| dc.description.abstract | Obesity is a strong risk factor for type 2 diabetes and cardiovascular disease partly because of the changes that occur in white adipose tissue (WAT) during weight gain. As obesity progresses, WAT expands, becomes dysfunctional, and increases its secretion of numerous adipokines, including two that will be highlighted in this dissertation, the hormone leptin and the chemokine macrophage inflammatory protein-1α (MIP-1α). Our underlying hypothesis was that elevated secretion of leptin and MIP-1α from WAT during obesity would influence development of obesity-related atherosclerosis, WAT inflammation, and systemic insulin resistance.
To test the role of hematopoietic cell leptin receptor (LepR) in aortic root lesion formation, we conducted three different bone marrow transplantation studies in which bone marrow, with or without LepR, was transplanted into lethally irradiated: 1) low density lipoprotein receptor deficient (LDLR-/-) mice with moderate hyperleptinemia due to Western Diet (WD) feeding, 2) WD-fed LDLR-/- mice with pharmacologically induced hyperleptinemia (daily injection of 125 ìg leptin), or 3) obese, hyperleptinemic, LepR deficient LDLR-/- (LepRdb/db;LDLR-/-) mice. To test the role of MIP-1α in WAT inflammation, we fed WD to male and female MIP-1α deficient (MIP-1α-/-), heterozygous (MIP-1α+/-), and MIP-1α sufficient (MIP-1α+/+) mice for 16 weeks to induce obesity and examined their WAT. To identify the effects of hyperlipidemia on the metabolic role of MIP-1α, we fed WD to male and female MIP-1α-/-;LDLR-/-, MIP-1α+/-;LDLR-/-, and MIP-1α+/+;LDLR-/- mice and measured aortic root lesion area and fat mass.
Removal of macrophage LepR did not influence atherosclerotic lesion formation. This suggests that non-hematopoietic cells, rather than macrophages, are potential mediators of leptin’s effects on aortic root lesion formation. We also demonstrated that although expression of MIP-1α increases as a consequence of weight gain this chemokine is not critical for the recruitment of monocytes and T-lymphocytes to WAT in mice with diet induced obesity. Furthermore, in the presence of hyperlipidemia, the absence of MIP-1α was not sufficient to attenuate fat mass gain or atherosclerosis during WD feeding. Taken together, these data demonstrate that although MIP-1α may be involved in WAT growth under some circumstances, the metabolic phenotype of MIP-1α-/- mice is similar to that of MIP-1α+/+ mice. | |
