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.
Highlights
The most common weight loss strategy is caloric restriction and exercise, as obesity is typically due to chronic excess in caloric intake over energy expenditure [1]
Single injection of rapamycin inhibits food intake and body weight gain To examine the effect of acute RAP treatment on energy balance, 40 male Sprague Dawley rats were given a single i.p. injection of either 0, 0.1, 1.0 or 10 mg/kg of RAP (n = 10 for each group)
We found that food intake (FI) and food efficiency (FE) were significantly reduced during the first 3–5 days post-injection in a dose-dependent manner (Fig. 1A–D)
Summary
The most common weight loss strategy is caloric restriction and exercise, as obesity is typically due to chronic excess in caloric intake over energy expenditure [1]. It has been proposed that obesity is not a state where energy homeostasis is dysregulated, but where the defended body weight level, or set point, is shifted upwards [4]. In hypothalamic neurons that regulate energy balance and food intake, mTOR has been shown to mediate the anorexic and orexigenic effects of leptin and ghrelin, respectively. These effects can be blocked by direct injections of RAP into these areas [9,10,11]
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