Dnr:

SNIC 2017/7-254

Type:

SNAC Small

Principal Investigator:

Claes Ohlsson

Affiliation:

Göteborgs universitet

Start Date:

2017-11-29

End Date:

2018-12-01

Primary Classification:

30106: Physiology

Allocation

Abstract

Epidemiologic studies demonstrate that subjects who spend much time sitting have increased risk of obesity, and obesity-related diseases. The mechanism for the putative fat suppressing effect of standing is unknown. One factor known to be important in the regulation of fat mass is leptin. This fat-derived hormone constitutes an important afferent for the negative feed-back regulation of fat mass. Unfortunately, leptin is not sufficient to decrease body fat in obese subjects, possibly due to the existence of another, previously unknown, afferent signal besides leptin that participates in the homeostatic regulation of body fat mass. We hypothesized that there is such a second homeostatic regulation of body weight. Our preliminary data suggests that increased loading of mice, achieved using capsules with different weights implanted in the abdomen or placed subcutaneously on the back, decreases the biological body weight and fat mass via reduced food intake. The resulting homeostat for body weight regulates body fat mass independently of the well-established effect of fat-derived leptin, revealing two independent negative feed-back systems for fat mass regulation. Increased body weight activates a sensor dependent on the osteocytes of the weight bearing bones. This induces an afferent signal, which includes liver-derived endocrine FGF21 acting on central FGF receptor 1c to reduce food intake. These findings demonstrate a novel body weight homeostat (“gravitostat”) that regulates fat mass independently of leptin. However, the factor that induces FGF21 elevation remains elusive. We have ruled out osteocalcin, FGF23 and sclerostin, the most well-known endocrine factors produced by bone. To identify this factor, we plan a combined approach of RNA sequencing and proteomics, for a profound characterization of the genes and proteins affected by loading in osteocytes. This experiment will be carried out in mice, and all samples in this project will be murine.