Calorie-Restricted Weight Loss Reverses High-Fat Diet-Induced Ghrelin Resistance, Which Contributes to Rebound Weight Gain in a Ghrelin-Dependent Manner

Abstract

Twelve weeks of high-fat diet feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons. In the current study, we investigated whether diet-induced weight loss could restore NPY/AgRP neuronal responsiveness to ghrelin and whether ghrelin mediates rebound weight gain after calorie-restricted (CR) weight loss. Diet-induced obese (DIO) mice were allocated to one of two dietary interventions until they reached the weight of age-matched lean controls. DIO mice received chow diet ad libitum or chow diet with 40% CR. Chow-fed and high-fat-fed mice served as controls. Both dietary interventions normalized body weight, glucose tolerance, and plasma insulin. We show that diet-induced weight loss with CR increases total plasma ghrelin, restores ghrelin sensitivity, and increases hypothalamic NPY and AgRP mRNA expression. We propose that long-term DIO creates a higher body weight set-point and that weight loss induced by CR, as seen in the high-fat CR group, provokes the brain to protect the new higher set-point. This adaptation to weight loss likely contributes to rebound weight gain by increasing peripheral ghrelin concentrations and restoring the function of ghrelin-responsive neuronal populations in the hypothalamic arcuate nucleus. Indeed, we also show that DIO ghrelin-knockout mice exhibit reduced body weight regain after CR weight loss compared with ghrelin wild-type mice, suggesting ghrelin mediates rebound weight gain after CR weight loss.

Glycine supplementation during calorie restriction accelerates fat loss and protects against further muscle loss in obese mice

“…The extent of weight gain by the mice in our study is very similar to that in previous reports using a similar diet. Indeed, a 40% reduction in energy intake in obese mice rapidly reduces body weight and fat mass to that of control mice within 15 days [23]. Consistent with these observations we demonstrated that, in general, CR in HFD-induced obese mice reduced body weight by~7 g and fat mass by 4e5 g within 20 days.…”

Diet-induced obesity causes ghrelin resistance in reward processing tasks

“…Subsequent time course studies show that this ghrelin resistance occurs after just 3 weeks exposure to HFD (Briggs et al, 2014)and that ghrelin resistance was reversible after diet-restricted weight loss (Briggs et al, 2013). In this study, we determined if HFD causes ghrelin resistance in the VTA, a key nodefor reward processing.…”

“…These deficits occur after several weeks of HFD feeding (Briggs et al, 2014), and persist while body weight remains high, but can be reversed with dietinduced weight loss (Briggs et al, 2013). Others have recently demonstrated ghrelin resistance in the vagal afferents and nodose ganglion, suggesting that this phenomenon is not limited to the hypothalamus (Naznin et al, 2015).…”

Butyrylcholinesterase gene transfer in obese mice prevents postdieting body weight rebound by suppressing ghrelin signaling

“…Diet-induced obesity causes central ghrelin resistance (14), but enforced CR restores ghrelin sensitivity, which in turn promotes weight rebound (15). To see if long-term high BChE and low acyl-ghrelin levels affected ghrelin receptor sensitivity, we tested acyl-ghrelin's power to stimulate appetite and growth hormone release.…”

“…Recent studies suggest that ghrelin receptor sensitivity also responds to body weight. Thus, diet-induced weight gain causes central ghrelin resistance (14) while CR and body weight loss restore receptor sensitivity (15). Recently, Zigman et al (16) raised the idea that obesity-induced central ghrelin resistance can be reversed by dietinduced weight loss and that the restored receptor sensitivity may well be the major factor that drives rebound weight gain.…”