Body weight homeostat that regulates fat mass independently of leptin in rats and mice

Abstract

Subjects spending much time sitting have increased risk of obesity but the mechanism for the antiobesity effect of standing is unknown. We hypothesized that there is a homeostatic regulation of body weight. We demonstrate that increased loading of rodents, achieved using capsules with different weights implanted in the abdomen or s.c. on the back, reversibly decreases the biological body weight via reduced food intake. Importantly, loading relieves diet-induced obesity and improves glucose tolerance. The identified homeostat for body weight regulates body fat mass independently of fat-derived leptin, revealing two independent negative feedback systems for fat mass regulation. It is known that osteocytes can sense changes in bone strain. In this study, the body weight-reducing effect of increased loading was lost in mice depleted of osteocytes. We propose that increased body weight activates a sensor dependent on osteocytes of the weight-bearing bones. This induces an afferent signal, which reduces body weight. These findings demonstrate a leptin-independent body weight homeostat ("gravitostat") that regulates fat mass.

Keywords: diet-induced obesity; glucose metabolism; osteocytes; weight loss.

Fig. 1.

Body weight sensing for fat mass homeostasis in rats and mice with diet-induced obesity. (A) Effect of loading on change in biological body weight (= total body weight − capsule weight) in rats (n = 8) and (B) mice (n = 10) implanted with capsules weighing 15% of the body weight (load) or empty capsules (control; ∼1.5% and ∼3% of the body weight for rats and mice, respectively). (C) Coronal (Top) and corresponding transversal (Bottom) MR images of a control (Left) and a load (Right) animal (day 14), acquired without fat suppression. Hyperintense regions represent body fat. Yellow dotted line and white bar indicate the position of the corresponding transversal images Below and 10 mm, respectively. (D) The fat mass (day 14), (E) the serum leptin levels (day 14), and (F) the food intake as percent of body weight (days 4–6) were measured in load and control rats (n = 8) and (G) mice (n = 10). (H) The effect of pair feeding on body weight change in control mice compared with ad libitum fed control and load mice (n = 9). (I) Change in biological body weight, (J) the fat mass (day 17), and (K) the skeletal muscle mass (day 17) after removal of load (heavy capsule followed by empty capsule) or sustained load (heavy capsule followed by heavy capsule) 14 d after the first implantation (n = 10). (L) HOMA-IR in fasted control and load mice (n = 10). (M) Blood glucose, (N) blood glucose area under the curve (AUC), (O) serum insulin, and (P) insulin AUC during an oral glucose tolerance test in load and control mice (n = 10). (Q) Effect of loading on long-term change in biological body weight in load and control mice (n = 10) followed during 7 wk after capsule implantation. Data are expressed as mean ± SEM *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 2.

Leptin-independent body weight sensing for fat mass homeostasis. (A) The effect of increased loading on the change in body weight in leptin deficient Ob/Ob mice (control n = 7 and load n = 10). The effect of combined loading and leptin treatment (1.5 µg/g BW twice daily) on (B) changes in biological body weight, (C) fat mass, and (D) muscle mass in mice (n = 10). Data are expressed as mean ± SEM *P < 0.05.

Fig. 3.

The suppression of body weight and fat mass by loading is dependent on osteocytes. Effect of increased loading on change in biological body weight in (A) control female mice with intact osteocytes (control n = 11 and load n = 12) and in (B) osteocyte-depleted (OCyD) female mice (n = 9). The effect of loading of control mice with intact osteocytes and OCyD mice on (C) fat mass, (D) serum leptin levels, and (E) muscle mass, as measured 21 d after initiation of loading. Data are expressed as mean ± SEM *P < 0.05. (F) Hypothesis for homeostatic regulation of body fat mass by two different signal systems. The first previously known pathway is fat-derived leptin in circulation acting on the brain to decrease food intake and fat mass. The second mechanism is that increased fat mass is counteracted by the body weight homeostat (gravitostat). Increased body weight activates a sensor dependent on the osteocytes of the weight-bearing bones. This induces an afferent signal to reduce food intake.