REPRODUCTIVE AND NEUROENDOCRINE AGING--ROLE OF LEPTIN
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Broadly speaking a "typical" (though not universal) profile of neuroendocrine change during aging in mammals could be described as often involving decreased plasma luteinizing hormone (LH)and sexual function, decreased plasma growth hormone(GH), decreased plasma thyroxine, and increased plasma glucocorticoid, Interestingly, a similar neuroendocrine profile is exhibited during fasting and in genetically obese mice. Recent studies have indicated that at least some of the neuroendocrine effects of fasting are mediated through the product of the obese gene, leptin, leptin levels fall during fasting, and injection of leptin attenuates the effects of fasting on the hormones described above. It has recently been shown that leptin mRNA and peptide progressively decline with age in C57B1/6J mice. These data suggest the hypothesis that some age-related neuroendocrine impairments are due to relative leptin insufficiency, and therefore that some neuroendocrine impairments may be partially revered by treatment with leptin. There the study will asses if injection of leptin in aging mice, at doses which will restore leptin to youthful levels, will partially restore some neuroendocrine functions toward youthful levels, Six-, 12-, and 24-month-old male and female C57/B1 6j mice will be assessed for sexual behavioral (for males), estrous cycles (for females), metabolic rate, and locomotor activity. Blood will be obtained by reto- orbital puncture to plasma leptin. Mice will then injected for 7 days with either saline or 1 ug/gm b.w. leptin (previously show to produce fed levels of leptin in fasted C57b1/6j mice). During this treatment, behaviors, estous cycles, and metabolic parameters will continue to be assessed. One hour after the last injection of leptin, mice will be sacrificed by decapitation to allow assessment of non-stresses levels of L H, testosterone, GH, T3, glucocoriticoids, insulin, and leptin, and also to allow assessment of leptin-stimulated c-fos mRNA (to assess if aging mice show evidence of leptin resistance), as well as body composition. These studies may provide evidence that some age-related impairments my be treatable by leptin replacement therapy.
