Evidence for a Non-leptin System that Defends against Weight Gain in Overfeeding

Abstract

Weight is defended so that increases or decreases in body mass elicit responses that favor restoration of one's previous weight. While much is known about the signals that respond to weight loss and the central role that leptin plays, the lack of experimental systems studying the overfed state has meant little is known about pathways defending against weight gain. We developed a system to study this physiology and found that overfed mice defend against increased weight gain with graded anorexia but, unlike weight loss, this response is independent of circulating leptin concentration. In overfed mice that are unresponsive to orexigenic stimuli, adipose tissue is transcriptionally and immunologically distinct from fat of ad libitum-fed obese animals. These findings provide evidence that overfeeding-induced obesity alters adipose tissue and central responses in ways that are distinct from ad libitum obesity and activates a non-leptin system to defend against weight gain.

The unidentified hormonal defense against weight gain

“…For example, when rats are fed energy-diluted diets or are treated in ways that elevate their metabolic rate, they respond by increasing food intake to an extent that defends their normal body weight [12]. Conversely, when forced into a positive energy balance by infusion of liquid calories, either by gavage or via implanted gastric tubes, animals compensate by lowering their voluntary intake of food [13][14][15][16][17]. Moreover, voluntary feeding completely stops if the quantity of infused calories is sufficiently high.…”

“…In fact, it was shown that a 20-fold higher dose of leptin than that found within the media was needed to produce the level of hypophagia induced by adipose-conditioned media [71]. Moreover, rodents overfed by infusion of liquid diets through gastric tubing compensate for the weight gain by decreasing their voluntary intake of chow [15,17,77]. This response can be observed in both wild-type and genetically obese rodents [15][16][17].…”

“…Moreover, rodents overfed by infusion of liquid diets through gastric tubing compensate for the weight gain by decreasing their voluntary intake of chow [15,17,77]. This response can be observed in both wild-type and genetically obese rodents [15][16][17]. In wild-type mice and rats, this adaptive hypophagia continues for several days postoverfeeding until body weight has normalized [15][16][17].…”

“…This response can be observed in both wild-type and genetically obese rodents [15][16][17]. In wild-type mice and rats, this adaptive hypophagia continues for several days postoverfeeding until body weight has normalized [15][16][17]. In contrast, rats with defective leptin receptors return to their inherent hyperphagic behavior within just 1 day after cessation of overfeeding.…”

“…However, several studies show that this is not the case. Although the amount of circulating leptin increases profoundly during overfeeding, it rapidly returns to baseline just a couple of days after overfeeding has ended, while the animals are still hypophagic [15][16][17]. As White and colleagues have asked, "How can leptin suppress food intake when its levels are no longer elevated?"…”