Influence of Leptin on Vascular, Gonadal, and Metabolic Function

Leptin is the prototypical adipokine that circulates in direct proportion to whole body adiposity. As such, serum leptin levels decrease when white adipose tissue depletes by calorie restriction whereas they increase as white adipose tissue expands by overnutri-tion. At both sides of the spectrum, i.e. too little and too much leptin, the adipokine con-tributes to vascular complications such as atherosclerosis and reproductive dysfunction. Mice that lack both leptin and the low density lipoprotein receptor (LDLR−/−;ob/ob) are an ideal model to study atherosclerosis as they present with atherosclerotic plaques in the aortic root and brachiocephalic artery. In this thesis, dose-dependent effects of re-combinant leptin administration from the subphysiological to physiological range on atherosclerotic plaque formation and fertility was studied in LDLR−/−;ob/ob mice. Lep-tin dose-dependently reduced plaque lesions and improved Leydig cell function and spermatogenesis. The effect of leptin treatment on atherosclerotic plaques was inde-pendently and significantly associated with improvements in lipid homeostasis and liver steatosis, as well as increased adiponectin. The beneficial effects of leptin treatment on several measures of fertility such as intratesticular testosterone, circulating follicle stim-ulating hormone, and seminiferous tubule morphology appeared to be direct and body weight-independent. Besides genetic leptin-deficiency, lipodystrophy (LD) patients and lipodystrophic mice were studied. LD is a leptin-deficient condition caused by the lack of subcutaneous white adipocytes leading to several metabolic complications including severe insulin resistance and hypertriglyceridemia. The effects of adipose tissue loss in LD on the adipokines chemerin, progranulin, and fibroblast growth factor 21 have not been investigated so far. Circulating levels of these three adipokines were all increased in LD patients as compared to weight- and age-matched controls. Furthermore, none of these adipokines was significantly regulated in 10 LD patients by leptin treatment over 6 months. In a mouse model of generalized LD, increased expression of these adipokines was found in various adipose tissue depots at the mRNA level providing first preliminary evidence as to the source of higher circulating levels in LD patients. Collec-tively, the findings of this thesis show for the first time dose-dependent beneficial ef-fects of leptin on atherosclerosis and reproductive function and provide new information about the association of LD with changes in various adipokines that have an established impact on metabolic function