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Identification of adipocyte genes regulated by caloric intake
Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences.
Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Department of Mathematical Statistics, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden; Applied Mathematics and Computer Sciences Department,National Research Institute for Agronomy, Paris, France; Centre for Ecology and Evolutionary Synthesis, Department of Biology, University of Oslo, Oslo, Norway.
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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. Vol. 96, no 2, E413-E418 p.
Keyword [en]
Obesity, DNA microarray, caloric restriction, overfeeding, adipose tissue
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-18464DOI: 10.1210/jc.2009-2534ISI: 000286972500025OAI: oai:DiVA.org:liu-18464DiVA: diva2:219628
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)
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Available from: 2009-05-28 Created: 2009-05-28 Last updated: 2013-09-10Bibliographically approved

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Franck, NiclasNyström, Fredrik H.

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Internal MedicineFaculty of Health SciencesDepartment of Endocrinology and Gastroenterology UHL
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