The Role of the Small Bowel in the Regulation of Circulating Ghrelin Levels and Food Intake in the Obese Zucker Rat

Abstract

Circulating levels of ghrelin, a stomach peptide that promotes food intake, rise before and fall after meal. We aimed to investigate whether there is an independent contribution of the small bowel to the regulation of ghrelin and appetite. A duodenal-jejunal bypass (DJB) with preservation of normal gastric volume and exposure to nutrients was performed in 12-wk-old obese Zucker ZDF fa/fa rat. Food intake, weight gain, 48-h fasting, and 24-h refeeding levels of total and acylated ghrelin were measured. The DJB was challenged against gastric banding (GB), diet, and a sham operation in matched animals. Normal controls were age-matched Wistar rats, which underwent either DJB or a sham operation. The Zucker obese animals showed a paradoxical increase of acylated ghrelin levels after refeeding (+30% with respect to fasting levels; P = 0.001), an abnormality that was completely reversed only by the DJB (-30%; P = 0.01) but not after GB, diet, or sham operation. In obese rats, the DJB resulted in significantly less food intake and weight gain compared with both GB (P < 0.05) and sham operation (P < 0.01). In sharp contrast, the DJB did not alter food intake and weight gain in normal rats. The DJB does not physically restrict the flow of food but restores meal-induced suppression of acylated ghrelin and significantly reduces food intake in Zucker obese rats. These findings suggest an independent intestinal contribution to the regulation of the dynamic ghrelin response to eating and the possibility that defective signaling from the proximal bowel could be involved in the pathogenesis of obesity/hyperphagia.

Is Type 2 Diabetes an Operable Intestinal Disease?

“…Studies in rodents have shown that DJB improves diabetes both in obese (Zucker fa/fa rats) (19) and lean (GK rats) (6) type 2 diabetic animals, consistent with several clinical observations of diabetes remission when RYGB or BPD are performed in moderately obese (11,12) or even lean patients (13). On the other hand, other parameters may better define both the risk from diabetes and the diabetes-related outcomes of surgery.…”

Endocrine mechanisms mediating remission of diabetes after gastric bypass surgery

“…Similar observations have subsequently been made with independent investigations of non-obese diabetic Goto-Kakizaki rats 20,21 and obese diabetic Zucker rats. 18 Likewise, several small, ongoing human studies of DJB all show improvements in glycemic control, including among non-obese patients, with little or no weight loss (Cohen et al 46 and personal communications with Arguelles-Sarmiento J et al, Lakdawala M et al, and Ramos AC et al).…”

“…Consistent with this concept, experimental studies indicate that variations of RYGB improve T2DM not only in obese but also in nonobese diabetic animals. [18][19][20][21] Despite a growing interest in using RYGB to treat T2DM, even among less obese or non-obese patients, the underlying mechanisms of action of this procedure have not been fully evaluated. As gastrointestinal (GI) surgery appears to eliminate T2DM more effectively, rapidly and durably than any existing non-surgical method, and because the usage of bariatric surgery is rapidly increasing worldwide, elucidating the mechanisms by which these operations improve glycemia is an important research priority.…”

The economic impact of morbid obesity

“…Although diabetes can sometimes be controlled through diet and exercise or by pharmaceutical intervention, bariatric surgery offers a permanent solution, precedent to significant weight loss [39,40] for reasons that remain the subject of investigation [41][42][43]. Irrespective of the reason that bariatric surgery works, its economic value can be seen from the preceding analysis of one of obesity's comorbidities.…”