Gastric Inhibitory Polypeptide as an Endogenous Factor Promoting New Bone Formation after Food Ingestion

Abstract

Calcium plays a fundamental role as second messenger in intracellular signaling and bone serves as the body's calcium reserve to tightly maintain blood calcium levels. Calcium in ingested meal is the main supply and inadequate calcium intake causes osteoporosis and bone fracture. Here, we describe a novel mechanism of how ingested calcium is deposited on bone. Meal ingestion elicits secretion of the gut hormone gastric inhibitory polypeptide (GIP) from endocrine K cells in the duodenum. Bone histomorphometrical analyses revealed that bone formation parameters in the mice lacking GIP receptor (GIPR(-/-)) were significantly lower than those of wild-type (GIPR(+/+)) mice, and that the number of osteoclasts, especially multinuclear osteoclasts, was significantly increased in GIPR(-/-) mice, indicating that GIPR(-/-) mice have high-turnover osteoporosis. In vitro examination showed the percentage of osteoblastic cells undergoing apoptosis to be significantly decreased in the presence of GIP. Because GIPR(-/-) mice exhibited an increased plasma calcium concentration after meal ingestion, GIP directly links calcium contained in meal to calcium deposition on bone.

Glucose-dependent insulinotropic polypeptide receptor deficiency leads to modifications of trabecular bone volume and quality in mice

“…This is in contradiction of what was observed in previous studies were these two parameters were increased [13,14]. Connections between fat and bone metabolism have been evidenced, with a role for adipokines in controlling bone remodeling.…”

“…Furthermore, 6 week-old GIPR-deficient mice did not present with a reduction of the trabecular bone volume. However, the number of osteoclasts was augmented at both ages [13]. On the other hand, using the same GIPR-deficient model, Xie et al described a reduction in trabecular bone volume in younger animals (4-week-old) [14].…”

“…However, the possible role that GIP might have in controlling bone resorption and/or bone remodeling in vivo is more controversial. Indeed, although Zhong et al, reported that GIP directly reduced osteoclast activity in mature murine osteoclasts in vitro [12], Tsukiyama et al observed no direct effects of GIP on the same cells [13]. By using a model of GIPR-deficient mice, Tsukiyama et al described a decrease in trabecular thickness at 8 weeks of age, but this decrease was not observed in 6-week-old animals.…”

Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

“…There are GIP-specific receptors located on osteoblasts (25) and osteoclasts (26). GIP operates as an anabolic hormone in the bone, where it stimulates incorporation of meal-derived Ca 2+ into bone and bone building (13), and reduces bone absorption by inhibiting osteoclastic activity. Studies in GIPRKO mice have shown that the absence of GIPR signaling leads to significant osteoporosis due to lower osteoblast and higher osteoclast action (13).…”

“…In addition to its insulinotropic effect, in the absence of which glucose intolerance develops (7), GIP stimulates islet growth (8) and proliferation of b-cells (9), and reduces b-cell apoptosis (10,11). Studies of GIP receptor (GIPR) knock-out (GIPRKO) mice (7) describe GIP as an obesitypromoting factor in high-fat diet (HFD) conditions, and show that deletion of GIPR signaling causes resistance to obesity (12) but leads to osteoporosis (13), revealing an important role of GIP in bone metabolism. However, in these studies, as well as in a model of GIPR antagonism (14), the reported changes were focused on disrupted or blocked GIPR signaling.…”