Studies On Mechanism For Body Weight Loss By Neuropeptide Y-Y5 Receptor Antisense Oligodeoxynucleotides

The disarrangement of appetite regulation is tightly associated with obesity, which is a serious health problem in modern society. Therefore its treatment has become the subject of intense interest in the scientific community. Neuropeptide Y (NPY), an important determinant in obesity onset, is the most abundant peptide presented in the brain, appears to play a central role in the control of feeding behavior. NPY exerts its physiological effects through activating of a family of Grotein coupled receptors. In vivo and in vitro characterization of the recently cloned rat Y5 receptor subtype suggests that it is a primary mediator of NPYnduoed feeding. It was reported that central administration of Y5 receptor aritisense oligodeoxynueleotides (ODNs) decreased spontaneous food intake and induced significant body weight loss. But the exact mechanisms for body weight mitigating have not been completely elucidated. The objective of this study was to observe rats?body weight, feeding behavior and examine the change of white adipocytes, including the change of the cell number and cubic content. So we can get the precise mechanisms for body weight loss. Phosphothioate endrotected antisense ODNs targeted to 3 the initiation codon of NPY Y5 receptor mRNA were intracerebroventricularly injected to male SD rats to assess the functional importance of this novel receptor subtype in vivo. Food intake~ body weight and adipose tissue weight were observed. Average adipocyte area was calculated by MPIAS (Multimedia Pathological Image & Word Analysis System) ?00. Adipocyte apoptosis were detected by DNA gel electrophoresis. And the expressions of Bcl? and Bax gene were detected by RT-PCR. Repeated central administration of Y5 antisense ODNs significantly inhibited food intake and dramatically decreased body weight and the weight of white adipose tissue. The number and cubic content of adipocyte were decreased significantly. Adipocyte apoptosis were obviously observed as fragment by DNA gel electrophoresis. Bcl? gene expression decreased while Bax increased in rats which received antisense therapy. And apoptosis was occured mainly in epididymal adipoeyte. These results are consistent with the suggestion that Y5 receptor is a key mediator of NPYnduced feeding. The decreased adipose tissue weight was tightly associated with the reduced adipocyte number arid cubic content. The decreased Bcl? gene expression and increased Bax gene expression may be an important mechanism of adipocyte apoptosis Because NPY Y5 receptor antisense ODNs can inhibit food intake of rats, decrease their body weight and adipose tissue weight and induce adipocyte apoptosis. We conjecture that this therapy can induce significant body weight mitigation in obese rats. Male Spragueawley rats were provided high nutrition diet for seven weeks. And stainless steel guide cannulas were stereotaxically implanted in cerebroventriculus. The random grouped rats were centrally administrated with antisense, sense, mismatched ODNs or saline after a week's recovery. We report here that repletion of NPY Y5 antisense ODNs could significantly inhibit obese rats to eat and decrease body weight and adipose tissue weight, especially to retroperitoneal adipose tissue. The retroperitoneal adipocyte cubic content decreased more dramatically than...