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Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.

ABSTRACT: The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs). (IEC)LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (HFD). The analyses of the animals involved histology and immunohistochemistry of intestinal mucosa, indirect calorimetric measurements, whole-body composition, and expression and activities of nutrient transporters. (IEC)LEPR-B-KO mice exhibited a 2-fold increase in length of jejunal villi and have normal growth on a normal diet but were less susceptible (P<0.01) to HFD-induced obesity. No differences occurred in energy intake and expenditure between (IEC)LEPR-B-WT and -KO mice, but (IEC)LEPR-B-KO mice fed an HFD showed increased excreted fats (P<0.05). Activities of the Na(+)/glucose cotransporter SGLT-1 and GLUT2 were unaffected in LEPR-B-KO jejunum, while GLUT5-mediated fructose transport and PepT1-mediated peptide transport were substantially reduced (P<0.01). These data demonstrate that intestinal LEPR-B signaling is important for the onset of diet-induced obesity. They suggest that intestinal LEPR-B could be a potential per os target for prevention against obesity.

SUBMITTER: Tavernier A

PROVIDER: S-EPMC4139897 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.

Tavernier Annabelle A Cavin Jean-Baptiste JB Le Gall Maude M Ducroc Robert R Denis Raphaël G P RG Cluzeaud Françoise F Guilmeau Sandra S Sakar Yassine Y Barbot Laurence L Kapel Nathalie N Le Beyec Johanne J Joly Francisca F Chua Streamson S Luquet Serge S Bado Andre A

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20140613 9

The importance of B-isoform of leptin receptor (LEPR-B) signaling in the hypothalamus, pancreas, or liver has been well characterized, but in the intestine, a unique site of entry for dietary nutrition into the body, it has been relatively ignored. To address this question, we characterized a mouse model deficient for LEPR-B specifically in intestinal epithelial cells (IECs). (IEC)LEPR-B-knockout (KO) and wild-type (WT) mice were generated by Cre-Lox strategy and fed a normal or high-fat diet (H ...[more]

PMID: 24928195

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Project description:Fasting older broiler chickens (>7 d of age) enlarges the intestinal tight junction (TJ) pore size, resulting in high paracellular intestinal permeability. Broiler chickens often do not receive feed and water (nutrition) directly after hatch, which may result in fasting up to 72 h of age. Whether perinatal fasting affects intestinal permeability is minimally studied. We therefore investigated whether delayed access to nutrition after hatch increases intestinal permeability, compared with broilers receiving early access to nutrition. Therefore, 432 hatched broilers received nutrition 72 h after hatch (delayed nutrition [DN]) or directly after hatch (early nutrition [EN]) and were reared under similar conditions until 14 d of age. Two hours after application of an oral pulse dose (3.85 mg) of fluorescein isothiocyanate-dextran (4000 Da) at 4, 10, and 14 d of age, blood plasma concentrations of the marker were measured in 24 to 36 broilers per treatment and time point. Marker concentration in plasma did not differ between DN and EN broilers at any age. The villus width measured in at least 8 broilers per treatment was smaller in DN than in EN broilers at 4 d for both the ileum (92 ± 3 μm vs. 121 ± 4; P < 0.001) and colon (100 ± 3 vs. 120 ± 4; P < 0.01). Real-time quantitative PCR revealed that the expression of TJ protein claudin 3 in the ceca was elevated in DN, compared with EN broilers at 4 d of age, whereas that of zonula occludens 1 in the ileum was reduced. Expression of host defense-related genes was reduced in DN, compared with EN broilers, in the ileum (cyclo-oxygenase 2, mucin 2) and ceca (interleukin 1β, cyclo-oxygenase 2). We conclude that 72-hour DN reduced the BW up to 14 d of age, coinciding with transient effects on the villus width in the ileum and colon, and divergent expression of genes involved in TJ formation and host defense. These effects likely reflect the delayed onset of intestinal and immune development in DN, compared with EN broilers, while DN does not fundamentally alter intestinal permeability.

Project description:BackgroundIntestinal nutrient sensing regulates food intake and energy metabolism by acting locally and relaying nutritional status to the brain. It is unclear whether these mechanisms are altered in obese humans.ObjectivesWe aimed to investigate differences in duodenal nutrient sensing in humans with or without obesity and the effects of transiently blocking vagal transmission on nutrient sensing, hunger, and appetite.MethodsIn a single-blinded, randomized, cross-over design, subjects with or without obesity (n = 14 and n = 11, respectively) were infused intraduodenally with saline or a combination of glucose and oleic acid for 90 min (glucose load: 22.5 g, 1 kcal/min; oleic acid load: 10 g, 1 kcal/min) in the presence or absence of local anesthetic (benzocaine). Blood was sampled at 10-min intervals (120-240 min) and 15-min intervals until termination of the study for measurements of gut hormones, insulin, leptin, and C-peptide. Hunger and satiety sensations were scored using the visual analog scale, and hepatic glucose production and glucose oxidation rates were measured.ResultsDuodenal nutrient infusion in lean subjects led to a 65% drop in acyl ghrelin release and robustly increased cholecystokinin 8 (CCK-8) release (65%; P = 0.023); benzocaine infusion delayed this response (2-factor repeated-measures analysis of variance, P = 0.0065). In contrast, subjects with obesity had significantly blunted response to nutrient infusion, and no further effects were observed with benzocaine. Additionally, significant delays were observed in peptide YY (3-36), pancreatic polypeptide, glucose inhibitory peptide, and glucagon-like peptide 1 (7-36) response. No significant interactions were found between body mass index (BMI) or baseline hormone levels and areas under the curve for hormones except CCK-8 (BMI, P = 0.018; baseline CCK, P = 0.013). Nutrient-induced hunger and satiety sensations were impeded by benzocaine only in the lean cohort. Hunger and satiety sensations in subjects with obesity were not responsive to nutrient entry into the duodenum, and no additional effects were observed by blocking neural signaling.ConclusionNutrient-induced gut hormone release and response to transient vagal blockade are significantly blunted in subjects with obesity. This trial was registered at clinicaltrials.org as NCT02537314.

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Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.

Publications

Intestinal deletion of leptin signaling alters activity of nutrient transporters and delayed the onset of obesity in mice.

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