Hypertrophy Dependent Doubling of L-Cells in Roux-en-Y Gastric Bypass Operated Rats

Abstract

Background and AimsRoux-en-Y gastric bypass (RYGB) leads to a rapid remission of type 2 diabetes mellitus (T2DM), but the underlying mode of action remains incompletely understood. L-cell derived gut hormones such as glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are thought to play a central role in the anti-diabetic effects of RYGB; therefore, an improved understanding of intestinal endocrine L-cell adaptability is considered pivotal.MethodsThe full rostrocaudal extension of the gut was analyzed in rats after RYGB and in sham-operated controls ad libitum fed or food restricted to match the body weight of RYGB rats. Total number of L-cells, as well as regional numbers, densities and mucosa volumes were quantified using stereological methods. Preproglucagon and PYY mRNA transcripts were quantified by qPCR to reflect the total and relative hormone production capacity of the L-cells.ResultsRYGB surgery induced hypertrophy of the gut mucosa in the food exposed regions of the small intestine coupled with a doubling in the total number of L-cells. No changes in L-cell density were observed in any region regardless of surgery or food restriction. The total gene expression capacity of the entire gut revealed a near 200% increase in both PYY and preproglucagon mRNA levels in RYGB rats associated with both increased L-cell number as well as region-specific increased transcription per cell.ConclusionsCollectively, these findings indicate that RYGB in rats is associated with gut hypertrophy, an increase in L-cell number, but not density, and increased PYY and preproglucagon gene expression. This could explain the enhanced gut hormone dynamics seen after RYGB.

The physiology underlying Roux-en-Y gastric bypass: a status report

“…19,53,95). The hypertrophy should probably be seen as an adaptive measure that helps to maintain an almost unaltered availability of ingested nutrients, despite the fact that nutrients and major digestive juices from the liver and pancreas only mix rather distally in the small intestine, i.e., at the junction of the Roux and biliopancreatic limbs into the common channel (Fig.…”

“…This has usually been thought to be mainly due to an effect in more distal parts of the small intestine, which have a higher density of L-cells embedded in the mucosa (87). It is, however, important to note that the absolute number of L-cells is far higher in the proximal small intestine compared with the distal small intestine (53), indicating that such an effect on L-cells could also be due to the exposure of the Roux limb to nutrients entering this limb immediately after ingestion (35). Of note, experiments testing the causal role of such effects for the exaggerated L-cell response are still pending.…”

“…It is important to note that not all organs regress but that some organs in fact increase in size or weight after RYGB surgery. The best studied example is the gastrointestinal tract and, in particular, the small intestine where specific segments show a marked hypertrophic reaction after RYGB surgery (19,53,71,95); the latter may potentially be linked to altered metabolic pathways in the intestinal epithelium (116, 148) and also to the increase in total energy expenditure. …”

Diabetes, Neurodegenerative Diseases, GLP-1 & Surgery: Evidence Calls for Exploration

“…The mentioned effects over GLP-1 secretion are maintained 5 years after surgery, and further [55,56]. Another path way by which serum levels of GLP-1 and PYY increase, is a noted hyperplasia and hypertrophy of L cells observed after gastric bypass [57,58]. Recent evidence suggests that the metabolic effects of gastric bypass (improvement in nitric oxide availability, reduced oxidative stress, HDL disfunction, reduced endothelial disfunction, anti inflammatory effects, antiapoptotic and antioxidant effects) were reversed when using a GLP-1 antagonist (exendin 9-39) as well as observing the same metabolic effects when increasing GLP-1 levels in rats without surgery through the administration of intravenous liraglutide [59].…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…The density of the GLP-1-producing L-cells increases in more distal parts of the small intestine and in the colon; however, the total number of L-cells, at least in rats, is highest in the jejunum, including its proximal part. 4 L-cells express a large number of receptors or transporters that trigger L-cell secretion in response to a variety of stimuli; these include glucose, long-or short-chain fatty acids but also bile acids that act on the TGR5 receptor. 5 Which of these stimuli contributes most to the postprandial release of GLP-1 is still a matter of debate, in particular in individuals undergoing Roux-en-Y gastric bypass surgery who have largely elevated secretions of postprandial GLP-1.…”