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Y4 receptor knockout rescues fertility in ob/ob mice
Amanda Sainsbury1, Christoph Schwarzer, Michelle Couzens
1Neurobiology Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, Sydney NSW 2010, Australia.
Abstract:
Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4(-/-)) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4(-/-),ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4(-/-) and Y4(-/-),ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4(-/-) and Y4(-/-),ob/ob animals. Y4(-/-) mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP). However, Y4 deficiency had no beneficial effects to reduce body weight or excessive adiposity of ob/ob mice. These data suggest that central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated central NPY-ergic tonus.
Insights
Deleting the Y4 receptor in mice with obesity (ob/ob) restored reproductive function and fertility. This suggests Y4 receptor signaling inhibits reproduction when neuropeptide Y (NPY) levels are high.
Area of Science:
- Neuroendocrinology
- Reproductive Biology
- Obesity Research
Background:
- Hypothalamic neuropeptide Y (NPY) regulates energy balance and reproduction.
- Elevated NPY is linked to obesity and impaired reproductive function.
- The specific Y receptor mediating these NPY effects was unknown.
Purpose of the Study:
- To investigate the role of the Y4 receptor in NPY-mediated regulation of reproduction in obese mice.
- To determine if Y4 receptor deletion impacts fertility and reproductive parameters in the ob/ob mouse model.
Main Methods:
- Generation of Y4 receptor knockout (Y4(-/-)) mice.
- Crossing Y4(-/-) mice with obese (ob/ob) mice to create double knockout (Y4(-/-),ob/ob) animals.
- Assessment of reproductive parameters, hormone levels, gonadotropin-releasing hormone (GnRH) expression, body weight, and adipose tissue mass.
Main Results:
- Y4 receptor deletion in ob/ob mice restored plasma testosterone levels, testis and seminal vesicle size, and morphology.
- Fertility was significantly improved in Y4(-/-),ob/ob mice, with a high percentage producing live offspring.
- Mammary gland development and GnRH expression were enhanced in Y4(-/-) and Y4(-/-),ob/ob mice.
- Y4(-/-) mice showed reduced body weight and adipose tissue, but Y4 deficiency did not ameliorate obesity in ob/ob mice.
Conclusions:
- Central Y4 receptor signaling specifically inhibits reproductive function under conditions of elevated hypothalamic NPY.
- Targeting the Y4 receptor may offer a strategy to improve reproductive function in certain obesity-related conditions.
- Y4 receptor's role in energy balance appears distinct from its role in reproduction.