OBJECTIVE: Increased levels of hypothalamic neuropeptide-Y (NPY) are thought to contribute to the manifestation of the obese phenotype. The aim of this study was to characterize the interactions between leptin, insulin and NPY in the pathogenesis of polygenic obesity. DESIGN AND METHODS: A polygenic obese animal model, the New Zealand obese mouse (NZO) and its age-matched control, was used to assess the hypothalamic mRNA expression of NPY, the insulin receptor (IR) and the leptin receptor (Ob-Rb), by semiquantitative polymerase chain reaction. Experiments were performed early (at eight weeks old) and late (at 40 weeks old) in the life of these animals. RESULTS: Serum glucose was signi®cantly elevated in obese mice. Serum insulin levels were not different between obese and lean mice, whereas serum leptin levels were signi®cantly elevated in obese mice and increased continuously during life [reaching extremely high values at 40 weeks (41.5 AE 4.1 vs 3.4 AE 0.25 ngaml for obese and lean, respectively). The hypothalamic expression of NPY mRNA was signi®cantly higher in NZO mice compared to controls at both eight weeks (2.3-fold) and 40 weeks (1.9-fold), respectively, whereas expression of IR and Ob-Rb remained unaffected. CONCLUSION: Increased hypothalamic expression of NPY due to leptin resistance, may be involved in the development of polygenic obesity. Unchanged Ob-Rb expression suggests that either a defective hypothalamic uptake or defects in Ob-Rb signalling underly this process.

Previous studies have demonstrated that tumor necrosis factor-alpha (TNF-alpha) production from adipose tissue is elevated in obese animal models and in obese humans. It plays an important role in the induction of insulin resistance in experimental animals. In this study, we examined hypothalamic tissue expression of TNF-alpha and its receptors and TNF-alpha expression of adipose tissue in lean C57BLKSJ+/+ and obese polygenic New Zealand obese (NZO) mice. Obese animals exhibited hyperglycemia, hyperinsulinemia, hypertriglyceridemia, and hypercholesterinemia. Using RT-PCR, we observed increased expression (2.4-fold) of TNF receptor 2 (p75) in the hypothalamus of obese mice. TNF-alpha expression in adipose tissue of obese mice was eight times higher than in controls. TNF-alpha and TNF receptor 1 (p55) expression in hypothalamic tissue was similar in obese and lean animals. These results suggest that the hypothalamic TNF receptor 2 (p75) might play a role in obesity by modulating the actions of TNF-alpha in conditions of leptin resistance.

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