dc.description.abstract | Obesity is associated with the risks of diabetes, hypertension, cancer, and cardiovascular diseases and is characterized with increased mitogenesis and adipogenesis of fat cells. In turn, adipocyte mitogenesis and adipogenesis can be regulated by endocrine, genetic, growth factors, and nutritional cues. The overall objective of the dissertation was designed to understand the endothelin (ET) signaling pathways in controlling preadipocyte mitogenesis in relation to green tea epigallocatechin gallate (EGCG; the major catechin), insulin (INS), and insulin-like growth factors (IGFs). The results of this study (Chapter One) indicated that ET-1 stimulated 3T3-L1 preadipocyte growth via the ETAR, PKC, STAT3, AMPK, c-JUN, ERK, sphingosine kinase, and sphingomyelinase pathways. ET-3 (Chapter Two) was found to stimulate 3T3-L1 preadipocyte growth via the ETAR, AMPK, JNK/c-JUN, but not ERK or PKC, pathways. This suggests that ET-3 exhibits somewhat different signals from ET-1 to stimulate preadipocyte proliferation. ET-1 (Chapter Three) was found to stimulate human primary preadipocyte growth possibly via the ETAR, ETBR, PKC, STAT3, and AMPK pathways. Interestingly, neither ET-2 nor ET-3 altered the growth of human white preadipocyte. EGCG (Chapter Four) was found to suppress ET-1-induced growth of 3T3-L1 preadipocytes though the ERK, c-JUN, and STAT3 pathways. Interestingly, gallic acid, catechin, but not epicatechin, or epigallocatechin, or epicatechin gallate, were also found to inhibit ET-1-induced growth of preadipocytes, suggesting the catechin-specific effect of green tea. The interactive effect of ET with INS or IGF on preadipocyte growth (Chapter Five) indicated that ET-1 and insulin had a synergistic effect on preadipocyte growth via the ERK but not p38 or JNK pathway. A similar synergistic effect of either ET-2 or ET-3 with INS to stimulate preadipocyte growth was observed. In addition, ET-1, ET-2, or ET-3 generally enhanced IGF-stimulated growth of 3T3-L1 preadipocytes. The results of this dissertation delineate distinct signal pathways of various ET hormones in controlling white preadipocyte growth and may provide a mechanism by which ETs interact with EGCG, INS, and IGF to mediate preadipocyte growth and thereby leading to changes in fat cell activity and coordinating fat cell-related obesity and other biomedical diseases. | en_US |