Decreased basal chloride secretion and altered cystic fibrosis transmembrane conductance regulatory protein, Villin, GLUT5 protein expression in jejunum from leptin-deficient mice

Leung, Lana; Kang, Jonathan; Rayyan, E.; Bhakta, Ashesh; Barrett, Brennan; Larsen, David A.; Jelinek, Ryan; Willey, Justin; Cochran, Scott; Al‐Nakkash, Layla

doi:10.2147/dmso.s63714

Cited by 12 publications

(9 citation statements)

References 45 publications

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“…To our knowledge, only one study determined jejunal SGLT1 protein in ob/ob mice which, supporting our findings, showed comparable SGLT1 protein expression to lean mice. 55 Since leptin levels were comparable between wild-type and intestine-specific LEPRb knockout mice, and yet they still observed diminished SGLT1 expression, 46 it is important to determine if this is a direct effect of LEPRb on SGLT1 or if administration of exogenous leptin could even further reduce intestinal SGLT1 abundance.…”

Section: Discussionmentioning

confidence: 99%

Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

Rieg

Chirasani

Koepsell

et al. 2016

Laboratory Investigation

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The small intestine is the major site for nutrient absorption, which is critical in maintenance of euglycemia. Leptin, a key hormone involved in energy homeostasis, directly affects nutrient transport across the intestinal epithelium. Catestatin (CST), a 21-amino acid peptide derived from proprotein chromogranin A, has been shown to modulate leptin signaling. Therefore, we reasoned that leptin and CST could modulate intestinal Na+-glucose transporter 1 (SGLT1) expression in the context of obesity and diabetes. We found that hyperleptinemic db/db mice exhibit increased mucosal mass, associated with an enhanced proliferative response and decreased apoptosis in intestinal crypts, a finding absent in leptin deficient ob/ob mice. Intestinal SGLT1 abundance was significantly decreased in hyperleptinemic, but not leptin-deficient mice, indicating leptin regulation of SGLT1 expression. Phlorizin, a SGLT1/2 inhibitor, was without effect in an oral glucose tolerance test in db/db mice. The alterations in architecture and SGLT1 abundance were not accompanied by changes in the localization of intestinal alkaline phosphatase, indicating intact differentiation. Treatment of db/db mice with CST restored intestinal SGLT1 abundance and intestinal turnover, suggesting a cross-talk between leptin and CST, without affecting plasma leptin levels. Consistent with this hypothesis, we identified structural homology between CST and the AB-loop of leptin and protein-protein docking revealed binding of CST and leptin with the Ig-like binding site III of the leptin receptor. In summary, downregulation of SGLT1 in an obese type 2 diabetic mouse model with hyperleptinemia is presumably mediated via the short form of the leptin receptor and reduces overt hyperglycemia.

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Section: Discussionmentioning

confidence: 99%

Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

Rieg

Chirasani

Koepsell

et al. 2016

Laboratory Investigation

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“…Relatively little is currently known regarding intestinal secretory function in the ob/ob mouse. Recently, we provided the first evidence to demonstrate that basal I sc (chloride secretion) is significantly reduced in male and female ob/ob mice compared to lean counterparts 3. Moreover, we also demonstrated that feeding both male and female ob/ob mice a genistein-containing diet (600 mg genistein/kg diet) for 4 weeks had beneficial effects on basal I sc , returning levels back to those measured in leans 4.…”

Section: Introductionmentioning

confidence: 57%

“…The cystic fibrosis transmembrane conductance regulatory (CFTR) protein (a Cl − channel) provides the major route for Cl − exit across the apical membrane in the normal murine intestine 5–7. Aside from our initial published findings describing the loss of Cl − secretory function in the small intestine of the ob/ob mouse,3 and recovery of Cl − secretory function following intake of dietary genistein,4 there have been no further studies aimed to better understand the consequence or the mechanisms involved.…”

Section: Introductionmentioning

confidence: 99%

“…The objective of this current study was to determine whether dietary genistein improved intestinal secretory function in the ob/ob diabetic model via effects on epithelial proliferation and overall crypt structure in ob/ob mice. The dose of genistein used in this study was the same as in our previous studies: 600 mg genistein/kg diet (consumed ad libitum) for a period of 4 weeks 3,4,16,17. We utilized two methodologies, traditional cryostat sectioning and novel 3D optical clearing to evaluate morphological metrics (numbers of epithelial proliferative cells, crypt depth, and crypt width).…”

Section: Introductionmentioning

confidence: 99%

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Genistein diet does not modify crypt morphology in the ob/ob mouse jejunum: a comparison of cryostat and clearing techniques

Sandoval-Skeet¹,

Kaufman²,

Castro³

et al. 2018

DMSO

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IntroductionDiabetes is commonly associated with gastrointestinal dysfunction. We have previously shown that transepithelial short circuit current, Isc (chloride secretion), is significantly reduced in the jejunum from ob/ob mice vs lean controls, and consumption of 600 mg genistein/kg of diet (600 G) for 4 weeks significantly rescues Isc. We aimed to evaluate whether morphological changes in the jejunal crypts contribute to the rescue of Isc.MethodsMale mice (ob/ob and lean controls) were fed either a genistein-free diet or genistein-containing diet (600 G). Comparisons of crypt morphology were made for crypt depth, length, and numbers of proliferative cells. Assessments of crypt measures using DAPI and 5-ethynyl-2′-deoxyuridine (EdU) were performed using traditional cryostat sectioning and an innovative 3D optical clearing method.ResultsWe found that crypt length in the ob/ob genistein-fed group was significantly greater when measured with cleared tissue (85.19±4.73 µm, P<0.05, n=8) compared to lengths measured with cryostat (65.42±3.48 µm, n=8). In addition, proliferative EdU+ counts were approximately fivefold greater with clearing, compared to counts obtained via single plane images from cryostat sections for all groups measured. The average length to EdU+ ratio was unchanged between groups.ConclusionThus, we conclude that genistein diet does not affect overall cellular proliferation or crypt morphology, other than for the modest increased crypt length measured via clearing in the ob/ob genistein group. The increase in crypt length is likely indicative of the greater accuracy of the 3D measures compared to single plane. Genistein diet-induced increases in the intestinal Isc are therefore likely not attributed to changes in intestinal crypt morphology.

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“…Mice, consuming a genistein diet (600 mg genistein/kg diet), can generate serum genistein levels of 2–4 μ M [ 9 ] which is comparable to the serum levels obtained in humans consuming a soy milk diet [ 10 ]. We have previously shown that ob/ob mice have reduced basal transepithelial chloride secretory function across jejunum tissue [ 11 ]. More recently, we have established that consumption of a genistein diet (600 mg genistein/kg diet) for 4 weeks reverses this deficit in jejunal chloride secretion in the ob/ob mouse [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Dietary Genistein Influences Number of Acetylcholine Receptors in Female Diabetic Jejunum

Schacht

Masood

Catmull

et al. 2017

Journal of Diabetes Research

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Background Intestinal dysfunction in the ob/ob mouse model of diabetes mimics that seen clinically. Methods We determined the effects of a 4-week genistein diet (600 mg genistein/kg food) on intestinal function (contractility, morphology, AChR, and motility) in female ob/ob and lean mice. Results Contractility of the jejunum in response to incrementally increasing concentrations of KCl was comparable in ob/ob females and lean controls regardless of a genistein-diet. There were no changes in the wall thickness measured. We assessed the number of clusters of AChR in the jejunum wall; AChR were decreased by 48% in ob/ob mice versus leans, and the genistein diet reversed this. In utilizing a video-imaging system to evaluate gastrointestinal motility, we determined that the distance between consecutive contractile events was significantly increased by 1.87-fold in ob/ob mice versus leans, and the genistein diet was without effect. Conclusions These data suggest that slowed intestinal transit in the diabetic ob/ob mouse may be due in part to decreased AChR and decreased contraction events occurring per unit time. A genistein diet rescues the number of AChR to levels of leans yet did not change the number of contractile events. Feeding ob/ob mice a genistein-rich diet has potential therapeutic benefits towards improving the debilitating diabetes-related gastrointestinal dysfunction.

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Decreased basal chloride secretion and altered cystic fibrosis transmembrane conductance regulatory protein, Villin, GLUT5 protein expression in jejunum from leptin-deficient mice

Cited by 12 publications

References 45 publications

Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

Regulation of intestinal SGLT1 by catestatin in hyperleptinemic type 2 diabetic mice

Genistein diet does not modify crypt morphology in the ob/ob mouse jejunum: a comparison of cryostat and clearing techniques

Dietary Genistein Influences Number of Acetylcholine Receptors in Female Diabetic Jejunum

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