Stephen Bloom

Nutrient-independent increases in proglucagon and ornithine decarboxylase messenger RNAs after jejunoileal resection

To assess potential mediators of adaptive bowel growth, ileal proglucagon messenger RNA (mRNA) ornithine decarboxylase (ODC) mRNA, plasma enteroglucagons, and plasma glucagonlike peptide I (GLP-I) were analyzed in rats soon after jejunoileal resection or control transection. Analyses were performed before and after refeeding to establish whether responses are nutrient dependent. The elevation of ileal proglucagon and ODC mRNAs within 12 hours after resection and before refeeding shows a nutrient-independent component of the adaptive response. The onset of adaptive growth of the ileum required luminal nutrient but occurred very rapidly, within 4 hours of refeeding. The onset of adaptive growth was accompanied by transient elevation of ileal ODC mRNAs. Ileal proglucagon mRNA and plasma GLP-I levels were also elevated, and these increases were sustained up to 8 days after resection. These early and sustained increases in proglucagon mRNA and plasma GLP-I indicate that in addition to the enteroglucagons, other intestinal proglucagon-derived peptides must be considered as potential mediators of adaptive growth after jejunoileal resection.

Increased ileal proglucagon expression after jejunectomy is not suppressed by inhibition of bowel growth

After jejunectomy, a rapid and sustained increase in the abundance of proglucagon mRNA occurs in residual ileum and is accompanied by increases in plasma intestinal proglucagon-derived peptides. This response may be a component of adaptive growth, or proglucagon-derived peptides may regulate adaptive growth. To distinguish these possibilities, rats were treated with difluoromethylornithine, blocking ornithine decarboxylase activity and thereby adaptive bowel growth. Three groups fedad libitum were compared: (1) resect: rats with 80% proximal small bowel resection; (2) resect + difluoromethylornithine: resected rats given difluoromethylornithine in drinking water; and (3) transect: transected controls. Six days after surgery, the resect + difluoromethylornithine group demonstrated inhibition of adaptive bowel growth. Abundance of ileal proglucagon mRNA in resect and resect + difluoromethylornithine groups was double that in the transect group (P<0.02), whereas ornithine decarboxylase mRNA levels did not differ. Plasma enteroglucagon and glucagon-like peptide-I levels were greater in resect than transect groups (P<0.002) and did not differ between resect and resect + difluoromethylornithine groups. The rise in ileal proglucagon mRNA after proximal small bowel resection is not inhibited by difluoromethylornithine despite blocking bowel growth and, therefore, is not merely a component of adaptive growth. Proglucagon-derived peptides are possible modulators of adaptive bowel growth but cannot stimulate growth when ornithine decarboxylase activity is inhibited.

Peptide YY (PYY) and Neuromedin U (NMU): Effects on Ingestive Behavior

ABSTRACT Many peptides are synthesized and released from the gastrointestinal (GI) tract and the central nervous system (CNS). It is now evident that these peptides influence eating behavior. Peptide YY (PYY) is released postprandially from the gastrointestinal L cells and neuromedin U (NMU) has been found in significant concentrations in both the GI tract and the CNS. Recently NMU has been shown to be a potent anorexigenic peptide and alterations of NMU signaling have been shown to predispose to obesity. Following peripheral administration of PYY3–36, the circulating form of PYY, to mouse, rat, or human, there is marked inhibition of food intake. Obese subjects have lower basal fasting PYY levels and have a smaller postprandial rise. However, obesity does not appear to be associated with resistance to PYY. The effects of NMU and PYY on ingestive behavior and their potential as anti-obesity agents are the focus of this review.