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Interplay between hormones, nutrients and adipose depots in the regulation of insulin sensitivity: an experimental study in rat and human adipocytes
Umeå University, Faculty of Medicine, Public Health and Clinical Medicine.
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity and specifically central obesity is related to insulin resistance, type 2 diabetes and other components of the so-called metabolic syndrome. The aim of this study was to elucidate the interplay between hormones, nutrients and adipose depots in normal and insulin-resistant fat cell metabolism.

High levels of free fatty acids (FFAs) induce insulin resistance in muscle and liver in vivo. In the present study, rat adipocytes were treated with high physiological levels of oleic or palmitic acid in vitro for 4-24 h. This treatment had no effect on basal or insulin-stimulated glucose uptake capacity in these cells, neither did it affect the levels of the insulin signalling proteins; insulin receptor substrate (IRS)-1 or –2, phosphatidylinositol 3-kinase (PI3-K), protein kinase B (PKB) or glucose transporter (GLUT) 4, or the regulation of lipolysis rate.

Visceral adiposity is considered to be more harmful than peripheral adiposity with respect to metabolic and cardiovascular complications. In adipose biopsies from subjects undergoing abdominal surgery, we found that glucose uptake capacity was elevated in omental as compared to subcutaneous adipocytes. The sensitivity (EC50) or maximum relative response to insulin, measured as % of basal, did however not differ between the depots. In women, subcutaneous adipocytes displayed a higher lipolysis rate following cAMP-stimulation than omental adipocytes, whereas there was a tendency towards the opposite in adipocytes from men. No differences were found between depots or sexes in the ability of insulin to inhibit lipolysis or in the levels of the lipolysis regulating proteins, i.e. protein kinase A (PKA), hormone sensitive lipase (HSL) and perilipin.

Glucocorticoids, e.g. cortisol, exert pronounced insulin-antagonistic effects and are associated with redistribution of fat from peripheral to central fat depots in humans. Treatment of human subcutaneous and omental adipocytes in vitro, with the cortisol analogue dexamethasone, resulted in a dose dependent down-regulation of basal and insulin-stimulated glucose uptake capacity in omental, but not in subcutaneous cells. Concomitantly, the levels of IRS-1 and PKB were decreased only in omental adipocytes after dexamethasone treatment. The relative effect of insulin to stimulate glucose uptake was however not altered by dexamethasone treatment. The cAMP-stimulated lipolysis rate was elevated by dexamethasone treatment in cells from the subcutaneous depot in women and tended to be elevated in omental cells from men. No alterations however, were seen in the levels of the assessed lipolysis regulating proteins.

Subcutaneous as well as omental fat cell size correlated negatively to insulin action in subcutaneous fat cells in vitro after adjusting for age, sex and body fat parameters in non-diabetic, but not in type 2 diabetic, subjects. Large subcutaneous fat cell size was strongly related to plasma leptin levels in non-diabetic and in type 2 diabetic subjects.

We conclude that 1) adipocytes seem to be less vulnerable to elevated levels of fatty acids than muscle and liver cells, 2) the interactions between glucocorticoids and insulin in the regulation of glucose uptake differ between adipose depots, 3) depot specific hormonal lipolysis regulation differs between sexes and 4) fat cell size is related to insulin action in subcutaneous fat cells and to circulating levels of leptin.

Place, publisher, year, edition, pages
Umeå: Folkhälsa och klinisk medicin , 2006. , 59 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 996
Keyword [en]
adipose tissue, cAMP, glucocorticoids, glucose, insulin, insulin resistance, lipolysis, subcutaneous fat, type 2 diabetes, visceral fat
National Category
Clinical Science
Identifiers
URN: urn:nbn:se:umu:diva-677ISBN: 91-7305-987-0 (print)OAI: oai:DiVA.org:umu-677DiVA: diva2:144213
Public defence
2006-02-24, Sal B, plan 9, 1D, NUS, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2006-01-30 Created: 2006-01-30 Last updated: 2009-10-12Bibliographically approved
List of papers
1. No in vitro effects of fatty acids on glucose uptake, lipolysis or insulin signaling in rat adipocytes.
Open this publication in new window or tab >>No in vitro effects of fatty acids on glucose uptake, lipolysis or insulin signaling in rat adipocytes.
2004 (English)In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 36, no 4, 203-209 p.Article in journal (Refereed) Published
Keyword
1-Phosphatidylinositol 3-Kinase/metabolism, Adipocytes/cytology/*drug effects/metabolism, Animals, Cells; Cultured, Female, Glucose/*pharmacokinetics, Glucose Transporter Type 4, Insulin/*metabolism, Lipolysis/drug effects, Male, Monosaccharide Transport Proteins/metabolism, Muscle Proteins/metabolism, Oleic Acid/*pharmacology, Palmitates/*pharmacology, Phosphoproteins/metabolism, Protein-Serine-Threonine Kinases/metabolism, Proto-Oncogene Proteins/metabolism, Proto-Oncogene Proteins c-akt, Rats, Rats; Sprague-Dawley, Signal Transduction/*drug effects
Identifiers
urn:nbn:se:umu:diva-12996 (URN)doi:10.1055/s-2004-814446 (DOI)15114517 (PubMedID)
Available from: 2007-04-26 Created: 2007-04-26 Last updated: 2017-12-14Bibliographically approved
2. Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes.
Open this publication in new window or tab >>Glucocorticoids down-regulate glucose uptake capacity and insulin-signaling proteins in omental but not subcutaneous human adipocytes.
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2004 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 89, no 6, 2989-2997 p.Article in journal (Refereed) Published
Keyword
Adipocytes/cytology/*drug effects/*metabolism, Adolescent, Adult, Aged, Aged; 80 and over, Biological Transport/drug effects, Carbon Radioisotopes/diagnostic use, Cells; Cultured, Dexamethasone/*pharmacology, Female, Glucocorticoids/*pharmacology, Glucose/pharmacokinetics, Glucose Transporter Type 4, Humans, Insulin/metabolism, Male, Middle Aged, Monosaccharide Transport Proteins/metabolism, Muscle Proteins, Omentum/*cytology/metabolism, Signal Transduction/drug effects, Subcutaneous Tissue/metabolism
Identifiers
urn:nbn:se:umu:diva-12997 (URN)10.1210/jc.2003-031157 (DOI)15181089 (PubMedID)
Available from: 2007-12-05 Created: 2007-12-05 Last updated: 2017-12-14Bibliographically approved
3. Sex differences in depot-specific lipolysis regulation in human adipocytes: interplay between adrenergic stimulation, glucocorticoids and insulin
Open this publication in new window or tab >>Sex differences in depot-specific lipolysis regulation in human adipocytes: interplay between adrenergic stimulation, glucocorticoids and insulin
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(English)Manuscript (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:umu:diva-4926 (URN)
Available from: 2006-01-30 Created: 2006-01-30 Last updated: 2010-06-17Bibliographically approved
4. Fat cell size in relation to circulating adipokines, insulin resistance and type 2 diabetes
Open this publication in new window or tab >>Fat cell size in relation to circulating adipokines, insulin resistance and type 2 diabetes
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(English)Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-4927 (URN)
Available from: 2006-01-30 Created: 2006-01-30 Last updated: 2010-03-11Bibliographically approved

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