LOSS OF LEPTIN SENSITIVITY IN AGING HYPERLEPTINEMIC TRANSGENIC MICE
F. Chehab, J. Qiu, S. Ogus.
Dept. of Laboratory Medicine, University of California San Francisco
Sensitivity to leptin is associated with a normal and tight regulation of the adipose mass whereas decreased leptin sensitivity or resistance results in elevated adipose tissue stores. To address whether the effects of chronic hyperleptinemia are sustained with age, we generated transgenic mice that overexpress leptin under the control of the fat specific aP2 promoter/enhancer. The transgenic mice secreted at least fivefold human leptin throughout their lifetime and showed at 6-9 weeks of age, low body weights, reduced brown and white fat depots and lipid-depleted adipocytes. However at 33-37 weeks of age, despite continuous secretion of human leptin, the transgenic mice showed a rebound effect characterized by an increase in body weight, accumulation of adipose mass and lipid-filled adipocytes. Thus, this mouse model exhibits a two-stage age related phenotype with respect to fat accumulation. Leptin treatment of the older transgenic mice stimulated weight loss demonstrating that the leptin pathway still responds to pharmacological levels of leptin but may be blocked to modest hyperleptinemia. Overall, these studies show that hyperleptinemia in normal mice results in a sensitivity of the adipose mass to leptin at a younger but not older age. The mechanisms that lead to the accumulation of fat at an older age remain largely unknown and this hyperleptinemic mouse model will allow the uncovering of at least some of these mechanisms.
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