Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

Abstract

Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an mTOR inhibitor, is sufficient to shift the set point in rats. Intraperitoneal RAP decreased food intake and daily weight gain for several days, but surprisingly, there was also a long-term reduction in body weight which lasted at least 10 weeks without additional RAP injection. These effects were not due to malaise or glucose intolerance. Two RAP administrations with a two-week interval had additive effects on body weight without desensitization and significantly reduced the white adipose tissue weight. When challenged with food deprivation, vehicle and RAP-treated rats responded with rebound hyperphagia, suggesting that RAP was not inhibiting compensatory responses to weight loss. Instead, RAP animals defended a lower body weight achieved after RAP treatment. Decreased food intake and body weight were also seen with intracerebroventricular injection of RAP, indicating that the RAP effect is at least partially mediated by the brain. In summary, we found a novel effect of RAP that maintains lower body weight by shifting the set point long-term. Thus, RAP and related compounds may be unique tools to investigate the mechanisms by which the defended level of body weight is determined; such compounds may also be used to complement weight loss strategy.

Chronic Rapamycin Treatment Improved Metabolic Phenotype but Inhibited Adipose Tissue Browning in High-Fat Diet-Fed C57BL/6J Mice

“…Consistent with previous investigations, 4,5,16,17) rapamycin was demonstrated to decrease the body weights of the high-fat diet-induced fatty mice. Moreover, mice in Rap group had significantly reduced tissue weights of gWAT and scWAT, which was in accordance with previous study that chronic rapamycin treatment impaired lipid deposition, reduced adiposity and fat cell number in rats.…”

Role of FOXO1 in aldosterone-induced autophagy: A compensatory protective mechanism related to podocyte injury

“…S6K1, downstream of mTOR, protects against age- and diet-induced obesity in mice [36]. Furthermore, single intraperitoneal RP led to decreased food intake and daily weight gain [37], both of which may offer a potential explanation for the consistent inhibitory effect of RP on weight gain. Animals that were administered CQ also lost weight throughout the 4-week period with a concomitant reduction in food consumed (data not shown), which is consistent with a previous study [38].…”

High‐fat diet‐induced downregulation of anorexic leukemia inhibitory factor in the brain stem

“…If LIF induces malaise, the animals are expected to later display aversion to the flavor associated with the LIF injection. We have previously used this test and showed that lithium chloride induces conditioned taste aversion to saccharin as expected . On the conditioning day, rats were given access to a novel 0.1% saccharin solution for 1 h and then immediately injected i.c.v.…”