title: 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.
authors: Department of Physiology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia.
authors: Dana I
authors: DI
authors: Briggs
authors: Sarah H
authors: SH
authors: Lockie
authors: Qunli
authors: Q
authors: Wu
authors: Moyra B
authors: MB
authors: Lemus
authors: Romana
authors: R
authors: Stark
authors: Zane B
authors: ZB
authors: Andrews
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D031204:Caloric Restriction; D059305:Diet, High-Fat; D004038:Diet, Reducing; D004351:Drug Resistance; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000178:diet therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015430:Weight Gain; D015431:Weight Loss
chemical_list: D054369:Agouti-Related Protein; D054439:Ghrelin; D009478:Neuropeptide Y; D012333:RNA, Messenger