RYGB increases the satiating effect of intrajejunal lipid infusions in female rats
Introduction
Meal-ending satiation is controlled in part by feedback signals from the small intestines that are initiated by ingested nutrients or their digestive products (“intestinal satiation; ” (Ritter, 2004; Smith, 1996; Steinert et al., 2017)). Intestinal satiation is thought to be mediated largely by gastrointestinal (GI) hormones released from small-intestinal enteroendocrine cells that sense intra-intestinal glucose, fatty acids, amino acids and other nutrients (Monteiro & Batterham, 2017; Moran & Ladenheim, 2016; Ritter, 2004; Steinert et al., 2017). For this reason, the increased meal-related secretion of GI hormones that occurs following bariatric surgery, especially Roux-en-Y gastric bypass (RYGB), is hypothesized to be a mechanism for the early satiation and reduced overall food intake produced by bariatric surgery, although this has not been proven (Abdeen & le Roux, 2016; Lutz & Bueter, 2014; Münzberg, Laque, Yu, Rezai-Zadeh, & Berthoud, 2015; Steinert et al., 2017). The present investigation focused on altered intestinal satiation elicited by lipids after RYGB in a rat model and the role of one gut hormone, cholecystokinin (CCK in humans, Cck in rats and mice). CCK has long been recognized to mediate intestinal satiation in humans (Steinert et al., 2017) and rats (Smith and Gibbs, 1992), but has been rather neglected in RYGB research, despite the facts the numbers of CCK-producing cells increase in the Roux limb and meal-related CCK secretion increases after RYGB (Lutz & Bueter, 2014; Steinert et al., 2017).
A critical piece of evidence supporting CCK's role in satiation is the reversal of intestinal satiation by antagonism of the CCK-A receptor (CCKAR in humans; Cckar in rats and mice). Peripheral Cckar antagonism reduced intestinal satiation elicited by intraduodenal infusions of several nutrients in male rats that were sham-feeding with open gastric cannulas, a procedure that prevents the effects of gastric distension or of mixing of ingested food with the infusate from clouding the eating-inhibitory action of the infusion per se (Ritter, 2004; Smith and Gibbs, 1992). Cckar antagonism also increased meal size in real-feeding rats under several conditions (Ritter, 2004; Smith and Gibbs, 1992). Similarly, in humans, CCKAR antagonism reduced the eating-inhibitory effect of intraduodenal lipid infusions in healthy males who were eating normally (Matzinger et al., 1999) and increased meal size when administered alone (Beglinger, Degen, Matzinger, D'Amato, & Drewe, 2001). CCK is unique at present in that it fulfills this criterion for endogenous physiological function in humans (Steinert et al., 2017).
Because obesity and RYGB have special relevance to women, we conducted our experiments in female rats. In most countries, more women than men suffer from morbid obesity (NCD Risk Factor Collaboration, 2016; Ogden, Carroll, Kit, & Flegal, 2014), and, at least in the USA, about three quarters of patients who elect RYGB are women (DeMaria, Pate, Warthen, & Winegar, 2010). Several factors probably contribute to the disproportionate number of women electing RYGB. First, more obese women than obese men are subjected to weight discrimination, i.e., negative, unequal treatment (Puhl, Andreyeva, & Brownell, 2008). Obesity increases the risk for female-specific health disorders, such as endometrial and breast cancer (Pi-Sunyer, 2009) and disturbed reproductive function and infertility (Klenov & Jungheim, 2014). Obesity also increases the risks of anxiety disorder and of major depression more in women than in men (Anderson, Cohen, Naumova, Jacques, & Must, 2007; Pickering et al., 2011). Finally, although it is not widely recognized, overweight and obesity increase the risk of type-2 diabetes mellitus twice as much in women as in men (Guh et al., 2009). Because food intake and body adiposity are reduced by estrogens in rats and probably in women as well (Asarian & Geary, 2013; Leeners, Geary, Tobler, & Asarian, 2017), we controlled estrogen levels here by using ovariectomized rats that were chronically treated with a cyclic, near-physiological regimen of estradiol (E2) or were treated with the oil vehicle (Asarian & Geary, 2002). Importantly, there are mechanistic links between the estrogenic inhibition of feeding in rats, Cck and intestinal satiation. Tests of Cckar antagonism indicate that Cck contributes both to the decrease in meal size and daily food intake that occurs during the pre-ovulatory phase of the ovarian cycle in intact rats (Eckel & Geary, 1999) and to the E2-dependent increase in the satiating effect of intraduodenal lipid infusions in ovariectomized, sham-feeding rats (Asarian & Geary, 2007).
Our design had two further noteworthy features. First, because RYGB prevents ingesta from contacting the duodenum and proximal jejunum, we delivered lipids via chronic catheters that ended in the Roux limb of RYGB rats and the corresponding jejunal locus of sham-operated rats (Fig. 1). Although various intra-intestinal nutrient infusions have been tested after RYGB (e.g., (Bhutta et al., 2014;Gero, Steinert, Hosa, Cummings, & Bueter, 2018; Nguyen et al., 2014)), to our knowledge, none has been compared to infusions into the same intestinal locus in intact subjects. Second, to approximate the advantages of the sham-feeding preparation mentioned above, rats were offered test meals of a low-energy (0.1 kcal/g) artificially sweetened gel diet (ASD) designed to minimize nutrient-related satiation signals. RYGB rats ingest ASD avidly; indeed, whereas RYGB rats' meals of nutrient-rich foods are smaller than those of intact rats, their meals of ASD are larger (Geary, Bächler, Whiting, Lutz, & Asarian, 2016).
Section snippets
Subjects, housing and diets
The Veterinary Office of the Canton of Zurich approved all procedures. Two cohorts of female Long-Evans rats (Centre d'Elevage R. Janvier, Le Genest-Saint-Isle, France) were used. Rats weighed 180–200 g at arrival, were offered regular chow (#3430; Provimi Kliba, Kaiseraugst, Switzerland) and water ad libitum, and were housed 4/cage in a room that was maintained at 23 ± 2 °C, with a 12:12 h light:dark cycle (lights off, 1600 h). Rats' weights were measured (±1 g) 2–3 times/wk throughout.
In the
Results
Body weight data from the first cohort of rats are shown in Fig. 2. At surgery, Ensure-fed rats weighed 300 ± 4 g (mean ± SEM) and chow-fed rats, 253 ± 3 g, t (33) = 7.00, P < 0.001. Data from a similar experiment (Gloy, Langhans, Hillebrand, Geary, & Asarian, 2011) suggest that the excess ∼47 g body weight of the Ensure-fed rats is ∼23 g excess adipose tissue. Sham-Oil rats continued to gain weight throughout testing. At the onset of infusion tests in wk 10, Sham-E2, RYGB-Oil and RYGB-E2 rats
Discussion
Tonic reductions in meal size and food intake contribute to weight loss after RYGB in humans (Laurenius et al., 2011) and rats (Abdeen & le Roux, 2016; Lutz & Bueter, 2014; Münzberg et al., 2015; Zheng et al., 2009), but how RYGB produces these effects is poorly understood (Abdeen & le Roux, 2016; Lutz & Bueter, 2014; Münzberg et al., 2015). The present experiments produced two results relevant to this issue. First, intrajejunal lipid infusions reduced ASD intake more in RYGB rats than in
Funding
Any grants or fellowships supporting the writing of the paper: NIH DK092608 (LA).
Disclosure summary
The authors declare nothing to disclose.
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- 1
Currently: Department of General Surgery, Bülach Hospital, Spitalstrasse 24, 8180 Bülach, Switzerland.
- 2
Retired.
- 3
Currently: Department of Medicine, University of Vermont, Burlington VT 05405.