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Intestinal Gene Expression Profiling and Fatty Acid Responses to a High-fat Diet
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The gastrointestinal tract (GIT) regulates nutrient uptake, secretes hormones and has a crucial gut flora and enteric nervous system. Of relevance for these functions are the G protein-coupled receptors (GPCRs) and the solute carriers (SLCs). The Adhesion GPCR subfamily is known to mediate neural development and immune system functioning, whereas SLCs transport e.g. amino acids, fatty acids (FAs) and drugs over membranes. We aimed to comprehensively characterize Adhesion GPCR and SLC gene expression along the rat GIT. Using qPCR we measured expression of 78 SLCs as well as all 30 Adhesion GPCRs in a twelve-segment GIT model. 21 of the Adhesion GPCRs had a widespread (≥5 segments) or ubiquitous (≥11 segments) expression. Restricted expression patterns were characteristic for most group VII members. Of the SLCs, we found the majority (56 %) of these transcripts to be expressed in all GIT segments. SLCs were predominantly found in the absorption-responsible gut regions. Both Adhesion GPCRs and SLCs were widely expressed in the rat GIT, suggesting important roles. The distribution of Adhesion GPCRs defines them as a potential pharmacological target.

FAs constitute an important energy source and have been implicated in the worldwide obesity increase. FAs and their ratios – indices for activities of e.g. the desaturase enzymes SCD-1 (SCD-16, 16:1n-7/16:0), D6D (18:3n-6/18:2n-6) and D5D (20:4n-6/20:3n-6) – have been associated with e.g. overall mortality and BMI. We examined whether differences in FAs and their indices in five lipid fractions contributed to obesity susceptibility in rats fed a high fat diet (HFD), and the associations of desaturase indices between lipid fractions in animals on different diets. We found that on a HFD, obesity-prone (OP) rats had a higher SCD-16 index and a lower linoleic acid (LA) proportions in subcutaneous adipose tissue (SAT) than obesity-resistant rats. Desaturase indices were significantly correlated between many of the lipid fractions. The higher SCD-16 may indicate higher SCD-1 activity in SAT in OP rats, and combined with lower LA proportions may provide novel insights into HFD-induced obesity. The associations between desaturase indices show that plasma measurements can serve as proxies for some lipid fractions, but the correlations seem to be affected by diet and weight gain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 98 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 872
Keyword [en]
Adhesion GPCR, delta-5 desaturase, delta-6 desaturase, desaturase index, Diet-induced obesity, estimated desaturase activity, fatty acid composition, gas chromatography, gastrointestinal tract, G-protein coupled receptor, high-fat diet, intestine, linoleic acid, liver, mRNA expression, palmitoleic acid, plasma, phospholipids, proximodistal, RT-qPCR, solute carrier, SCD-1, SCD-16, SCD-18, stearoyl-CoA desaturase, subcutaneous adipose tissue, subsection, triacylglycerols.
National Category
Nutrition and Dietetics Cell and Molecular Biology Medical Genetics
Research subject
Medical Genetics; Nutrition; Nutrition
Identifiers
URN: urn:nbn:se:uu:diva-196207ISBN: 978-91-554-8612-9 (print)OAI: oai:DiVA.org:uu-196207DiVA: diva2:609487
Public defence
2013-04-18, B22, Biomedicinskt centrum, Husargatan 3, UPPSALA, 13:15 (English)
Opponent
Supervisors
Available from: 2013-03-27 Created: 2013-03-05 Last updated: 2013-04-02Bibliographically approved
List of papers
1. Adhesion GPCRs are widely expressed throughout the subsections of the gastrointestinal tract
Open this publication in new window or tab >>Adhesion GPCRs are widely expressed throughout the subsections of the gastrointestinal tract
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2012 (English)In: BMC gastroenterology, ISSN 1471-230X, Vol. 12, 134- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: G protein-coupled receptors (GPCRs) represent one of the largest families of transmembrane receptors and the most common drug target. The Adhesion subfamily is the second largest one of GPCRs and its several members are known to mediate neural development and immune system functioning through cell-cell and cell-matrix interactions. The distribution of these receptors has not been characterized in detail in the gastrointestinal (GI) tract. Here we present the first comprehensive anatomical profiling of mRNA expression of all 30 Adhesion GPCRs in the rat GI tract divided into twelve subsegments.

METHODS: Using RT-qPCR, we studied the expression of Adhesion GPCRs in the esophagus, the corpus and antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum.

RESULTS: We found that twenty-one Adhesion GPCRs (70%) had a widespread (expressed in five or more segments) or ubiquitous (expressed in eleven or more segments) distribution, seven (23%) were restricted to a few segments of the GI tract and two were not expressed in any segment. Most notably, almost all Group III members were ubiquitously expressed, while the restricted expression was characteristic for the majority of group VII members, hinting at more specific/localized roles for some of these receptors.

CONCLUSIONS: Overall, the distribution of Adhesion GPCRs points to their important role in GI tract functioning and defines them as a potentially crucial target for pharmacological interventions.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-190104 (URN)10.1186/1471-230X-12-134 (DOI)000312734600001 ()23009096 (PubMedID)
Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2013-04-02Bibliographically approved
2. Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract
Open this publication in new window or tab >>Comprehensive analysis of localization of 78 solute carrier genes throughout the subsections of the rat gastrointestinal tract
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 411, no 4, 702-707 p.Article in journal (Refereed) Published
Abstract [en]

Solute carriers (SLCs), the second largest super-family of membrane proteins in the human genome, transport amino acids, sugars, fatty acids, inorganic ions, essential metals and drugs over membranes. To date no study has provided a comprehensive analysis of SLC localization along the entire GI tract. The aim of the present study was to provide a comprehensive, segment-specific description of the localization of SLC genes along the rat Cl tract by employing bioinformatics and molecular biology methods. The Unigene database was screened for rat SLC entries in the intestinal tissue. Using qPCR we measured expression of the annotated genes in the Cl tract divided into the following segments: the esophagus, the corpus and the antrum of the stomach, the proximal and distal parts of the duodenum, ileum, jejunum and colon, and the cecum. Our Unigene-derived gene pool was expanded with data from in-house tissue panels and a literature search. We found 44 out of 78 (56%) of gut SLC transcripts to be expressed in all Cl tract segments, whereas the majority of remaining SLCs were detected in more than five segments. SLCs are predominantly expressed in gut regions with absorptive functions although expression was also found in segments unrelated to absorption. The proximal jejunum had the highest number of differentially expressed SLCs. In conclusion, SLCs are a crucial molecular component of the Cl tract, with many of them expressed along the entire GI tract. This work presents the first overall road map of localization of transporter genes in the Cl tract.

Keyword
Solute carriers, GI tract, RT-qPCR, Anatomical localization, Twelve subsections
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-159051 (URN)10.1016/j.bbrc.2011.07.005 (DOI)000294317300009 ()
Available from: 2011-09-22 Created: 2011-09-21 Last updated: 2017-12-08Bibliographically approved
3. Adipose tissue stearoyl-CoA desaturase 1 index is increased and linoleic acid is decreased in obesity-prone rats fed a high-fat diet
Open this publication in new window or tab >>Adipose tissue stearoyl-CoA desaturase 1 index is increased and linoleic acid is decreased in obesity-prone rats fed a high-fat diet
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2013 (English)In: Lipids in Health and Disease, ISSN 1476-511X, E-ISSN 1476-511X, Vol. 12, no 2Article in journal (Refereed) Published
Abstract [en]

BACKGROUND

Fatty acid (FA) composition and desaturase indices are associated with obesity and related metabolic conditions. However, it is unclear to what extent desaturase activity in different lipid fractions contribute to obesity susceptibility. Our aim was to test whether desaturase activity and FA composition are linked to an obese phenotype in rats that are either obesity prone (OP) or resistant (OR) on a high-fat diet (HFD).

METHODS

Two groups of Sprague-Dawley rats were given ad libitum (AL-HFD) or calorically restricted (HFD-paired; pair fed to calories consumed by chow-fed rats) access to a HFD. The AL-HFD group was categorized into OP and OR sub-groups based on weight gain over 5 weeks. Five different lipid fractions were examined in OP and OR rats with regard to proportions of essential and very long-chain polyunsaturated FAs: linoleic acid (LA), alpha-linolenic acid, eicosapentaenoic acid, docosahexaenoic acid and the stearoyl-CoA desaturase 1 (SCD-1) product 16:1n-7. FA ratios were used to estimate activities of the delta-5-desaturase (20:4n-6/20:3n-6), delta-6-desaturase (18:3n-6/18:2n-6), stearoyl-CoA desaturase 1 (SCD-1; 16:1n-7/16:0, SCD-16 and 18:1n-9/18:0, SCD-18), de novo lipogenesis (16:0/18:2n-6) and FA elongation (18:0/16:0). Fasting insulin, glucose, adiponectin and leptin concentrations were measured in plasma.

RESULTS

After AL-HFD access, OP rats had a significantly higher SCD-16 index and 16:1n-7 proportion, but a significantly lower LA proportion, in subcutaneous adipose tissue (SAT) triacylglycerols, as well as significantly higher insulin and leptin concentrations, compared with OR rats. No differences were found between the two phenotypes in liver (phospholipids; triacylglycerols) or plasma (cholesterol esters; phospholipids) lipid fractions or for plasma glucose or adiponectin concentrations. For the desaturase indices of the HFD-paired rats, the only significant differences compared with the OP or OR rats were higher SCD-16 and SCD-18 indices in SAT triacylglycerols in OP compared with HFD-paired rats.

CONCLUSION

The higher SCD-16 may reflect higher SCD-1 activity in SAT, which in combination with lower LA proportions may reflect higher insulin resistance and changes in SAT independent of other lipid fractions. Whether a lower SCD-16 index protects against diet-induced obesity is an interesting possibility that warrants further investigation.

Keyword
Desaturase, Diet-induced obesity, Fatty acid composition, High-fat diet, Linoleic acid, Obesity prone, Obesity resistant, Subcutaneous adipose tissue, SCD-1, Stearoyl-CoA desaturase
National Category
Nutrition and Dietetics Physiology
Research subject
Nutrition; Nutrition; Medical Biochemistry
Identifiers
urn:nbn:se:uu:diva-196188 (URN)10.1186/1476-511X-12-2 (DOI)000315111200001 ()23298201 (PubMedID)
Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06Bibliographically approved
4. Fatty acid desaturase indices in rats: Associations between plasma, liver and adipose tissue lipid fractions and the effects of a high-fat diet and diet-induced obesity
Open this publication in new window or tab >>Fatty acid desaturase indices in rats: Associations between plasma, liver and adipose tissue lipid fractions and the effects of a high-fat diet and diet-induced obesity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Alterations in fatty acid (FA) desaturase indices are linked to obesity-related disorders. As desaturases affect FA composition increased understanding of their regulation across lipid fractions with varying functions is essential. In this study we have examined desaturases and selected FAs to establish their degree of co-regulation in five different lipid fractions and under different dietary conditions, including diet-induced obesity (DIO).

Methods: Sprague-Dawley rats were randomly grouped into three groups, one fed a chow diet ad libitum (control) and two fed a high-fat diet (HFD): one ad libitum (AL-HFD) and the other one calorically pair fed to the chow-fed group (HFD-paired). FA composition in subcutaneous adipose tissue triacylglycerols (SAT-TG), liver (phospholipids and triacylglycerols) and plasma (phospholipids and cholesterol esters) was assessed. Delta-5 desaturase (D5D), delta-6 desaturase (D6D) and stearoyl-CoA-desaturase 1 (SCD-16) indices were calculated from product-to-precursor FA ratios and proportions of long-chain FAs were measured.

Results: Positive correlations were found for the desaturase indices between the five lipid fractions, especially for SCD-16 and almost exclusively between liver and plasma fractions. Only SCD-16 in SAT-TG of the AL-HFD group correlated with gain in body weight. Independent of weight gain, the HFD decreased all SCD-16 indices and most FA proportions, but D5D and D6D indices were fraction- and tissue-dependently increased.

Conclusion: Desaturase indices are especially correlated for SCD-16 and between lipid and plasma lipid fractions, suggesting that SAT-TG desaturation is differentially regulated compared with the other studied lipid fractions. The correlations are however influenced by diet and weight gain, further suggesting such factors should be taken into account when using desaturase indices.

Keyword
diet-induced obesity, delta-5, delta-6, scd-1, fatty acid composition, high-fat diet, subcutaneous adipose tissue, scd-16
National Category
Nutrition and Dietetics
Research subject
Nutrition; Nutrition
Identifiers
urn:nbn:se:uu:diva-196190 (URN)
Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2013-04-02

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