Differential secretion of satiety hormones with progression of obesity in JCR:LA-corpulent rats

Abstract

Objective: To characterize the gastrointestinal tract at the onset and in well-established obesity.

Methods and procedures: Lean (+/?) and obese (cp/cp) male JCR:LA-cp rats lacking a functional leptin receptor were killed at 3.5 weeks and 9 months of age and plasma concentrations of satiety hormones determined. The small intestine, colon, and stomach were measured, weighed, and mRNA levels of satiety genes quantified.

Results: At the onset of obesity, obese rats had greater intestine, colon, and liver mass when adjusted for body weight compared to lean rats. Conversely, adult rats with established obesity had lower intestine and colon mass and length after adjustment for body weight. Early changes in gene expression included decreased ghrelin mRNA levels in stomach and increased peptide YY (PYY) mRNA levels in duodenum of young obese rats. After massive accumulation of adipose tissue had occurred, adult obese rats had increased proglucagon and ghrelin mRNA expression in the proximal intestine. In the distal small intestine, obese rats had lower proglucagon, ghrelin, and PYY mRNA levels. Finally, at the onset and in well-established obesity, obese rats had higher plasma insulin, amylin, glucagon like peptide-1 (GLP-1), and PYY, a finding, with the exception of insulin, unique to this model. Plasma total ghrelin levels were significantly lower at the onset of obesity and established obesity compared to the lean rats.

Discussion: Several defects are manifested in the obese gut early on in the disease before the accumulation of large excesses of body fat and represent potential targets for early intervention in obesity.

Figure 1

mRNA level of satiety hormones at the onset and in well-established obesity, as determined by real-time PCR. (a) Young 3.5-week-old rats. (b) Adult 9-month-old rats. Results represent the mean fold change ± s.e.m. compared to lean controls. An ANOVA was done to determine significance. Asterisk represents a significant difference between lean and obese within a specific tissue (P ≤ 0.05). PYY, peptide YY.

Figure 2

Plasma glucagon, amylin and insulin for lean and obese rats at the onset and in well-established obesity. (a) Young 3.5-week-old rats. (b) Adult 9-month-old rats. Plasma, obtained via a cardiac bleed, was analyzed using a LINCOplex kit to determine glucagon, total amylin, and insulin. Results represent mean ± s.e.m. Due to the marked hyperinsulinemia of adult rats, actual insulin concentrations in (b) are tenfold higher than represented on the graph for presentation purposes (i.e., lean were 55.9 ± 7.1 and obese were 938.1 ± 99.2). Asterisk represents a significant difference between lean and obese (P ≤ 0.05).

Figure 3

Plasma peptide YY (PYY), glucagon like peptide-1 (GLP-1), and total ghrelin levels for lean and obese rats at the onset and in well-established obesity. (a) PYY and was quantified using an ELISA kit (Diagnostic Systems Laboratories). (b) Active GLP-1 and was quantified using a LINCOplex kit (Linco Research Inc.). (c) Total ghrelin and was quantified using an RIA kit (Linco Research Inc). Results represent mean ± s.e.m. Asterisk represents a significant difference between lean and obese rats in either onset or well-established obesity (P < 0.05).