The effect of leptin administration and recovery on energy metabolism, uncoupling proteins, and adipose tissue apoptosis
Gullicksen, P. Scott Scott
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Administering leptin, an adipocyte-derived hormone related to fat mass, to rodents dramatically reduces food intake and body weight while enhancing energy expenditure. After treatment withdrawal, body weight recovery was retarded compared to pair-fed rodents that lost less weight and exhibited a faster regain. The changes induced by leptin and the processes behind a slower recovery were investigated here. The first objective was to determine the period of leptin influence on food intake, body weight, and energy expenditure. Rats were injected ICV with either leptin or the vehicle for 4 days before being killed or placed in calorimetry chambers for 21 days. Leptin-treated rats maintained a lower body weight up to 6 days after treatment ended. An overshoot of food intake and respiratory quotient during recovery was offset by a greater heat production (HP) throughout recovery. These responses paralleled an increase in uncoupling protein (UCP) expression in brown (BAT) and white adipose tissues. BAT was the most responsive to leptin by dramatically changing UCP1 & UCP3 mRNA levels. The second objective was to determine the sustained effect of leptin on adipose tissue cellularity, measured using the Coulter counter, and apoptosis. Leptin significantly reduced the masses of all white fat pads [retroperitoneal (RP) > inguinal (ING) > epididymal (EPI)] but not BAT. Cell volume was significantly reduced in EPI and ING. Only ING had a significantly reduced cell number and exhibited apoptosis by increased DNA fragmentation and DNA laddering, plus upregulation of pro-apoptosis Bax protein. The other fat pads exhibited a general increase in the Bcl-2/Bax ratio. Recovery allowed for normalization of white fat pad mass, cell number and cell volume; however, BAT mass increased dramatically. After recovery, apoptosis was not detected, Bcl-2 protein increased in ING, and the Bcl-2/Bax ratio had risen overall. These results indicate that leptin induces apoptosis, at least in ING, and has lasting effects on energy metabolism that contribute to a slower body weight recovery. A secondary effect that opposed adipocyte loss during recovery supported near full normalization of body weight and adiposity. This demonstrated a resiliency with respect to energy homeostasis after leptin treatment.