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Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medicine, Department of Endocrinology and Gastroenterology UHL.
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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2007 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 50, no 1, 195-201 p.Article in journal (Refereed) Published
Abstract [en]

AIMS/HYPOTHESIS: The amount of visceral fat mass strongly relates to insulin resistance in humans. The transcription factor peroxisome proliferator activated receptor gamma (PPARG) is abundant in adipocytes and regulates genes of importance for insulin sensitivity. Our objective was to study PPARG activity in human visceral and subcutaneous adipocytes and to compare this with the most common model for human disease, the mouse.

MATERIALS AND METHODS: We transfected primary human adipocytes with a plasmid encoding firefly luciferase controlled by PPARG response element (PPRE) from the acyl-CoA-oxidase gene and measured PPRE activity by emission of light. RESULTS: We found that PPRE activity was 6.6-fold higher (median) in adipocytes from subcutaneous than from omental fat from the same subjects (n = 23). The activity was also 6.2-fold higher in subcutaneous than in intra-abdominal fat cells when we used a PPARG ligand-binding domain-GAL4 fusion protein as reporter, demonstrating that the difference in PPRE activity was due to different levels of activity of the PPARG receptor in the two fat depots. Stimulation with 5 micromol/l rosiglitazone did not induce a PPRE activity in visceral adipocytes that was as high as basal levels in subcutaneous adipocytes. Interestingly, in mice of two different strains the PPRE activity was similar in visceral and subcutaneous fat cells.

CONCLUSIONS/INTERPRETATION: We found considerably lower PPARG activity in visceral than in subcutaneous primary human adipocytes. Further studies of the molecular mechanisms behind this difference could lead to development of drugs that target the adverse effects of visceral obesity.

Place, publisher, year, edition, pages
2007. Vol. 50, no 1, 195-201 p.
Keyword [en]
x-ray, vibrational, spectrum, Hartree-Fock, static exchange, Franck-Condon
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-18462DOI: 10.1007/s00125-006-0515-xISI: 000243188000026PubMedID: 17106695OAI: oai:DiVA.org:liu-18462DiVA: diva2:219615
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-12-13Bibliographically approved
In thesis
1. On the importance of fat cell size, location and signaling in insulin resistance
Open this publication in new window or tab >>On the importance of fat cell size, location and signaling in insulin resistance
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity has reached epidemic proportions worldwide and is associated with insulin resistance, type 2 diabetes and cardiovascular disease. During the past decades, substantial evidence has demonstrated that not only the amount of adipose tissue constitutes a major determinant in the development of metabolic disorders, but also the distribution. The visceral adipose tissue has shown to be stronger correlated with insulin resistance, type 2 diabetes and cardiovascular disease than the subcutaneous depot. When we measured the activity of the nuclear receptor PPARγ in visceral and subcutaneous adipocytes, we found considerably lower activity in fat cells obtained from the visceral portion. This finding provides additional evidence to the unfavorable consequences of visceral obesity. The common PPARγ polymorphism Pro12Ala was studied in type 2 diabetic patients. We found that men with the Ala isoform exhibited higher sagittal abdominal diameter, waist circumference and body weight compared with homozygotes for the Pro isoform. However, no differences in either gender with regard to blood pressure or markers of cardiovascular disease and organ damage could be observed.

In addition to an excessive visceral adipose tissue mass, obese subjects with enlarged adipocytes display an increased risk for developing metabolic disorders compared with individuals exhibiting smaller fat cells but a similar degree of adiposity. The insulin responsiveness in small and large adipocytes obtained from the same subject was examined. Upon insulin stimulation, we found approximately a 2 fold increase of GLUT4 at the plasma membrane in small adipocytes, whereas the large fat cells were refractory to insulin induced GLUT4 translocation. This finding demonstrates a causal relationship between the accumulation of large fat cells in obese subjects and reduced insulin responsiveness.

Caloric restriction in humans ameliorates insulin responsiveness in liver and muscle prior to any substantial weight loss. By combining gene expression profiles of adipose tissue and adipocytes from human subjects undergoing either caloric restriction or overfeeding, we identified genes regulated by changes in caloric intake independent of weight loss per se. We found several genes under the control of mTOR and SREBP1 as well as genes involved in β-oxidation, liberation of fatty acids and glyceroneogenesis to be regulated during the interventions. These genes may indicate pathways and mechanisms mediating the effects of nutrient deprivation and obesity on morbidity and mortality.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 51 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1123
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18466 (URN)978-91-7393-640-8 (ISBN)
Public defence
2009-06-03, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2013-09-10Bibliographically approved
2. Transcriptional activity of PPARγ in primary human adipocytes
Open this publication in new window or tab >>Transcriptional activity of PPARγ in primary human adipocytes
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The prevalence of obesity is increasing in most parts of the world and is a strong risk factor for the development of insulin resistance, type 2 diabetes and hypertension. Adipose tissue is mainly composed of adipocytes which store energy in the form of triglycerides and release it as free fatty acids. Adipose tissue is one of the major regulators of energy homeostasis in the body. Adipose tissue in different regions of the body has different characteristics and adipocytes in intra-abdominal fat depots are more associated with insulin resistance than adipocytes from subcutaneous fat depots.

Research performed during the past several years has led to an explosion in the understanding of adipose tissue and the active role that it plays in aspects of physiology and pathophysiology. One important discovery has been identification of the nuclear hormone receptor called peroxisome proliferator-activated receptor γ (PPARγ). Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor, which is highly expressed in adipocytes. PPARγ has been shown to affect several genes of importance for lipid metabolism, differentiation of fat cells and insulin sensitivity. The PPARγ receptor can be activated by thiazolidinediones (TZD), a class of insulinsensitising drugs, which promote fatty acid storage in fat depots and decrease glucose levels in plasma, thus, demonstrating the importance of PPARγ activity in insulin resistance and metabolic syndrome.

This thesis has investigated the transcriptional activity of PPARγ in a clinically relevant cell type for insulin resistance and type 2 diabetes; the primary human adipocyte. For this purpose, a method for transfection of primary human adipocytes by electroporation and for measurement of the activity of PPARγ has been developed and optimised. This method has been used to study the effect of saturated and unsaturated fatty acids on the transcriptional activity of PPARγ. Interestingly, it was been found that saturated fatty acids can activate PPARγ, thus promoting a protection against diabetes. The strongest activator was the monounsaturated palmitoleic acid. The transcriptional activity of PPARγ in primary human adipocytes from intra-abdominal and subcutaneous adipose tissues was also examined. It was found that PPARγ activity is considerably lower in adipocytes from visceral compared with subcutaneous fat from the same subject. Another reason for using human tissue to reach clinical relevance shown here was that the same difference in PPARγ activity could not be found between intra-abdominal and subcutaneous fat tissues in mice. This finding may serve as the basis of why excess intraabdominal fat tissue is associated with high risk for development of type 2 diabetes and cardiovascular diseases.

The blood pressure regulating renin-angiotensin system (RAS) in human adipose tissue and in isolated adipocytes was examined and related to PPARγ. It was found that the production of angiotensin II, which is an important hormone for increasing the blood pressure, can be produced by isolated adipocytes and that the production is higher in adipocytes coming from omental than subcutaneous fat tissue. Further, it was shown that angiotensin II inhibits PPARγ activity in omental adipocytes, thus reducing the insulin sensitivity. Therefore, this study connects two of the major risk factors in obesity; diabetes and hypertension, and may also explain how drugs, which inhibit the RAS, can also be protective against diabetes. In conclusion, the findings in this thesis give new knowledge about regulating mechanisms of fat cells and its importance in diabetes and cardiovascular disease.

Abstract [sv]

Prevalensen av fetma ökar drastiskt i stora delar av världen och utgör en stor riskfaktor för att utveckla insulinresistens, typ 2 diabetes och hypertoni. Fett kan lagras i olika fettdepåer i kroppen. Fettet som inlagras inuti kroppen, intraabdominellt fett, skiljer sig från fettväven som lagras direkt under huden (subkutant fett). Nyare rön visar att en stor mängd intra-abdominell fettvävnad är en särskilt stark riskfaktor för att utveckla insulinresistens och typ 2 diabetes, samt att avlägsnande av subkutant fett knappast alls påverkar riskfaktorer för kardiovaskulär sjukdom.

Under de senaste åren har forskningen lett till en djupare förståelse av fettvävnaden och dess aktiva roll i fysiologin och patofysiologin av insulinresistens. En viktig upptäckt har varit identifieringen av en nukleär receptor som kallas för PPARγ (peroxisome proliferator-activated receptor gamma). PPARγ receptorn uttrycks huvudsakligen i fettceller och är viktig för fettcelldifferentieringen och fettcellsfunktionen. Receptorn aktiveras av vissa läkemedel för behandling av insulinresistens och hyperglykemi, de så kallade tiazolidindionerna (avandia och actos finns på den svenska marknaden), som sänker blodsockret och även påverkar blodtrycket samt blodfetterna i gynnsam riktning. Detta utgör ett tydligt bevis för betydelsen av PPARγ aktiviteten vid insulinresistens och det metabola syndromet.

Den här avhandlingen studerar transkriptionsaktiviteten av PPARγ i en klinisk relevant celltyp för insulinresistens och typ 2 diabetes, den mänskliga fettcellen. För detta ändamål har en metod för transfektion av primära humana fettceller utvecklats. Metoden användes för att studera insulinsignaleringen i detalj och också för att mäta aktiviteten hos transkriptionsfaktorer. Aktiviteten av PPARγ i primära humana fettceller påverkades olika av olika mättade och omättade fettsyror, som alltså kan verka som hormoner. Intressant nog visades att mättat fett, som av många anses vara särskilt ”onyttigt”, i form av stearinsyra kan aktivera PPARγ och därmed tänkas medföra ett skydd mot diabetes. Den starkaste aktivatorn var enkelomättad palmoljesyra. Aktiviteten hos PPARγ i fettceller från de två olika fettdepåerna, intra-abdominella och subkutana fettvävnaden, studerades. Aktiviteten av PPARγ i isolerade fettceller från intra-abdominellt fett befanns vara betydligt lägre än i subkutant fett från samma person. Som en ytterligare anledning att använda mänsklig vävnad för att nå klinisk relevans visades också av att möss inte har samma skillnad i PPARγ aktivitet mellan subkutant och intra-abdominellt. Fynden ger underlag till varför stor mängd intraabdominellt fett är förknippat med hög risk för diabetes och därmed kopplad ökad kardiovaskulär risk.

Det blodtrycksreglerande renin-angiotensin systemet (RAS) i human fettvävnad och i isolerade fettceller och relationen till PPARγ studerades. Produktionen av angiotensin II, som är ett viktigt blodtryckshöjande hormon, producerades av isolerade human fettceller och produktionen var högre från fettceller som kommer från mänskligt omentfett än från subkutant fett. Vidare visades att tillsatt angiotensin II hämmade PPARγ aktiviteten i fettceller från omentfettet. Detta fynd kopplar alltså samman två av de stora riskfaktorerna vid fetma; diabetes och högt blodtyck. Det ger också nya intressanta infallsvinklar i hur blodtrycksläkemedel som hämmar reninsystemet kan tänkas skydda mot diabetesuppkomst.

Sammanfattningsvis visar denna avhandling att man kan transfektera primära humana fettceller och studera PPARγ aktivitet i denna celltyp, och att PPARγ aktiviteten kan styras av fettsyror, vilket alltså innebär att matkomponenter (fettsyror) har direkt hormonella effekter i kroppen. Omentfett visades ha särskilt låg PPARγ aktivitet. Slutligen befanns att fettväven och isolerade fettceller kan producera olika komponenter i RAS. Det är tydligt att dessa fynd tillsammans har givit upphov till viktig ny kunskap om fettcellens reglermekanismer och dess betydelse för diabetes och kardiovaskulär sjukdom.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 49 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1046
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19169 (URN)978-91-7393-970-6 (ISBN)
Public defence
2009-04-10, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2013-10-23Bibliographically approved

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Sauma, LilianFranck, NiclasPaulsson, Johan FWestermark, Gunilla T.Kjølhede, PrebenStrålfors, PeterSöderström, MatsNyström, Fredrik H.

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