Centrally administered gut hormones and leptin on food intake, bone and bone marrow adipocytes in rats

Abstract

The discovery of the role of leptin on bone formation through the central nervous system marks the beginning of a new era for bone research. Several gut hormones play a role in mediating postprandial bone metabolism. Among them, GIP, GLP, and ghrelin are known to have either direct or indirect effects on bone formation. However, the idea that gut hormones binding to their receptors in the brain modulate bone metabolism has not been tested before. To investigate whether gut hormones modulate bone metabolism centrally we employed the techniques of densitometry, histomophormetry, measuring of serum bone turnover markers, as well as real time RT-PCR. The hormones we tested included leptin, GIP and ghrelin. In the first study, we found that centrally administered GIP (10 µg / inj.) decreased food intake and body weight while also affecting feeding behavior although there was no expected bone effect. Leptin treatment decreased rat tibia bone marrow size and number, and increased spinal bone mineral density. In the second study, ICV ghrelin (G20, 20 pmol / inj.) increased tibia bone mineral density. Leptin increased bone mineral density while decreasing bone marrow adipocytes size and number. The third study was designed to confirm the previous study, and to explain the underlying mechanism by measuring and comparing the expression level of a set of pre-selected gene markers. Tibial bone mineral density was increased by leptin and G20, while spinal BMD was only increased by leptin. Gene expression data from non-adherent bone marrow cell cultures show that G20 increased gene expression of apoptosis marker, CASP2. Ghrelin also resulted in decreased adipogenesis gene expression in bone marrow. Thus, we suggest that centrally administered ghrelin resulted in increased bone mineral density by decreasing osteoclastogenesis through apoptosis, as well as by reducing bone marrow adipogenesis. In summary, gut hormones affect bone marrow adipocytes and bone metabolism when binding to receptors in the brain. Histomophormetry, densitometry, as well as measuring mRNA expression levels employing microfluidic technology provide sensitive, convenient and effective ways of measuring changes in bone marrow adipocytes and bone mass, and for developing new therapeutic strategies for treatment of osteoporosis.