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On the importance of fat cell size, location and signaling in insulin resistance
Linköping University, Department of Medicine and Health Sciences, Internal Medicine . Linköping University, Faculty of Health Sciences.
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: urn:nbn:se:liu:diva-18466ISBN: 978-91-7393-640-8 (print)OAI: oai:DiVA.org:liu-18466DiVA: diva2:219644
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
List of papers
1. Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes
Open this publication in new window or tab >>Peroxisome proliferator activated receptor gamma activity is low in mature primary human visceral adipocytes
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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.

Keyword
x-ray, vibrational, spectrum, Hartree-Fock, static exchange, Franck-Condon
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18462 (URN)10.1007/s00125-006-0515-x (DOI)000243188000026 ()17106695 (PubMedID)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2013-10-22Bibliographically approved
2. Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
Open this publication in new window or tab >>Insulin-induced GLUT4 translocation to the plasma membrane is blunted in large compared with small primary fat cells isolated from the same individual
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2007 (English)In: Diabetologia, ISSN 0012-186X, Vol. 50, no 8, 1716-1722 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: Several studies have suggested that large fat cells are less responsive to insulin than small fat cells. However, in these studies, large fat cells from obese individuals were compared with smaller fat cells from leaner participants, in effect making it impossible to draw conclusions about whether there is a causal relationship between fat cell size and insulin sensitivity. We hypothesised that small fat cells might be more insulin-responsive than large adipocytes when obtained from the same individual.

Materials and methods: We developed a method of sorting isolated primary human fat cells by using nylon filters of two different pore sizes. The cells were stained to visualise DNA, which allowed discrimination from artefacts such as lipid droplets. The sorted cells were left to recover overnight, since we had previously demonstrated that this is necessary for correct assessment of insulin response.

Results: We found similar amounts of the insulin receptor (IR), IRS-1 and GLUT4 when we compared small and large adipocytes from the same volunteer by immunoblotting experiments using the same total cell volume from both cell populations. Activation of IR, IRS-1 and Akt1 (also known as protein kinase B) by insulin was similar in the two cell populations. However, immunofluorescence confocal microscopy of plasma membrane sheets did not reveal any increase in the amount of GLUT4 in the plasma membrane following insulin stimulation in the large fat cells, whereas we saw a twofold increase in the amount of GLUT4 in the small fat cells.

Conclusions/interpretation: Our results support a causal relationship between the accumulation of large fat cells in obese individuals and reduced insulin responsiveness.

Keyword
Adipocyte, GLUT4, Human, Insulin, Insulin receptor, Insulin resistance, IRS-1, Primary fat cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14541 (URN)10.1007/s00125-007-0713-1 (DOI)
Available from: 2007-06-01 Created: 2007-06-01 Last updated: 2013-09-10Bibliographically approved
3. Identification of adipocyte genes regulated by caloric intake
Open this publication in new window or tab >>Identification of adipocyte genes regulated by caloric intake
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2011 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 96, no 2, E413-E418 p.Article in journal (Refereed) Published
Abstract [en]

CONTEXT: Changes in energy intake have marked and rapid effects on metabolic functions and some of the effects may be due to changes in adipose tissue gene expression that precede alterations in body weight.

OBJECTIVE: To identify genes in adipose tissue regulated by changes in caloric intake independent of changes in body weight.

RESEARCH DESIGN AND METHODS: Obese subjects were given a very-low calorie diet (VLCD; 450 kcal/day) for 16 weeks. After the diet, ordinary food was gradually reintroduced during 2 weeks while there were minimal changes in body weight. Adipose tissue gene expression was measured by microarray analysis. First, genes regulated during caloric restriction and in the opposite direction during the weight stable re-feeding phase were identified. To verify opposite regulation to that observed during caloric restriction, identified genes were further analyzed using adipocyte expression profiles from healthy subjects before and after overfeeding. Results were confirmed using real time PCR or immunoassay.

RESULTS: Using a significance level of p<0.05 for all comparisons, 52 genes were downregulated and 50 were up-regulated by caloric restriction and regulated in the opposite direction by re-feeding and overfeeding. Among these were genes that affect lipogenesis (ACLY, ACACA, FASN, SCD), protein synthesis (4EBP1, 4EBP2), beta-oxidation (CPT1B), liberation of fatty acids (CIDEA) and glyceroneogenesis (PCK2). Interestingly, several of these are under control of the master regulator mTOR.

CONCLUSIONS: The observed transcriptional changes indicate that mTOR plays a central role in the control of diet-regulated adipocyte genes involved in lipogenesis and protein synthesis.

Place, publisher, year, edition, pages
Endocrine society, 2011
Keyword
Obesity, DNA microarray, caloric restriction, overfeeding, adipose tissue
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18464 (URN)10.1210/jc.2009-2534 (DOI)000286972500025 ()
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2012-03-30Bibliographically approved
4. The Ala isoform of the PPARγ Pro12Ala polymorphism is related to increased abdominal obesity in men but has little impact on cardiovascular risk markers in patients with type 2 diabetes
Open this publication in new window or tab >>The Ala isoform of the PPARγ Pro12Ala polymorphism is related to increased abdominal obesity in men but has little impact on cardiovascular risk markers in patients with type 2 diabetes
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2009 (English)Article in journal (Other academic) Submitted
Abstract [en]

Background: The interaction of the PPARγ Pro12Ala with obesity and cardiovascular risk is controversial. We aimed to study potential associations of the Ala isoform of this polymorphism with obesity, blood pressure and markers of cardiovascular disease and organ damage in middle aged patients with type 2 diabetes.

Subjects and methods: We recruited 148 women and 246 men in the CArdiovascular Risk factors in Patients with DIabetes – a Prospective study in the Primary health care setting (CARDIPP) study in which early markers of organ damage by cardiac echocardiography, determination of carotid intima media thickness (IMT) and measurement of pulse wave velocity (PWV) was performed. Blood pressures were measured as both as 24-hour ambulatory blood pressure and as a noninvasive recording of central blood pressure. Allelic discrimination was detected with the ABI prism 7500HT Sequence Detection System. Due to the low prevalence of Ala homozygotes, heterozygotes and homozygotes of Ala were defined as Ala isoform in the analyses.

Results: Men with Ala isoform exhibited higher sagittal abdominal diameter (Pro: 25.4±3.4 cm, Ala: 26.7±4.9 cm, p= 0.04) waist circumference (Pro: 104±11 cm, Ala: 108±15 cm, p= 0.046) and body weight (Pro: 91.6±14, Ala: 96.5±18, p= 0.035) than homozygotes for the Pro isoform. However, there were no differences in either gender with respect to blood pressures, left-ventricular mass-index, carotid IMT or carotid-femoral PWV in the participants.

Conclusion: It is unlikely that determination of the PPARγ Pro12Ala isoform in clinic practice adds any major information on cardiovascular risk or circulatory organ damage in patients with type 2 diabetes.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18465 (URN)
Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2017-03-27Bibliographically approved

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