Elsevier

Peptides

Volume 29, Issue 9, September 2008, Pages 1603-1608
Peptides

Impacts of peripheral obestatin on colonic motility and secretion in conscious fed rats

https://doi.org/10.1016/j.peptides.2008.05.003Get rights and content

Abstract

Obestatin, a novel putative 23-amino acid peptide, was found to be derived from a mammalian preproghrelin gene by using a bioinformatics approach. Although the effects of obestatin on food intake and upper gut motility remain controversial, no studies have been carried out to explore its influence on lower gut motility and secretion. We investigated the impacts of intravenous (IV) injection of obestatin on rat colonic motor and secretory functions. Colonic transit time, fecal pellet output, and fecal content were measured in freely fed, conscious rats, which were chronically implanted with IV and colonic catheters. To test the validity of this animal model, human/rat corticotropin-releasing factor (h/rCRF) served as a stimulatory inducer of colonic motility and secretion. IV injection of obestatin (45, 100, and 300 nmol/kg) did not affect the colonic transit time, whereas IV injection of h/rCRF (30 nmol/kg) effectively accelerated colonic transit time. IV obestatin, in every dose we tested, also did not modify fecal pellet output, frequency of watery diarrhea, total fecal weight, fecal dried solid weight, or fecal fluid weight in the first hour after injection. On the other hand, IV injection of h/rCRF significantly enhanced fecal pellet output, as well as increased the frequency of watery diarrhea, total fecal weight, fecal dried solid weight, and fecal fluid weight during the first hour after injection compared with IV saline controls. In conclusion, peripheral obestatin administration has no impact on colonic motility and secretion in conscious fed rats.

Introduction

Obestatin, a novel 23-amino acid peptide recently identified from rat stomach, is derived from the mammalian preproghrelin gene which also encodes ghrelin [38]. It has been proposed that these newly discovered preproghrelin-derived peptides, ghrelin and obestatin, have opposite effects on feeding behaviors, e.g., ghrelin enhances food intake whereas obestatin inhibits it [38]. It was originally suggested that obestatin binds to an orphan G protein-coupled receptor (GRP), termed GPR39 [5], [38]. High levels of GPR39 mRNA have been found in the amygdala, hippocampus, and auditory cortex but not in the hypothalamus [16], [21]. However, recent studies indicate that obestatin is not the endogenous cognate ligand for GRP39 [6], [15], [19], [37].

Obestatin has been shown to inhibit food intake in rodents, however, controversial results exist regarding its anorexigenic actions on feeding behaviors [2], [4], [8], [11], [12], [14], [18], [24], [29], [31], [36], [37], [38], [40]. Obestatin may modulate many brain functions [4], [26], [32], decrease growth hormone secretion in vivo [40], and stimulate the secretion of pancreatic juice enzymes [17] in rats. Human studies indicate that increased obestatin levels, decreased ghrelin levels, and a decreased ghrelin/obestatin ratio characterize obesity in women [35], whereas plasma obestatin level is decreased in patients with type 2 diabetes mellitus and impaired glucose tolerance [25]. Both obestatin and ghrelin levels are increased in anorexic subjects and decreased in human obesity [23], suggesting that obestatin may serve as a marker reflecting changes in the nutritional state in modulating human energy homeostasis. Surprisingly, very recent research identified a new role for obestatin in promoting β-cell and human islet cell survival and stimulating the expression of the main regulatory β-cell genes [13]. Taken together, these observations imply that obestatin may have some unknown but important novel multifaceted roles in the regulation of biological functions that have not been investigated and which deserve further exploration.

With respect to gastrointestinal motility, the majority of obestatin studies have focused on its regulation on the upper gut [1], [8], [10], [11], [38]. For example, peripheral obestatin treatment inhibits gastric emptying and gastroduodenal motility [10], [38], whereas some studies show that obestatin does not impact gastric and small intestinal motility in vivo or in vitro [1], [8], [11]. Ghrelin, the appetite rival of obestatin, accelerates colonic transit time in rats [34]. Very recently, obestatin-immunoreactive cells were found to be present in the pancreas and in the most parts of the gastrointestinal tract in rats, including the colon [39]. Therefore, it would be very intriguing to know the potential effects of obestatin on colon motor functions. Until now, there has been no study performed to address the impacts of obestatin on rat colonic motor functions. In the present study, we attempted to determine the possible effects of intravenously (IV) injected obestatin on colonic motor and secretory functions, including colonic transit time, fecal pellet output, and fecal content in conscious fed rats. Since corticotropin-releasing factor (CRF) is a well-known colonoprokinetic peptide [20], we used it as a stimulatory agent in our newly developed colon transit and secretory model to assess the value of this model for evaluating prokinetics.

Section snippets

Animals

Male Sprague-Dawley rats (National Laboratory Animal Center, Taipei, Taiwan), weighing 250–320 g, were used at the start of the experiment and housed in group cages under controlled illumination (light cycle: 08:00–20:00), humidity, and temperature (22.5 ± 1.5 °C) with free access to water and laboratory chow pellets (LabDiet®, Brentwood, MO, USA). All experiments were performed beginning at 9 AM in freely moving conscious rats, in accordance with guidelines, which have been approved by the

Colonic transit time

IV injection of obestatin at 45, 100, and 300 nmol/kg did not affect the colonic transit time (323.7 ± 31.8, 327.1 ± 40.8, and 354.9 ± 40.0 min vs. 299.3 ± 33.4 min, p > 0.05) compared with IV saline controls (Fig. 1). In contrast, IV injection of h/rCRF at 30 nmol/kg significantly accelerated colonic transit time (68.1 ± 23.9 min vs. 299.3 ± 33.4 min, p < 0.001) in conscious fed rats.

Fecal pellet output

IV obestatin (45, 100, and 300 nmol/kg) did not modify the fecal pellet output (0.83 ± 0.59, 0.50 ± 0.20, and 1.17 ± 0.30 h−1 vs. 1.25 ± 0.61 h−1

Discussion

Our study was carried out to investigate the peripheral effects of obestatin on colonic transit and secretion in rodents. Previous studies only investigated either colonic motility or secretory function. Thus, we designed an animal model for simultaneous measurement of both functions. The mean obtained colonic transit time of IV saline-injected control rats was 299 min in our study which was comparable to a transit time of 320 min in a previous study that used a similar trypan blue dye method [34]

Acknowledgements

This work was supported by grants from Veterans General Hospitals University System of Taiwan Joint Research Program (by Tsou's Foundation, VGHUST96-P1-03 to C.Y.C. and E.J.C.) and in part from National Science Council, Taiwan (NSC 95-2314-B-010-098-MY2 to C.Y.C.). The authors also thank Chung Wen-Pin, MS and Miss Lee Chieh-Ju for their excellent technical assistance, as well as Chi Chin-Wen, Ph.D., Hung Mei-Whey, MS, and the Clinical Research Core Laboratory, Taipei Veterans General Hospital.

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