Assessment of different bariatric surgeries in the treatment of obesity and insulin resistance in mice

Abstract

Objective: To assess the effects of different bariatric surgical procedures on the treatment of obesity and insulin resistance in high fat diet-induced obese (DIO) mice.

Background: Bariatric surgery is currently considered the most effective treatment for morbid obesity and its comorbidities; however, a systematic study of their mechanisms is still lacking.

Methods: We developed bariatric surgery models, including gastric banding, sleeve gastrectomy, Roux-en-Y gastric bypass (RYGB), modified RYGB (mRYGB) and biliopancreatic diversion (BPD), in DIO mice. Body weight, body fat and lean mass, liver steatosis, glucose tolerance and pancreatic beta cell function were examined.

Results: All bariatric surgeries resulted in significant weight loss, reduced body fat and improved glucose tolerance in the short term (4 weeks), compared with mice with sham surgery. Of the bariatric surgery models, sleeve gastrectomy and mRYGB had higher success rates and lower mortalities and represent reliable restrictive and gastrointestinal (GI) bypass mouse bariatric surgery models, respectively. In the long term, the GI bypass procedure produced more profound weight loss, significant improvement of glucose tolerance and liver steatosis than the restrictive procedure. DIO mice had increased insulin promoter activity, suggesting overactivation of pancreatic beta cells, which was regulated by the mRYGB procedure. Compared with the restrictive procedure, the GI bypass procedure showed more severe symptoms of malnutrition following bariatric surgery.

Discussions: Both restrictive and GI bypass procedures provide positive effects on weight loss, fat composition, liver steatosis and glucose tolerance; however, in the long term, the GI bypass shows better results than restrictive procedures.

Figure 1. Mouse bariatric surgery models

Bariatric surgeries include: A. gastric banding (Banding); sleeve gastrectomy (Sleeve); C. Roux-en Y gastric bypass (RYGB); D. modified RYGB (mRYGB); and E. biliopancreatic diversion (BPD). Surgical procedures were described in the Methods.

Figure 2. Imaging of bariatric surgery

After 7 to 10 days of bariatric surgery, imaging was performed using MicroCat-II. The contrast (Optiray 320, 0.8ml) was administered into the mouse by gavage. Continuous photos were taken every 4 seconds, for a total of 16 photos per mouse. Each figure represents one of 16 photos.

Figure 3. Body weight and composition

A. Weight loss and gain. DIO mice were weighed after bariatric and sham surgeries (n = 5 in each group except BPD* that only one mouse was alive at 8 weeks). All mice lost weight in a few days after surgeries; however, mice with sham surgeries gained weight after one week of surgery, and mice with bariatric surgeries maintained their weight loss for more than one month. B. Body composition was measured by a NMR analyzer, as described in the Methods. Fat composition was expressed as grams per body weight (n = 4 in each group except BPD* that only one mouse was alive at 8 weeks). C. Lean mass was also measured by a NMR analyzer (N = 4 in each group except BPD* that only one mouse was alive at 8 weeks). D. Bariatric surgery improves hepatic steatosis (H&E, × 100, the figure represents one of three pathological examinations in each group). (A), naïve lean mouse; (B), naïve DIO mouse; (C), DIO mouse with sham surgery at 4 weeks; (D), DIO mouse with sham surgery at 8 weeks; (E), DIO mouse with mRYGB at 4 weeks; (F), DIO mouse with mRYGB at 8 weeks; (G), DIO mouse with sleeve gastrectomy at 4 weeks; and (H), DIO mouse with sleeve gastrectomy at 8 weeks.

Figure 3. Body weight and composition

A. Weight loss and gain. DIO mice were weighed after bariatric and sham surgeries (n = 5 in each group except BPD* that only one mouse was alive at 8 weeks). All mice lost weight in a few days after surgeries; however, mice with sham surgeries gained weight after one week of surgery, and mice with bariatric surgeries maintained their weight loss for more than one month. B. Body composition was measured by a NMR analyzer, as described in the Methods. Fat composition was expressed as grams per body weight (n = 4 in each group except BPD* that only one mouse was alive at 8 weeks). C. Lean mass was also measured by a NMR analyzer (N = 4 in each group except BPD* that only one mouse was alive at 8 weeks). D. Bariatric surgery improves hepatic steatosis (H&E, × 100, the figure represents one of three pathological examinations in each group). (A), naïve lean mouse; (B), naïve DIO mouse; (C), DIO mouse with sham surgery at 4 weeks; (D), DIO mouse with sham surgery at 8 weeks; (E), DIO mouse with mRYGB at 4 weeks; (F), DIO mouse with mRYGB at 8 weeks; (G), DIO mouse with sleeve gastrectomy at 4 weeks; and (H), DIO mouse with sleeve gastrectomy at 8 weeks.

Figure 4. Bioluminescence (BLI) for islet viability

DIO was induced in mice expressing luciferase under the control of an insulin promoter (MIP-luc), and BLI was performed after bariatric surgeries, compared to untreated DIO mice (DIO) and lean mice (Lean). Luciferase was expressed as the regions of interest (ROI). The figures represent one of four BLI examinations. Data in the bar chart represent means ± SEM.

Figure 5. Bioluminescence (BLI) for NF-κB activation

DIO was induced in mice expressing luciferase under the control of an NF-κB promoter (NF-κB-luc), and BLI was performed after bariatric surgeries, compared to untreated DIO mice (DIO) and lean mice (Lean). Luciferase was expressed as the regions of interest (ROI). The figures represent one of three BLI examinations. Data in the bar chart represent means ± SEM.

Figure 6. Hematocrit (HCT) levels in bariatric surgery-treated mice

HCT was performed in DIO mice with different bariatric surgeries one month after bariatric surgery, compared to sham surgery (Sham), untreated-DIO (DIO) and untreated-lean mice (Lean, n = 3 - 4 in each group). Data in Figure 6 represent means ± SEM. *: p < 0.05; ** p < 0.01.