Adipokines, peroxisome Proliferator Activated Receptor (PPAR) Agonists and Serotonin-Common Regulators of Bone and Fat Metabolism
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Osteporosis and obestity are diseases with rapidly increasing prevalence, and have both become major health problems. These diseases share several common genetic and enviromental factors, and thus a relation between bone and fat metabolism has been suggested. Both adipocytes (fat cells) and the bone forming osteoblasts derive from pluripotent mesenchymal stem cells (MSC)s, which are able to differentiate into a number of cell types. The fate of the MSCs in the bone marrow are influenced by several transcription factors, proteins and hormones that regulate differentiation "switches" along the osteoblat or adipocyte lineage. The regulation of these processes is highly complex and not fully explored, and the complexity is increased by the fact that there is a significantly plasticity between the adipocyte and the osteoblasts linage. Adipokines are a large group of cytokines and hormones mainly secreted by, or first discovered in, adipocytes. The adipokine resistin is assumed to be a regulator of inflammation and energy homeostasis. In paper I we demonstrate that resistin, in accordance with other adipokines like leptin and adiponectin, is expressed in, and affects bone cells, and therfore might influence skeletal regulation as well. Peroxisome proliferator activated recptor (PPAR)α is the target for fibrates , used for treatment of hyperlipidemia. PPARγ is known as a key regulator in adipocyte differentiation, and also as a target for the drug class of thiazolidinediones (TZDs), used in treatment of T2DM. In paper II and III we demonstrate that PPARα and PPARγ agonists have opposite skeletal impacts in both normal and ovariectomized rats. PPARα activation by fenofibrate results in an increase in bone mineral density, while PPARγ activation by pioglitazone causes bone loss, impaired mechanical strength, and deterioration of the bone architecture. In vitro studies in human and murine bone cells confirm that PPARα and PPARγ agonists exhibit opposite skeletal effects. Factors known to be involved in the central regulation of energy metabolism, like leptin and the neuropeptide serotonin, are now discovered to exhibit direct peripherally affects on bone cells. In paper IV we demonstrate that adipocytes, in resemblance with osteoblasts, express a functional system for receptor activation, reuptake and synthesis of serotonin. Short and long term hyperserotoninemia in rats cause weight reduction, a decrease in circulating leptin levels, and affect gene expression in visceral fat tissue. Serotonin might regulate adipocyte recruitment and function in a direct manner and not only via the central nervous system as previously assumed. Adipocytes and osteoblasts seem to be partly regulated by central as well as direct effects of serotonin and leptin, this contributes further to the consumption of a close relation between fat and bone metabolism.
UtgiverNorges teknisk-naturvitenskapelige universitet, Det medisinske fakultet, Institutt for kreftforskning og molekylær medisin
SerieDoktoravhandlinger ved NTNU, 1503-8181; 2008:313
Dissertations at the Faculty of Medicine, 0805-7680; 376