Introduction: Enteroendocrine cells (EEC) secrete satiety hormones Glucagon-like peptide 1 (GLP-1) and Peptide YY (PYY) in response to luminal content through nutrient-sensing GPCRs. In obesity, diet-induced weight loss (WL) by caloric restriction result in adaptations including reductions in postprandial levels of GLP-1 and PYY. Conversely, WL after Roux-en-Y Gastric Bypass (RYGB) is associated with increased postprandial levels of GLP-1 and PYY. We recently identified expression of regulator of G-protein signaling 9 (RGS9), a negative regulator of GPCR signaling, in human EECs and show that it may function to cease GLP-1 and PYY secretion. We hypothesized that RGS9 may play a role in altered synthesis or secretion of GLP-1 and PYY from EECs during WL interventions in humans. In the present study, we aimed to elucidate the role of RGS9 in Diet- and RYGB-induced WL in patients with obesity.
Methods: We recruited participants for two cohorts: 1)RYGB (n=8, age 42±4y, BMI 46±2kg/m2, 80% female) and 2) matched-controls based on age, BMI and gender for a Diet-only intervention that was calorie-matched, WL-matched to the RYGB diet(n=8, age 41±4y, BMI 45±2kg/m2, 75% female)(Table 1). The Diet-only cohort followed the same post-RYGB diet: 500kcal/day wk1, 600kcal/day wk2-4, 600-800kcal/day wk5-8, 800-1000kcal/day wk9-12. Eight participants followed up >1yr with RYGB (n=4) or Diet-only (n=4). At BSL, 9-weeks, and 1yr FU, intestinal mucosal biopsies were collected via endoscopy, and blood plasma was collected at fasting and at 15-min intervals after a meal. GLP-1 and PYY blood levels were assayed using ELISA. Area under the curve from fasting to 90mins (AUC_0-90) for BSL, 9-wks and >1yr was calculated. RNAlater preserved biopsies were processed for RT-qPCR gene expression.
Results: There were no significant differences in BSL characteristics, WL, %TBWL, or WL rate (kg/day) at 9-weeks between intervention. At >1yr FU, RYGB group achieved more %TBWL than the diet group compared to BSL (Fig1A)(p<0.01). At 9-weeks, there were no differences in the GLP-1 or PYY AUC_0-90(Fig1B-C) between interventions compared to BSL. At >1yr FU, RYGB group had significantly higher GLP-1 (p<0.05) and PYY(p<0.05) AUC_0-90 than diet group. Intestinal expression of GCG, PYY and RGS9 were unchanged between interventions at all time points (Fig1D-F). Regardless of intervention, weight loss was associated with increased RGS9 fold-change at 9wks(FigG-H, p=0.054, p=0.05), but this trend was nonsignificant trend at >1yr(p=0.08).
Conclusions: At 1-year post intervention RYGB is associated with increased postprandial GLP-1 and PYY, without respective changes in intestinal gene expression. While at 9-weeks, TBWL is associated with increased RGS9. Suggesting that in the long-term, gut adaptations in plasma hormone levels appear to be occurring independently from gut RGS9 in RYGB.

Table 1. Patient demographics for two interventions: RYGB and matched-controls based on age, BMI and gender for a Diet-only intervention that was calorie-matched, WL-matched to the RYGB group.

<b>Figure 1.</b> Gut mucosal adaptations to 9-weeks and >1 year weight loss with RYGB or Diet-only A.) Total body weight loss (TBWL%). Area under the curve from fasting to 90 minutes postprandial for B) GLP-1 and C) PYY plasma levels. Intestinal mRNA exressionD) GCG E)PYY F)RGS9. G) Paired intestinal RGS9 mRNA expression at BSL and after 9wks between groups, and H)TBWL(%) correlation with fold change of <i>RGS9 </i>from BSL to 9wks. *p<0.05, **p<0.01.

Figure 1. Gut mucosal adaptations to 9-weeks and >1 year weight loss with RYGB or Diet-only A.) Total body weight loss (TBWL%). Area under the curve from fasting to 90 minutes postprandial for B) GLP-1 and C) PYY plasma levels. Intestinal mRNA exressionD) GCG E)PYY F)RGS9. G) Paired intestinal RGS9 mRNA expression at BSL and after 9wks between groups, and H)TBWL(%) correlation with fold change of RGS9 from BSL to 9wks. *p<0.05, **p<0.01.

Alexander Ticho

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