Ghrelin induces adiposity in rodents
Authors: M L Heiman
D L Smiley
M Tschöp
Journal: Nature (2000)
Discipline: Multidisciplinary
Keywords: ghrelin; peptide hormone; GHS receptor; stomach; hypothalamus
Affiliations: Endocrine Research and BioResearch Technologies & Proteins, Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, Indiana 46285, USA. 

Abstract:  The discovery of the peptide hormone ghrelin, an endogenous ligand for the growth hormone secretagogue (GHS) receptor, yielded the surprising result that the principal site of ghrelin synthesis is the stomach and not the hypothalamus. Although ghrelin is likely to regulate pituitary growth hormone (GH) secretion along with GH-releasing hormone and somatostatin, GHS receptors have also been identified on hypothalamic neurons and in the brainstem. Apart from potential paracrine effects, ghrelin may thus offer an endocrine link between stomach, hypothalamus and pituitary, suggesting an involvement in regulation of energy balance. Here we show that peripheral daily administration of ghrelin caused weight gain by reducing fat utilization in mice and rats. Intracerebroventricular administration of ghrelin generated a dose-dependent increase in food intake and body weight. Rat serum ghrelin concentrations were increased by fasting and were reduced by re-feeding or oral glucose administration, but not by water ingestion. We propose that ghrelin, in addition to its role in regulating GH secretion, signals the hypothalamus when an increase in metabolic efficiency is necessary. 

Retracted: No

PubPeer comments:
 Following the ground breaking work of Kojima, Kangawa and others, this paper added further evidence that ghrelin acts in the brain to regulate body weight and adiposity showing highly significant results. ![file] It seems that there are discrepancies between Fig 1a and the legend about the length of the test period (12 vs 14 days). Also the plotted standard error in the controls seems to be smaller than being expected by the legend. Using the data in the legend we may calculate the final weight in both groups to be 26.51 g and 27.79 g as well as a SD of 3.61 g in each group. Using a one-way anova analysis as the authors did, P is 0.44 but not 0.0001. There are also some irregular features of Fig 1a after zooming in, here is the interval starting at day 4. ![file] There are also irregularities in Fig 2. * Fig 2a and 2c as well as 2b and 2d are sharing the same controls although the data are presented as different experiments * There are 26 data points during 24h which is an unlikely 56min interval between measurements. ![file] * There are also multiple artifacts in Fig 2a eg (1) asymmetrical error bars (2) error bars that are not horizontally centered (3) missing error bar at point #10 (4) drawing artifact above point #9 and (5) filled circle at point #1 although filled circles do not belong to this figure. Has the plot been edited manually? * The P values that are accompanying Fig 2a are contradictory: P=0.004 is given in the legend and P=0.001 in the text. When plotting 95% confidence limits from the SEM intervals, even both values are wrong; the recalculated P value is P=0.02. * The end of the 24h interval should somehow correspond to the beginning while the upward trend started already two hours too early invalidating the assumed standard error. Could the authors please comment? , 
 In Fig 1b a tick mark for the 4 g intake is missing while a cumulative intake of less than 4 g over 12 days is basically impossible in normally fed mice. Fig 1 also shows a confusing  Treatment(days) concept. I assume that x=1 represents 1 day of treatment but mice did neither eat anything nor show gain weight at x=1. Fig 3 is even more confusing as  Day of treatment x=1 leads to weight gain without food intake. The averaged final weight gain by food intake is questionable given normal activity patterns: Fig 1 mice: 2,0 g extra weight by 0,3 g extra food intake (??) Fig 3 dwarf rats: 6 g extra weight by 7 g extra food (?) Fig 4 rats: 11 g extra weight by 14 g extra food (?) NPY deficient mice: 1,5 g extra weight by 6,1 g extra food (reasonable). I also do not understand the error bars in Figure 4 as they show neither SD nor SEM. , 
 #2 agree, there is some sort of mistake with fig 1B. one mouse should eat a few grams per day. , 
 The claim to fame of this paper is the fact that  ghrelin caused weight gain by ... increase in food intake and body weight ... ghrelin signals the hypothalamus when an increase in metabolic efficiency is necesssary. Was that really unexpected? There are at least 3 papers that have been submitted more or less at the same time, including [Wren] (19 July 2000), [Nakazato] (9 August 2000) and [Asakawa](http: doi.org 10.1053 gast.2001.22158) (4 October 2000). More relevant, there are at least 4 papers that had been published **before** the submission of the current paper (7 July 2000). * [Bennett 1997] writing about rat ventromedial nuclei (VMN) synthetic GH secretagogues receptor (GHS-R) expression  VMN is also involved in the regulation of food intake, and this is known to be stimulated by GHSs independently from their effects on GH in rats. * She cites [Locke 1995] who showed that a ghrelin analogue is stimulating eating without affecting plasma growth hormone responses in rats. * Another review ([Clark 1999] ) is even reprinting a plot describing body weight gain in adult rats treated with a ghrelin analogue. * [McDowell 1995] therefore anticipated the experiments shown here. ![file] Why have these earlier papers omitted? Citation rules are clear ([Penders 2018] ) Omitting ... references can wrongfully suggest that your own publication is the origin of an idea, a question, a method, or a critique, thereby illegitimately appropriating them. , 
 when compared with other experiments of high energy diet in SD rats [doi:10.1038 oby.2003.186] the average increase between day 5 and 6 (Fig 4A as shown by #4) exceeds known max values. ,