A Body Weight Sensor Regulates Prepubertal Growth via the Somatotropic Axis in Male Rats

Abstract

In healthy conditions, prepubertal growth follows an individual specific growth channel. Growth hormone (GH) is undoubtedly the major regulator of growth. However, the homeostatic regulation to maintain the individual specific growth channel during growth is unclear. We recently hypothesized a body weight sensing homeostatic regulation of body weight during adulthood, the gravitostat. We now investigated if sensing of body weight also contributes to the strict homeostatic regulation to maintain the individual specific growth channel during prepubertal growth. To evaluate the effect of increased artificial loading on prepubertal growth, we implanted heavy (20% of body weight) or light (2% of the body weight) capsules into the abdomen of 26-day-old male rats. The body growth, as determined by change in biological body weight and growth of the long bones and the axial skeleton, was reduced in rats bearing a heavy load compared with light load. Removal of the increased load resulted in a catch-up growth and a normalization of body weight. Loading decreased hypothalamic growth hormone releasing hormone mRNA, liver insulin-like growth factor (IGF)-1 mRNA, and serum IGF-1, suggesting that the reduced body growth was caused by a negative feedback regulation on the somatotropic axis and this notion was supported by the fact that increased loading did not reduce body growth in GH-treated rats. Based on these data, we propose the gravitostat hypothesis for the regulation of prepubertal growth. This states that there is a homeostatic regulation to maintain the individual specific growth channel via body weight sensing, regulating the somatotropic axis and explaining catch-up growth.

Keywords: Prepubertal growth; growth hormone; homeostasis.

Figure 1.

Increased loading reduces body growth in young rats. Rats were implanted with either a high load capsule (20% of body weight) or a low load capsule (2% of body weight). (A) Effect of increased loading on the growth of biological body weight in the high load group compared with the low load group. (B) Total body weight, including both the biological body weight and the capsule weight in the high load group normalized to the low load group at each time point. (C) The efficiency of the homeostatic regulation of total body weight growth. This was calculated for each time point as: (average percent biological body weight growth in low load rats—percent biological body weight growth in high load rats)/18 × 100. Growth of (D) long bones (tibia, femur and humerus) and (E) the axial skeleton (crown–rump length) between day 0 and day 14 after capsule implantation. Growth data of body weight and bone lengths correspond to pooled results from 3 experiments (high load, n = 26; low load, n = 30). (F) Dynamic histomorphometric analyses of the growth rate in the proximal tibia during the last 4 days of the experiment (high load, n = 8; low load, n = 8). Growth was measured from the alizarin band to the edge of the proximal growth plate. (G) Fat mass percentage did not differ between the groups (high load, n = 10; low load n = 10). Data are expressed as means ± SEM. *P < .05, **P < .01, ***P < .001, high load vs low load.

Figure 2.

Increased loading does not cause adverse effects on growing rats. Two markers of stress was analyzed. Serum corticosterone was analyzed 4 (high load, n = 10; low load, n = 10) and 7 (high load, n = 9; low load, n = 10) days after loading, with no significant difference between the groups (A). Pituitary adrenocorticotrophic hormone (ACTH) was analyzed using real-time PCR (high load, n = 9; low load, n = 7) 4 days after loading, with no significant difference between the groups (B). Food consumption was measured the first week after loading (high load, n = 10; low load, n = 10) and it did not differ between the groups (C). Voluntary locomotor activity was analyzed 8 days after loading (high load, n = 9; low load, n = 10) and did not differ between the groups.

Figure 3.

Catch-up growth after removal of increased loading. We evaluated if removal of the increased loading would result in a catch-up growth. Rats were exposed to sustained high load (heavy capsule days 0-7 followed by heavy capsule days 7-14; n = 8), sustained low load (light capsule days 0-7 followed by light capsule days 7-14, n = 10) or removed high load (heavy capsule days 0-7 followed by light capsule days 7-14; n = 8). Effects of manipulation of loading on (A) growth in biological body weight between day 0 and day 14 and on (B) growth in biological body weight between days 0 and 7 (left panel) and days 7-14 (right panel). Data are expressed as means ± SEM. ANOVA followed by Turkey’s post hoc test. *P < .05, **P < .01, ***P < .001.

Figure 4.

Homeostatic regulation to maintain the individual specific growth channel via sensing of body weight in rats is mediated via the somatotropic axis. Effects of loading on (A) GHRH mRNA, somatostatin mRNA, and GHS-R1A mRNA in the hypothalamus (low load; n = 20; high load n = 20) 4 days after initiation of load. (B) liver IGF-1 mRNA (low load, n = 20; high load, n = 17) and (C) serum IGF-1 (low load, n = 17; high load, n = 16) on day 14 after capsule implantation. Effect of increased loading on growth in (D) biological body weight and (E) tibia length (days 0-14) in rats treated with saline (low load, n = 10; high load n = 9) or GH (1 µg/mL; low load, n = 9; high load n = 10). Data are expressed as means ± SEM. *P < .05, **P < .01, ***P < .001, high load vs low load. (F) The gravitostat hypothesis for homeostatic regulation to maintain the individual specific growth channel during prepubertal GH-dependent growth. (a) Balanced normal prepubertal growth. When the body weight is following the predefined growth channel, the body weight sensor indicates a normal body weight (lower panel; proposed by us to be represented by normal strain in the bone), resulting in a moderate negative feedback regulation on the somatotropic axis. (b) Reduced growth. After induction of artificially increased loading, the body weight sensor indicates elevated body weight (proposed by us to be represented by increased bone strain), resulting in increased negative feedback regulation on the somatotropic axis and thereby reduced body growth. Reduced growth can also be caused by illness via other mechanisms. (c) Catch-up growth. After removal of the increased loading, the body weight sensor indicates reduced body weight (proposed by us to be represented by reduced bone strain), resulting in reduced negative feedback regulation on the somatotropic axis and thereby increased body growth. (d) Normal balanced growth again. After the catch-up growth, the individual reaches its constitutional predefined growth channel and again grows at a normal rate associated with a neutral indication of the body weight sensor.